Anti-CD40 antibodies for use in treatment of hidradenitis suppurativa

Abstract

To provide methods, treatment regimens, uses, kits and therapies for treating hidradenitis suppurativa.SOLUTION: The present invention provides a CD40 antagonist for use in the treatment of hidradenitis suppurativa. Preferably, the CD40 antagonist is an anti-CD40 antibody.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present disclosure relates to CD40 antagonists, particularly anti-CD40 antibodies, such as CFZ533 ( Methods and treatment regimens for treating hidradenitis suppurativa using iscalimab , uses, kits and treatments. [Background technology]

[0002] Hidradenitis suppurativa (HS), also known as "acne inversa" or "Bernoulli's disease", typically presents as presents as deep, inflammatory, painful lesions in parts of the body that contain apocrine glands It is a chronic, recurrent and debilitating inflammatory skin condition. The most common sites affected are the axillae, inguinal and anogenital areas (Jemec 2012; Fimmel and Zo uboulis 2010).

[0003] HS currently involves a causative immune system imbalance that occurs in genetically predisposed individuals. It is thought to be an inflammatory disease of the pilosebaceous hair follicle (Kelly et al 2014 HS is thought to be a disease caused primarily by follicular blockage. , an inflammatory skin disease characterized by an abundance of neutrophils and macrophages in inflammatory lesions. (Lima et al. 2016, Shah et al. 2017). Pathogenesis of HS Although the science remains largely unknown, the benefits of tumor necrosis factor alpha (TNFα) blockade has been described in more studies (Kimball et al. 2016).

[0004] Anti-IL1 treatment (Tzanetakou et al 2016) and blocking IL-17A (Thorlacius et al. 2017, Schuch et al. 2018, Giuseppe et al. 2018, Jorgensen et al. l 2018) or anti-IL-23 treatment (Sharon et al 2012, Blok et al 2018). Evidence of efficacy from the study (M. et al. 2016) was also found in fewer studies and / or case reports. More recently, the oral PDE4 inhibitor apremilast (Weber et al. l 2017) or anti-complement 5a compounds (Kanni et al 2018). The investigative methodology is described.

[0005] The disease begins after puberty, and females are affected more frequently than males (3:1). Risk factors include obesity and smoking. Epidemiological prevalence estimates vary widely (0.0 3~4.3%;Jemec 2012,Jemec and Kimball 2015 ), with geographical variations, the prevalence is accepted by the scientific community to be approximately 0.1-1%. (Garg et al. 2018).

[0006] The clinical manifestations of HS are heterogeneous, but the disease is characterized by chronic, relapsing, profound, painful These tend to manifest with inflammatory skin lesions, primarily causing drainage and the potential for suppuration. The inflammatory lesions are inflammatory nodules and abscesses that cause sinus tract and fistula formation. Hypertrophic scarring, which may be complicated during disease progression and may have an impact on functional use This could result in:

[0007] HS is an often destructive mental disorder characterized by pain, foul-smelling discharge from wounds and scarring. HS certainly has a psychosocial impact. It is associated with a strong negative impact on quality of life (QoL). It is an extremely debilitating disease, and studies have shown that its effects are greater than those seen in other skin diseases. The results support the idea that HS is a major Patients with HIV often suffer from depression, social isolation, impaired sexual health and difficulty performing their job duties. It may be difficult to achieve this goal (Esmann and Jemec 2011, Fimm el and Zouboulis 2010, Janse et al. 2017).

[0008] HS is difficult to treat. European treatment guidelines were first published in 2015. A guideline has been created to indicate that patients should be offered adjuvant, medical and surgical treatments. This suggests that

[0009] For mild cases, topical antibiotics can be used, but for moderate to severe HS For tetracycline or clindamycin in combination with rifampicin ( followed by months or years of chronic antibiotic therapy) Long-term, multiple-dose systemic antimicrobial therapy is preferred (Bettoli et al. 2013). 16,Dessinioti et al 2016,Zouboulis et al 2015).

[0010] However, it is now widely recognized that HS is a chronic inflammatory condition, not an infectious disease. Jemec 2012). Anti-inflammatory drugs are therefore probably better than alternative and more effective treatments than antibiotics. It may be an appropriate treatment or may be complementary to antibiotics. The result of the treated inflammation over time is irreversible fibrosis, which can lead to scarring and duct or sinusitis. manifest as ducts and often do not respond to medical therapy. Persistent anatomical changes occur. and to reduce the volume of fibrotic tissue and improve functionality in affected areas of skin. The only treatment option for this condition is surgery (Andersen and Jemec 201 7) One of the goals of future treatments is to reduce permanent scarring and avoid surgery. These can be achieved by the prevention of inflammatory lesions or may require specific treatment.

[0011] In 2015, adalimumab (Humira®), a soluble, membrane-bound Recombinant human monoclonal immunoglobulin G1 (IgG1) antibody against combined TNF-α received regulatory approval for the treatment of moderate to severe HS. Efficacy has been confirmed, and the HiSCR (Hidradenitis Suppurativa Clinical Response) response rate compared to placebo was , and PIONEER I and II studies, respectively, were approximately 1 6% (41.8% adalimumab vs. 26% placebo) and 31% (27.6% placebo) 58.9% vs adalimumab (Kimball et al 2016) When captured with adalimumab labeling, adalimumab has been shown to be effective in preventing tuberculosis, invasive fungal infections and other There is an increased safety risk of serious infections, including opportunistic infections. An increased incidence of tumours has also been reported.

[0012] Therefore, it has a favorable safety profile for patients with moderate to severe HS. However, there remains an unmet need for systemic therapies that effectively reduce inflammation. There is.

[0013] CFZ533 (iscalimab) is a human monoclonal antibody directed against human CD40. It is a monoclonal antibody that belongs to the IgG1 isotype subclass and has FcγR binding and Aβ binding properties. Fc-silencing abolishes relevant effector functions such as DCC and CDC CFZ533 contains the mutation (N297A). No. 8,828,396 and U.S. Pat. No. 9,221,913.

[0014] Although the pathogenesis of HS remains poorly understood, this chronic skin disease is characterized by inflammation The HS lesions are characterized by a large number of neutrophils and macrophages. Phages appear to be key drivers of the pathological mechanisms of HS (Shah et al. CD40 is involved in the cutaneous proliferation of HS lesions. Abundantly expressed in tumor tissue (mainly by macrophages and B cells). L is expressed by T cells in skin biopsies of HS lesions. and an anti-CD40 antibody or a fragment thereof having ADCC activity. Any antagonist capable of inhibiting IL-1 signaling may be suitable for the treatment of HS. It is possible. Summary of the Invention [Means for solving the problem]

[0015] According to a first aspect of the present invention, there is provided a CD40 antagonist for use in the treatment of hidradenitis suppurativa. A strike is provided.

[0016] In a preferred embodiment, the CD40 antagonist is an anti-CD40 antibody.

[0017] In another embodiment of the first aspect, the anti-CD40 antibody or fragment thereof inhibits ADCC. It is an anti-CD40 antibody with CD40 activity.

[0018] The antibody is a. an immunoglobulin VH domain comprising the amino acid sequence of SEQ ID NO:7 and an immunoglobulin VH domain comprising the amino acid sequence of SEQ ID NO:8 an anti-CD40 antibody comprising an immunoglobulin VL domain comprising an amino acid sequence; b. Immunoglobulins comprising the hypervariable regions set forth as SEQ ID NO:1, SEQ ID NO:2 and SEQ ID NO:3. globulin VH domain and the high-density an anti-CD40 antibody comprising an immunoglobulin VL domain containing a frequency variable region; c. an immunoglobulin VH domain comprising the amino acid sequence of SEQ ID NO:7 and an immunoglobulin VH domain comprising the amino acid sequence of SEQ ID NO:8 and an anti-CD31 antibody comprising an immunoglobulin VL domain having the sequence of SEQ ID NO: 13 and an Fc region having the sequence of SEQ ID NO: 14. 40 antibodies, d. An immunoglobulin VH domain comprising the amino acid sequence of SEQ ID NO:7 and the amino acid sequence of SEQ ID NO:8. and an anti-CD31 antibody comprising an immunoglobulin VL domain having the sequence of SEQ ID NO: 14 and an Fc region having the sequence of SEQ ID NO: 15. 40 antibodies, and e. Anti-CD40 antibodies containing silent Fc IgG1 regions may be selected from the group consisting of:

[0019] The antibody has a heavy chain amino acid sequence of SEQ ID NO: 9 and a light chain amino acid sequence of SEQ ID NO: 10 or It may comprise a heavy chain amino acid sequence of SEQ ID NO:11 and a light chain amino acid sequence of SEQ ID NO:12.

[0020] The antibodies were mAb1 (also called CFZ533 or iscalimab), mAb2 and AS It may further be selected from the group consisting of KP1240.

[0021] In one embodiment, a therapeutically effective amount of an antibody for use according to the first aspect and a pharma- ceutically acceptable and one or more carriers that can be used in the preparation of pharmaceutical compositions are provided.

[0022] In one embodiment the route of administration is subcutaneous or intravenous or subcutaneous or intravenous administration of the antibody according to the first aspect. or an intravenous combination.

[0023] Dosages can be from about 3 mg to about 30 mg of active ingredient per kilogram for a human subject. This dose can be given weekly, every two weeks, or every four weeks.

[0024] In one embodiment, the dosage is about 10 mg of active ingredient per kilogram of human subject. .

[0025] In one embodiment, the dosage is from about 150 mg to about 600 mg of the active ingredient. It can be given weekly, every two weeks, or every four weeks.

[0026] In one embodiment, the dosage is about 300 mg of active ingredient.

[0027] In one preferred embodiment, the dosage is 150 mg of active ingredient. In one preferred embodiment, the dosage is 300 mg of active ingredient. The amount is 600 mg of active ingredient.

[0028] In one embodiment, the antibody is administered via a loading dose and a maintenance dose.

[0029] In one embodiment, the loading dose is administered via a subcutaneous injection of a first dose and the maintenance dose is is administered via subcutaneous injection of the second dose. The first dose is the same as the second dose. or higher than the first dose.

[0030] In one embodiment, the first dose comprises from about 150 mg to about 600 mg of the active ingredient, e.g., about 3 00 mg of active ingredient, and the second dose is from about 150 mg to about 600 mg of active ingredient. , for example about 300 mg of active ingredient.

[0031] In one embodiment, the first dose is 150 mg, 300 mg, or 600 mg of active ingredient. and the second dose is 150 mg, 300 mg or 600 mg of the active ingredient.

[0032] In one embodiment, the loading dose comprises at least two subcutaneous injections and the maintenance dose comprises every In one embodiment, the dose consists of weekly (Q1W), biweekly (Q2W) or monthly (Q4W) subcutaneous injections. In one embodiment, the loading dose consists of two subcutaneous injections. In another embodiment, the loading dose consists of three subcutaneous injections. It consists of shooting.

[0033] In one embodiment, each subcutaneous injection of the loading dose is a different dose. Each subcutaneous injection of the loaded medication is the same dose.

[0034] Patients with HS meet the following criteria: The patient had moderate to severe HS, The patient is an adult, The patient is an adolescent, The patient has an HS-PGA score of ≧3 prior to treatment with the CD40 antagonist; Patients must have at least three inflammatory lesions prior to treatment with a CD40 antagonist; or Ensure that patients do not have extensive scarring as a result of HS prior to treatment with CD40 antagonists. and (<10 fistulas) The saturation voltage may be selected according to one of the following:

[0035] In one embodiment, by week 16 of treatment, the HS patient has: Simple HiSCR, Reduction in HS erythema, NRS30, A decrease of ≦6 as measured by DLQI, and / or Improve DLQI Achieve at least one of the following.

[0036] In one embodiment, by week 16 of treatment, at least 40% of said patients have a simplified HiS achieve a CR or at least 25% of said patients achieve an NRS30 response; Or less than 15% of such patients experience HS flares.

[0037] In one embodiment, the patient is administered the following as early as one week after the first administration of the CD40 antagonist: under: A rapid reduction in pain as measured by VAS or NRS, and Rapid decrease in CRP as measured using a standard hsCRP assay The present invention has at least one of the following:

[0038] In one embodiment, patients are assessed three months after the end of treatment for inflammatory lesion counts, HS clinical response (Hi SCR), Numeric Rating Scale (NRS), Modified Sartorius HS score, Purulent Hidradenitis-Physician Global Assessment (HS-PGA) or Dermatology Life Quality Index (DLQI) The objective of the present invention is to achieve a sustained response as measured by

[0039] In one embodiment, the patient is in simplified HiSCR (sHiSCR) 3 months after the end of treatment. Thus, a sustained response is achieved as measured.

[0040] According to a second aspect, there is provided a method of treating HS in a human subject, comprising administering a therapeutically effective dose of Methods are provided that include administering to the subject a CD40 antagonist.

[0041] In a preferred embodiment, the CD40 antagonist is an anti-CD40 antibody.

[0042] In one embodiment, the antibody comprises: a. an immunoglobulin VH domain comprising the amino acid sequence of SEQ ID NO:7 and an immunoglobulin VH domain comprising the amino acid sequence of SEQ ID NO:8 an anti-CD40 antibody comprising an immunoglobulin VL domain comprising an amino acid sequence; b. Immunoglobulins comprising the hypervariable regions set forth as SEQ ID NO:1, SEQ ID NO:2 and SEQ ID NO:3. globulin VH domain and the high-density an anti-CD40 antibody comprising an immunoglobulin VL domain containing a frequency variable region; c. an immunoglobulin VH domain comprising the amino acid sequence of SEQ ID NO:7 and an immunoglobulin VH domain comprising the amino acid sequence of SEQ ID NO:8 and an anti-CD31 antibody comprising an immunoglobulin VL domain having the sequence of SEQ ID NO: 13 and an Fc region having the sequence of SEQ ID NO: 14. 40 antibodies, d. An immunoglobulin VH domain comprising the amino acid sequence of SEQ ID NO:7 and the amino acid sequence of SEQ ID NO:8. and an anti-CD31 antibody comprising an immunoglobulin VL domain having the sequence of SEQ ID NO: 14 and an Fc region having the sequence of SEQ ID NO: 15. 40 antibodies, and e. Anti-CD40 antibodies containing silent Fc IgG1 regions is selected from the group consisting of:

[0043] In one embodiment, the antibody has a heavy chain amino acid sequence of SEQ ID NO:9 and a light chain amino acid sequence of SEQ ID NO:10. or a heavy chain amino acid sequence of SEQ ID NO: 11 and a light chain amino acid sequence of SEQ ID NO: 12. nothing.

[0044] In one embodiment, the antibody is administered with one or more pharma- ceutically acceptable carriers.

[0045] In one embodiment, the antibody is administered subcutaneously or intravenously, or a combination of subcutaneously and intravenously. is administered.

[0046] In one embodiment, the antibody has an activity of about 3 mg to about 30 mg per kilogram of human subject. The components are administered as doses.

[0047] In one embodiment, the dosage is about 10 mg of active ingredient per kilogram of human subject. .

[0048] In one embodiment, the antibody is administered in a concentration of about 150 mg to about 600 mg of active ingredient, e.g., about 300 mg. It is administered as a dose of 1 g of active ingredient.

[0049] In one preferred embodiment, the dosage is 150 mg of active ingredient. In one preferred embodiment, the dosage is 300 mg of active ingredient. The amount is 600 mg of active ingredient.

[0050] In one embodiment, the antibody is administered with a loading dose and a maintenance dose.

[0051] In one embodiment, the loading dose is administered via a subcutaneous injection of a first dose and the maintenance dose is is administered via subcutaneous injection of the second dose.

[0052] The first dose can be the same as or higher than the second dose.

[0053] In one embodiment, the first dose comprises from about 150 mg to about 600 mg of the active ingredient, e.g., about 3 00 mg of active ingredient, and the second dose is from about 150 mg to about 600 mg of active ingredient. , for example about 300 mg of active ingredient.

[0054] In one embodiment, the first dose is 150 mg, 300 mg, or 600 mg of active ingredient. and the second dose is 150 mg, 300 mg or 600 mg of the active ingredient.

[0055] In one embodiment, the loading dose comprises at least two subcutaneous injections and the maintenance dose comprises every The treatment consists of weekly (Q1W), biweekly (Q2W) or monthly (Q4W) subcutaneous injections.

[0056] In one embodiment, the loading dose consists of two subcutaneous injections. consists of three subcutaneous injections.

[0057] In one embodiment, each subcutaneous injection of the loading dose is a different dose. Each subcutaneous injection of the loaded medication is the same dose.

[0058] According to a third aspect, there is provided an anti-CD40 antibody, a mitogen-activated ... Use of a liquid pharmaceutical composition comprising a buffer, a stabilizer and a solubilizer, and an anti-CD20 antibody for patients with HS A means is provided for subcutaneously administering the anti-CD40 antibody, wherein the anti-CD40 antibody is a. a first loading dose, and b. Thereafter, a second maintenance dose is administered subcutaneously, wherein the anti-CD40 antibody is i. an immunoglobulin VH domain comprising the amino acid sequence of SEQ ID NO:7 and an immunoglobulin VH domain comprising the amino acid sequence of SEQ ID NO:8; an anti-CD40 antibody comprising an immunoglobulin VL domain comprising an amino acid sequence; ii. Immunoglobulins comprising the hypervariable regions set forth as SEQ ID NO:1, SEQ ID NO:2 and SEQ ID NO:3. and the immunoglobulin VH domain, as depicted in SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6. an anti-CD40 antibody comprising an immunoglobulin VL domain containing a hypervariable region; iii. an immunoglobulin VH domain comprising the amino acid sequence of SEQ ID NO: 7 and the amino acid sequence of SEQ ID NO: 8 An antibody comprising an immunoglobulin VL domain comprising the amino acid sequence of SEQ ID NO: 13 and an Fc region of SEQ ID NO: 13. CD40 antibody, iv. an immunoglobulin VH domain comprising the amino acid sequence of SEQ ID NO:7 and an immunoglobulin VH domain comprising the amino acid sequence of SEQ ID NO:8 and an anti-C antigen comprising an immunoglobulin VL domain comprising the amino acid sequence of SEQ ID NO: 14 and an Fc region of SEQ ID NO: 15. D40 antibody, v. an anti-CD40 antibody comprising a silent Fc IgG1 region, and vi. The heavy chain amino acid sequence of SEQ ID NO: 9 and the light chain amino acid sequence of SEQ ID NO: 10 or SEQ ID NO: An anti-CD40 antibody comprising the heavy chain amino acid sequence of SEQ ID NO:11 and the light chain amino acid sequence of SEQ ID NO:12. is selected from the group consisting of:

[0059] The present invention relates to the treatment or prevention of HS in patients in need of such treatment and / or prevention. Combination of CD40 antagonists with one or more additional therapeutic agents for use in prophylaxis Further information on matching. [Brief description of the drawings]

[0060] [Figure 1] 1 is a pictorial representation of the dosing regimen according to the clinical trial design. [Diagram 2] 2A-C are pictorial representations of possible weekly loading doses of active ingredient given subcutaneously, followed by a biweekly maintenance regimen of active ingredient (subcutaneously). [Diagram 3] 1 is a graph showing in vitro CFZ533 inhibition of rCD154-induced pathway activation. [Figure 4] 1 is a graph showing the minimal stimulatory activity of CFZ533 in vitro. [Diagram 5] 1 is a graph showing that CFZ533 does not mediate cell depletion in vitro. [Figure 6] Representative images of individual RI-1 B cells showing internalization of the CD40 receptor upon binding by recCD154 or CFZ533. [Figure 7]1 is a graph showing the pharmacokinetic and pharmacodynamic (target engagement; non-B cell depletion) properties of CFZ533 in non-human primates. [Figure 8] Figure 8A is a schematic of the experimental design of the PK / PD and vaccination study in non-human primates. Figure 8B is a graph showing anti-KLH IgG and plasma CFZ533 concentrations (pharmacokinetics). Figure 8C shows the results of histological analysis of germinal centers. [Figure 9A] FIG. 9A is a graph showing CD40 expression in different tissue types, and FIG. 9B is a graph showing CD40L expression in different tissue types. [Figure 9B] (As stated above.) [Figure 10] The results of tissue diagnosis are shown. [Figure 11] 1 is a graph depicting predicted plasma concentration-time profiles for CFZ533. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0061] The CD40-CD154 (CD154 is the CD40 ligand, CD40L) pathway It has been shown that it may affect skin inflammation (Mehling et al. 2001).

[0062] The presence and upregulation of B cells has also been previously observed in HS lesions (Hunger et al 2008, van der Zee et al 2012). van d er Zee, compared with surrounding and healthy skin, HS lesions, especially (early stage In contrast to chronic lesions, B cells and plasma cells were detected. In chronic lesions, lymphoid follicles with CD20+ B cells were detected. A recent study conducted by Novartis (CJM112X2202 In the present study, tissue samples showed abundant B cell infiltration in the affected skin as well as in the affected areas. In the same study, gene expression from skin biopsies was shown to be consistent with the results in several germinal centers in tissues with The cell type signature in the current data is clear B cell based on transcriptomics. Consistent with these findings, the authors reported in 2018 that the IL-16 expression level in the IL-16 cells was similar to that in the control cells, but also showed characteristics of macrophages. European HS Foundation Conference in Rotterdam At the HS meeting, abnormalities in circulating B cell subsets and their association with HS were and upregulation have been reported (Musilova J, 2018).

[0063] Additionally, and perhaps more importantly, macrophages are involved in the development of HS-related inflammation in skin with chronic HS lesions. Recently, these macrophages have been found to be abundant in These cells were identified as potentially M2 CD163+ macrophages (Byrd et al. In the CJM112X2202 HS sample, CD40 was present in the HS lesions. It is expressed on macrophages and B cells and is abundant in skin biopsies with HS lesions. CD40L is expressed by T cells in skin biopsies of HS lesions, whereas CD40L is expressed by T cells in skin biopsies of HS lesions. Skin biopsies confirmed the pathway engagement seen along with transcriptional signatures. Thus, iscalimab may be able to inhibit the recently observed macrophage and B cell proliferation in HS. This may be the first-line treatment for HS, targeting alveolar pathophysiology.

[0064] Therefore, anti-CD40 antibodies with suppressed ADCC activity, such as CD40-CD1 54 Any CD40 pathway antagonist capable of blocking signaling would be able to inhibit the HS may be suitable for treatment.

[0065] Without wishing to be bound by theory, the inventors believe that the CFZ533 antibody in the maintenance regimen A sustained plasma concentration of at least 40 μg / mL of CD40 in target tissues was We also found that CFZ533 is required to block the 40L pathway. Subject to mediated loss (which is related to target turnover and expression) and HS patients Since EGFR has high CD40 expression in the body, it is recommended to use a higher dose or higher These patients have elevated CD40 levels, which require frequent regimens. A loading regimen is required at the start of treatment to fully saturate the CD40 receptor in Therefore, providing rapid saturation of CD40 receptors at the start of treatment (2–3 weeks) is followed by a loading regimen of at least 40 μg / mL or at least 100 μg / mL A maintenance dosing regimen that provides sustained plasma concentrations of 0.01 mL throughout the treatment period is recommended for patients with Therapeutic efficacy is expected in situations (severity of condition) where CD40 expression is likely to be increased in the affected tissue. The results are taken into account.

[0066] The appropriate dosage will depend, for example, on the particular CD40 pathway antagonist used, e.g., anti-CD40 D40 antibody or antigen-binding fragment thereof (e.g., mAb1 (referred to herein as CFZ533) (also referred to as mAb2, ASKP1240) or anti-CD40L antibodies (e.g., BIIB 063) or antigen-binding fragments thereof, the subject of treatment, the mode of administration and the nature of the condition to be treated, The treatment options vary depending on the severity of the disease and the nature of the prior treatment the patient has received. Each healthcare provider will determine the amount of CD40 pathway antagonist with which to treat each individual patient. In some embodiments, the responsible healthcare provider may prescribe a low dose or even a single dose. A CD40 pathway antagonist can be administered and the patient's response observed. In this condition, the initial dose of the CD40 pathway antagonist administered to the patient is high and then The dose is adjusted downward until symptoms of flares occur. Larger doses of the CD40 pathway antagonist may be administered, up to is generally not increased further.

[0067] In one embodiment, the present disclosure provides an anti-CD40 antibody or antigen-binding fragment thereof (e.g., mAb, b1 (also called CFZ533 or iscalimab), mAb2 or ASKP1240) The loading and maintenance doses of the antibody should be administered at a dose that produces a plasma or serum concentration of at least 40 μg / mL of antibody. According to any of the first, second or third aspects of the present disclosure described above, The present invention relates to an anti-CD40 antibody or antigen-binding fragment thereof for use.

[0068] In practicing some of the methods of treatment or use of the present disclosure, a therapeutically effective amount of a CD40 pathway antagonist is and an antagonist, such as an anti-CD40 antibody or an antigen-binding fragment thereof (e.g., mAb1 ( (also referred to as CFZ533 in the specification), mAb2, ASKP1240) or anti-CD40L The antibody or antigen-binding fragment thereof is administered to a patient, e.g., a mammal (e.g., a human). The method shown uses CD40 pathway antagonists (e.g., mAb1 / CFZ533, mAb 2, ASKP1240) to provide treatment for HS patients, The authors conclude that if patients are eventually treated with CD40 pathway antagonists, these CD40 pathway It is not excluded that tract antagonist therapy is necessarily a monotherapy. If selected for treatment with a CD40 pathway antagonist, For example, mAb1 / CFZ533, mAb2, ASKP1240) were synthesized according to the methods of the present disclosure. The therapeutic agents may be administered alone or in combination with other drugs and therapies.

[0069] Certain HS patients, for example, use CD40 pathway antagonists, e.g., anti-CD40 An antibody or antigen-binding fragment thereof (e.g., mAb1 (also referred to herein as CFZ533) ), mAb2, ASKP1240) or an anti-CD40L antibody or an antigen-binding fragment thereof A regimen change may be appropriate for patients who have an inadequate response to treatment with It will be understood that administration (e.g., mAb1 / CFZ533 or mAb 2) is more frequent than monthly dosing, for example, every other week (every two weeks) or weekly dosing. obtain.

[0070] Some patients may be treated with a loading regimen (e.g., weekly dosing for several weeks [e.g., 1–4 weeks, e.g. Dosing at weeks 0, 1, 2 and / or 3, e.g., week 2, loading dosing regimen at weeks 0 and 1 ]), followed by a maintenance regimen starting, for example, at week 3 or 4 (wherein CFZ533 is patients are likely to benefit from a combination of stomach.

[0071] For example, a suitable regimen for mAb1 / CFZ533 or mAb2 would be weekly for several weeks. [e.g., weeks 1-4, e.g., dosing at weeks 0, 1, 2, and 3], followed by monthly maintenance It may be a regimen.

[0072] In another example, a suitable regimen for mAb1 / CFZ533 or mAb2 is weekly. for several weeks (e.g., weeks 2-8, e.g., week 3, e.g., dosing at weeks 0, 1, and 2), followed by This is a biweekly maintenance regimen.

[0073] Administration (e.g., for mAb1 / CFZ533 or mAb2) may be more cost-effective than monthly dosing. Infrequent dosing, such as every 6 weeks, every 8 weeks (every 2 months), or 4 times a year (every 3 months) It will be understood that this is possible.

[0074] Certain HS patients, for example, use CD40 pathway antagonists, e.g., anti-CD40 An antibody or antigen-binding fragment thereof (e.g., mAb1 (also referred to herein as CFZ533) ), mAb2, ASKP1240) or an anti-CD40L antibody or an antigen-binding fragment thereof For patients with an inadequate response to treatment with , dose escalation is based on disease severity. It will be appreciated that subcutaneous (sc) dosages (negative) may be appropriate. The initial or maintenance dose is about 150 mg to about 900 mg (sc), for example, about 75 mg, about 100mg, about 125mg, about 175mg, about 200mg, about 250mg, about 350mg , about 400mg, about 450mg, about 500mg, about 600mg, etc. Similarly, the intravenous (iv) dosage is about 10 mg / kg, e.g., about 11 mg / kg. g, 12mg / kg, 15mg / kg, 20mg / kg, 25mg / kg, 30mg / k g, 35 mg / kg, etc. In some HS patients, e.g., CD40 Pathway antagonists (e.g., anti-CD40 antibodies or antigen-binding fragments thereof (e.g., mAbs b1 (also referred to herein as CFZ533), mAb2, ASKP1240) or anti Adverse events or reactions to treatment with CD40L antibody or its antigen-binding fragment It will also be appreciated that dose reduction may be appropriate for patients who Thus, CD40 pathway antagonists (e.g., anti-CD40 antibodies or antigen-binding fragments thereof) (e.g., mAb1 (also referred to herein as CFZ533), mAb2, ASKP1 The dosage of the anti-CD40L antibody or its antigen-binding fragment) is about 150 mg to About 900 mg (sc), for example, about 25 mg, about 50 mg, about 75 mg, about 100 mg , about 125mg, about 175mg, about 200mg, about 250mg, about 350mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, etc.

[0075] In some embodiments, a CD40 antagonist, such as an anti-CD40 antibody or the like, Antigen-binding fragments of (e.g., mAb1 (also referred to herein as CFZ533), mAb 2. ASKP1240) or anti-CD40L antibody or its antigen-binding fragment is delivered by sc. The patient may be administered an initial dose of 600 mg, which may then be administered by a physician. 150 mg or 300 mg delivered sc, as needed, as determined by can be adjusted to.

[0076] In some embodiments, a CD40 antagonist, such as an anti-CD40 antibody or the like, Antigen-binding fragments of (e.g., mAb1 (also referred to herein as CFZ533), mAb 2. ASKP1240) or anti-CD40L antibody or its antigen-binding fragment is administered intravenously. The patient can be administered an initial dose of 10 mg / kg, which is then 150 mg or 300 mg delivered sc as needed as determined by the physician Can be adjusted to mg.

[0077] In a specific embodiment, the first day (D1), the fifteenth day (D15), D29, D57, D85 CFZ533 was administered sc at 3 mg / kg on D99, D113 and D141.

[0078] In another specific embodiment, D1, D15, D29, D57, D85, D99, D113 and D141, 10 mg / kg CFZ533 will be administered iv.

[0079] In yet another specific embodiment, a negative control comprising four unit doses of 600 mg CFZ533. Loading doses were administered sc once weekly (Q1W) (i.e., on D1, D8, D15, and D22). of 600 mg CFZ533 (sc), followed by a unit dose of 300 mg Maintenance doses are administered sc once weekly (Q1W) (i.e., once a week from D29 to D85) once per dose of 300 mg CFZ533 (sc).

[0080] In a further specific embodiment, a single dose of 10 mg of CFZ533 per kg of subject is administered. A loading dose containing 300 mg of ribavirin was administered iv on day 1, followed by a single 300 mg unit dose containing 300 mg of ribavirin. A maintenance dose is administered once weekly (Q1W) sc (i.e., once a week from D8 to D85). once per dose of 300 mg CFZ533 (sc).

[0081] CFZ533 is administered four times a year, monthly, weekly or every other week, for example, at about 75 mg subcutaneously at about 150 ml about 75 mg, about 300 mg, about 450 mg, or about 600 mg by subcutaneous injection The dosage is from about 150 mg to about 300 mg. can.

[0082] CFZ533 is administered by subcutaneous injection weekly at a loading dose of approximately 150 mg to approximately 600 mg. wherein the loading dose is administered over a period of 1 to 4 weeks.

[0083] The loading dose can be from about 10 mg / kg to about 30 mg / kg administered iv. , loading doses are weekly at doses of about 150 mg, 300 mg and / or 600 mg of active ingredient. Or it can be administered subcutaneously every other week.

[0084] CFZ533 loading regimen or dosing (e.g., 150 / 300 / 600 mg, weekly or every other day) week) followed by a maintenance regimen or medication administered weekly, biweekly, or monthly (every 4 weeks) Maintenance doses are 300 mg (sc) every week or every other week, or 600 mg (sc) every other week. g, or 600 mg every 4 weeks.

[0085] The anti-CD40 antibody or antigen-binding fragment thereof may be CFZ533, a functional derivative thereof or a fragment thereof. It could be a follow-on product.

[0086] As defined herein, a "unit dose" is from about 75 mg to 900 mg, for example about 15 0 mg to about 600 mg, for example, about 150 mg to about 600 mg, for example, about 300 mg to about 6 "sc dose" refers to a sc dose which may consist of about 100 mg or, for example, about 150 mg to about 300 mg. For example, unit sc doses are about 75 mg, about 150 mg, about 300 mg, about 350 mg , about 400 mg, about 450 mg, about 500 mg, about 550 mg, and about 600 mg.

[0087] definition As used herein, CD40 is a member of the tumor necrosis factor receptor superfamily. The term CD40 refers to cluster of differentiation 40, also known as CD41, unless otherwise specified. Refers to human CD40 as defined in column number 19.

[0088] The term "about" in relation to a numerical value x means, for example, + / - 10%. When used before a list, the term "about" applies to each number in the series. For example, The expression "about 1 to 5" should be interpreted as "about 1 to about 5", or, for example, the expression "about "1, 2, 3, 4" should be interpreted as "about 1, about 2, about 3, about 4, etc."

[0089] The word "substantially" does not exclude "completely." For example, the group "substantially free" of Y The composition may be completely free of Y. Where necessary, the word "substantially" may be used in the context of the present disclosure. can be omitted from the definition of

[0090] The term "comprises" encompasses "includes" as well as "consists of," e.g., X is a group that "comprises" The composition may consist exclusively of X or may contain something additional (e.g. For example, X+Y is possible.

[0091] AUC0-t is the time from time 0 to time "t" (where t is a defined time point after dosing). The area under the plasma concentration-time curve from the time point at which the drug is administered to the patient (up to the time point at which the drug is administered) is shown as [mass x time / volume].

[0092] AUCtx-ty is the time from time "x" to time "y" (where "time x" and "time y" are represents the area under the plasma concentration-time curve up to a defined time point after administration).

[0093] C maxis the maximum plasma concentration observed after drug administration [mass / volume].

[0094] C min is the minimum plasma concentration observed after drug administration.

[0095] C トラフ is the plasma concentration observed just before the start of the dosing period or at the end of the dosing interval .

[0096] T max is the time to reach maximum concentration after drug administration [hours].

[0097] The ss subscript indicates that the parameters are defined at steady state.

[0098] As used herein, the term "antibody" or "anti-CD40 antibody" or the like refers to an antibody that binds to CD40 (e.g., It refers to the set of antibodies that interact with each other (e.g., by binding, steric hindrance, stabilization / destabilization, spatial distribution) A naturally occurring "antibody" is made up of at least two amino acids interconnected by disulfide bonds. It is a glycoprotein that contains a heavy (H) chain and two light (L) chains. Each heavy chain contains a heavy chain variable region ( In this specification, V H The heavy chain constant region consists of three domains: Each light chain is composed of a light chain variable region (hereinafter referred to as V L The light chain constant region consists of one domain, CL. V H and V L The more conserved regions are called framework regions (FR). These are further subdivided into regions of hypervariability called complementarity determining regions (CDRs), which are interrupted by Each V H and V L are in the following order from amino to carboxy terminus: : Three sequences arranged as FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4 The variable regions of the heavy and light chains are composed of CDRs and four FRs. The constant region of an antibody contains a domain that binds to various cells of the immune system, such as effector cells. ) and the first component of the classical complement system (Clq). The term "antibody" includes, for example, monoclonal antibodies, human antibodies, and the like. Antibodies include monoclonal antibodies, humanized antibodies, camelid antibodies or chimeric antibodies. Type (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), Class (e.g., , IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) or subclasses Exemplary antibodies include: As described in Table 1, CFZ533 (also referred to herein as mAb1) and mAb2 Examples include:

[0099] Both the light and heavy chains are divided into regions of structural and functional homology. and "variable" are used in functional references. In this regard, the light (VL) chain portion and the heavy (VH It should be understood that the variable domains of both the IL-1 and IL-2 chain portions determine antigen recognition and specificity. Conversely, the constant domains of the light chain (CL) and the heavy chain (CH1, CH2, or CH3) are involved in secretion, They confer important biological properties such as placental transport, Fc receptor binding, and complement fixation. The numbering of the constant region domains is as follows, moving distal from the antigen binding site or amino-terminus of the antibody: The N-terminus is a variable region, the C-terminus is a constant region, and the CH3 and CL domains are The domain essentially comprises the carboxy termini of the heavy and light chains, respectively. The term "antibody" particularly includes IgG-scFv types.

[0100] The term "antigen-binding portion" of an antibody (or simply "antigen portion"), as used herein, refers to Full length or fragments of antibodies, such as proteins that retain the ability to specifically bind to an antigen or epitope. It refers to one or more fragments (eg, a portion of CD40).

[0101] "Complementarity determining region" ("CDR") is defined as defined by Kabat et al. (1991), "S sequences of Proteins of Immunological In terest,” 5th Ed.Public Health Service, Nat. ional Institutes of Health,Bethesda,MD(`` Kabat numbering scheme), Al-Lazikani et al., (19 97) JMB 273,927-948 ("Chothia" numbering scheme) and and ImMunoGenTics (IMGT) numbering (Lefranc, M.-P. ,The Immunologist,7,132-136(1999);Lefran c,M.-P.et al.,Dev.Comp.Immunol.,27,55-77 (2003) (the "IMGT" numbering scheme) and amino acid sequences with boundaries determined using any of several well-known schemes. In IMGT, the CDR regions of an antibody are classified as IMGT / DomainGap Alignment. n program can be used to determine.

[0102] As used herein, the term "epitope" refers to a molecule that binds with high affinity to an immunoglobulin. An epitope is any determinant capable of eliciting an antibody that specifically targets that antigen. If the antigen is a protein, it is the region of the antigen that is in direct contact with the antibody. Epitopes contain specific amino acids that bind to a specific target molecule. Epitopes are most often found on proteins. However, epitopic determinants can also be present on other types of molecules, such as nucleic acids. They contain chemically active surface groups of molecules such as amino acids, sugar side chains, phosphoryl or sulfonyl groups. and may have specific three-dimensional structural characteristics and / or specific charge characteristics. In addition, the two domains of the Fv fragment, V L and V H is encoded by a different gene However, these are not bound to a single protein chain (here, V L Area and V H The region is paired to form a univalent These molecules (known as single-chain Fv (scFv); see, e.g., Bird et al., (1999) 88) Science 242:423-426; and Huston et al., ( See 1988) Proc. Natl. Acad. Sci. 85:5879-5883. The synthetic linker allows the recombinant method to act as a linker to form the desired target protein. These can be concatenated using the method:

[0103] The expression "isolated antibody" as used herein refers to an antibody that is isolated from other antibodies having different antigen specificities. It refers to an antibody that is substantially free of antibodies (e.g., an isolated antibody that specifically binds CD40). The body is substantially free of antibodies that specifically bind to antigens other than CD40. The isolated antibodies that specifically bind CD40 may be associated with other antigens, such as CD40 molecules from other species. Additionally, the isolated antibodies may have cross-reactivity with other cellular materials and / or As used herein, the term "monoclastic" refers to a material that is substantially free of chemicals. "Monoclonal antibody" or "monoclonal antibody composition" refers to the preparation of antibody molecules of single molecular composition. The term "human antibody" as used herein refers to a human antibody, including both the framework and CDR regions. The term "human" is intended to include antibodies having variable regions derived from sequences of human origin. A "human antibody" does not have to be produced by a human, human tissue, or human cells. Antibodies may be modified by amplifying amino acid residues that are not encoded by human sequences (e.g., by in vitro randomization). In vivo junctions during recombination of antibody genes by mutagenesis or site-directed mutagenesis (mutations introduced by N-nucleotide addition in the genome or by somatic mutation in vivo) may include.

[0104] "Identity" with respect to naturally occurring polypeptides and their functional derivatives is defined herein as up to After aligning the sequences and introducing gaps as necessary to obtain the percent identity of is defined as the percentage of amino acid residues in the candidate sequence that are identical to residues in the corresponding naturally occurring polypeptide. Any conservative substitutions are not considered part of the sequence identity. Insertions shall not be construed as reducing identity. Computer programs are well known. Percent identity can be calculated using standard alignment algorithms. Algorithms such as those described in Altshul et al. (1990) J. Mol. Biol. .,215:403 410) gnment Search Tool(BLAST);Needleman et a l. ((1970) J. Mol. Biol., 48:444 453) algorithm; or Meyers et al. ((1988) Comput. Appl. Biosci .,4:11 17) algorithm. A set of parameters The gap penalty is 12, the gap extension penalty is 4, and the frameshift penalty is 5. It can be a Blosum 62 score matrix with a gap penalty. Two amino acids or Percent identity between nucleotide sequences is calculated using the PAM120 weighted remainder table, 12 gaps. The ALIGN program (ve) was used with a loop length penalty of 0.2 and a gap penalty of 4. The paper by E. Meyers and W. Miller (1 989) CABIOS, 4:11-17) algorithm can also be used to determine do.

[0105] "Amino acid" refers to all naturally occurring L-α-amino acids, e.g., D-amino acids The expression "amino acid sequence variant" refers to a variant of an amino acid sequence that is different from the sequence according to the present disclosure. refers to a molecule that differs in some way in sequence. For example, the amino acid sequence of an antibody according to the present disclosure of a particular sequence. The mutants still retain the ability to bind human CD40. Variants include substitution variants (wherein at least one amino acid residue in a polypeptide according to the disclosure is and an amino acid has been inserted at the same position instead), insertion mutants (as disclosed herein), Inserting one or more amino acids immediately adjacent to an amino acid at a specific position in a polypeptide by and deletion variants (wherein one or more amino acids in a polypeptide according to the disclosure are removed).

[0106] As used herein, the term "Fc region" refers to the CH3, CH2 and CH3+ domains of the constant domain of an antibody. and at least a portion of the hinge region. may contain the CH4 domain present in some antibody classes. Fc region In one embodiment, the present invention provides a method for the preparation of a polypeptide comprising the steps of: comprises the Fc region and CH1 region of an antibody. In one embodiment, the present invention provides an antibody Fc region In another embodiment, the present invention provides a CH3 region from an antibody constant domain. , CH1 region and C κ / λ In one embodiment, a binding molecule of the invention comprises a constant region. , e.g., a heavy chain constant region. In one embodiment, such a constant region is a wild-type constant region. That is, the polypeptides of the invention disclosed herein have three to one or more of the heavy chain constant domains (CH1, CH2 or CH3) and / or to the light chain Examples of modifications include alterations or modifications to the constant region domain (CL). , including the addition, deletion or substitution of one or more amino acids in one or more domains. Such modifications can be included to optimize effector function, half-life, etc. do.

[0107] As used herein, the term "affinity" refers to the affinity between an antibody and an antigen at a single antigenic site. Within each antigen site, the variable regions of the antibody "arms" bind to each other at multiple sites. They interact with antigens through weak non-covalent forces; the more interactions there are, the stronger the affinity As used herein, the term refers to an IgG antibody or a fragment thereof (e.g., a Fab fragment). The term "high affinity" refers to a 10-fold increase in affinity for a target antigen. -8 M or less, 10 -9 M or less, or 10 -10 M or 10-11 M or less, or 10 -12 M or less, or 10 -13 K below M D have However, high affinity binding may differ for other antibody isotypes. For example, high affinity binding for the IgM isotype is 10 -7 M or less or 10 -8 K below M D It refers to an antibody having the following structure:

[0108] As used herein, an antibody or protein that "specifically binds to a CD40 polypeptide" Proteins have K values ​​of 100nM, 10nM, and 1nM. D Human CD40 polypeptide The term "antibody" is intended to refer to an antibody or protein that binds to the antibody.

[0109] Antibodies that "cross-react with antigens other than CD40" are those with a concentration of 1 μM or less, 100 nM or less, or 10 nM or less. M or less, K less than 1nM D "Antibody" is intended to refer to an antibody that binds to an antigen at a specific antigen. Antibodies that do not cross-react with D , or K of 1 μM or more D , or 10μ K over M D In certain embodiments, an antibody is intended to refer to an antibody that binds to an antigen at These antibodies, which do not cross-react with the original proteins, bind to these proteins in standard binding assays. The antibody exhibits essentially undetectable binding to

[0110] The term “K assoc " or "K a " as used herein refers to a particular antibody-antigen interaction whereas the term "K dis " or "K d "teeth As used herein, is intended to refer to the off-rate of a particular antibody-antigen interaction. do.

[0111] The term “K D " as used herein means K a K for d The ratio of (i.e., K d / K a ) and expressed as a molar concentration (M). About K D Values ​​can be determined using methods well established in the art. The K D The method for determining By using a biosensor system such as the ORE® system be.

[0112] As used herein, the term "ADCC" or "antibody-dependent cellular cytotoxicity" refers to the activity of cells. The ADCC activity refers to the depletion activity. The ADCC activity can be measured by an ADCC assay well known to those skilled in the art. This can be done.

[0113] As used herein, the term "silent" antibody refers to an antibody that is The term "ADCC" refers to an antibody that exhibits no or low ADCC activity when subjected to ADCC.

[0114] In one embodiment, the term "no or low ADCC activity" refers to a silenced antibody. but less than 50% specific cell lysis as measured in a standard ADCC assay, e.g. "ADC" means that the antibody exhibits ADCC activity, for example, specific cell lysis of less than 10%. "No ADCC activity" means that the silent antibody has less than 1% ADCC activity (specific cell lysis). It means to present.

[0115] Suppression of effector functions can be achieved by mutations within the Fc region of the antibody, and this has been described in the art. Described in the field: LALA and N297A (Strohl, W., 2009 ,Curr.Opin.Biotechnol.vol.20(6):685-691) ; and D265A (Baudino et al., 2008, J. Immunol. 181:6664-69; Strohl, W., supra). Silent Fc IgG1 antibodies An example of this is the so-called Another example of a silent IgG1 antibody contains a D265A mutation. Another silent IgG1 antibody is N297, which results in glycosylated / non-glycosylated antibodies Contains the A mutation.

[0116] As used herein, the terms "inhibit," "inhibit," or "inhibiting" refer to a given alleviation or inhibition of a condition, symptom, disorder, or disease, or biological activity or indicates a significant decrease in the baseline activity of a process.

[0117] As used herein, "treating" or "treating" any disease or disorder means Alternatively, the term "treatment" refers, in one embodiment, to ameliorating a disease or disorder (i.e. Slowing or halting the onset or progression of the disease or at least one of its clinical symptoms In another embodiment, "treat," "treating," or "alleviating" refers to "Treatment" refers to at least one condition, including conditions that may not be discernible by the patient. In yet another embodiment, "treating" refers to alleviating or ameliorating a physical parameter. "Treatment" or "treatment" includes any physical (e.g., stabilization of discernible symptoms) or physiologically (e.g., stabilization of physical parameters) or both. More specifically, the term "treating" the disease HS refers to modulating a disease or disorder. The term refers to the inflammatory lesions in HS patients (either in number or quality or reduced in volume and size). Treating inflammatory bowel disease (in reducing inflammation) and / or treating abscesses and inflammatory nodules and / or to drain fistulas and / or reduce the amount of scarring in HS patients. Treating the disease HS This may help relieve pain, fatigue and / or itching associated with HS, reduce pus discharge, and reducing the odor associated with pus discharge, and / or the health benefits for HS patients. It also refers to improving quality of life and / or reducing work disability.

[0118] As used herein, the term "prevention" refers to the delay of the onset or development or progression of a disease or disorder. More specifically, the term "preventing" the disease HS refers to preventing or preventing the progression of HS. Preventing erythema and / or the appearance of new lesions, preventing scarring and and / or functional limitations associated with HS Refers to preventing surgical intervention.

[0119] As used herein, a subject is a person who is a patient who has a medical condition that is caused by or is caused by a disease or injury that occurs biologically or medically from such treatment. A person is "in need of" treatment if he or she would benefit therapeutically or in quality of life.

[0120] The term "pharmaceutical acceptable" means a non-toxic material that does not interfere with the effectiveness of the biological activity of the active ingredient. This refers to the material.

[0121] As used herein, the terms "administration" or "administering" a subject compound refers to the administration of a therapeutic agent. It is intended to provide the compounds of the present invention and their prodrugs to subjects in need thereof. Administration "in combination with" one or more further therapeutic agents may include any combination in any order. This includes simultaneous (concurrent) and sequential administration of the above routes of administration. Depending on how much drug substance needs to be administered to achieve the desired effect, either as a single injection or multiple injections at once, There may be multiple injections delivered together.

[0122] As used herein, a "therapeutically effective amount" refers to a single dose or multiple doses administered to a patient (such as a human). Upon administration of the dose, at least one symptom of the disorder or a recurrent disorder is treated or prevented, Prevent, cure, delay, reduce the severity, or reverse the onset of or to prolong the survival of a patient beyond that expected in the absence of such treatment. It refers to the amount of anti-CD40 antibody or antigen-binding fragment thereof, e.g., mAb1, that is effective. When applied to the individual active ingredient being administered (e.g., an anti-CD40 antibody, e.g., mAb1), When applied to a combination, the term refers to that component alone. The active ingredients that produce the therapeutic effect, whether administered in combination, sequentially or simultaneously It refers to the combined amount of

[0123] The expression "therapeutic regimen" refers to a regimen used to treat a disease, e.g., the treatment of HS. The term "loading regimen" refers to the dosing protocol used during treatment. A loading dose may be included, followed by a maintenance regimen (or maintenance dose).

[0124] The expression "loading regimen" or "loading period" refers to a treatment regimen used for the initial treatment of a disease. In some embodiments, the disclosed methods include The uses, kits, processes and regimens (e.g., methods of treating HS) include loading regimens. (or loading dose) is used. In some cases, the loading period is continued until maximum efficacy is reached. The general goal of a loading regimen is to provide patients with The loading regimen is intended to provide high levels of drug at the same time as the patient is receiving a maintenance regimen. Administering a larger dose of a drug than would otherwise be required, or when a physician prescribes a drug during a maintenance regimen This may include administering the drug more frequently than one would normally administer the drug, or both. Dose escalation can occur during or after the loading regimen.

[0125] The phrase "maintenance regimen" or "maintenance period" refers to a period during which a patient is maintained during treatment of a disease, e.g. To keep patients in remission for extended periods (months or years) following a loading regimen or period It refers to the therapeutic regimen (or part of the therapeutic regimen) that is being used. In some embodiments, The disclosed methods, uses and regimens use a maintenance regimen. A maintenance regimen is a continuous therapy. (e.g., administering drugs at regular intervals, such as weekly, biweekly, or monthly (every 4 weeks), yearly, etc.) administering the drug to a patient in need of treatment, or intermittent therapy (e.g., intermittent treatment, intermittent treatment, treatment at the time of relapse or specific Treatment upon achievement of a predefined criterion (e.g., pain, disease manifestation, etc.) Dose escalation can occur during the maintenance regimen.

[0126] The expression "means for administering" includes, but is not limited to, a pre-filled syringe, a vial, Syringes, pen-type injectors, autoinjectors, IV bags, pumps, patch pumps, etc. To represent all available tools for systemically delivering drugs to patients, including These are used to allow patients to self-administer drugs (i.e. administer the drug themselves). The drug may be administered to the patient for his or her own benefit (administered to the patient for his or her own benefit) or by a physician. EXAMPLES

[0127] Example 1. CD40 antagonists Anti-CD40 mAbs with suppressed ADCC activity are herein incorporated by reference in their entirety. The specification of U.S. Patent No. 8,828,396 and the specification of U.S. Patent No. 9,221,913 in which the body is incorporated The anti-CD40 mAb with suppressed ADCC activity is disclosed in the specification. Expected to have an improved safety profile compared to CD40 antibodies, particularly It may be more suitable for oncological indications, such as hidradenitis suppurativa (HS).

[0128] According to the inventors' non-binding hypothesis, the antibodies designated mAb1 and mAb2 in U.S. Pat. Two mAbs according to U.S. Pat. No. 8,828,396 and U.S. Pat. No. 9,221,913 , which is believed to be a suitable compound for the treatment of HS. 1 is particularly preferred.

[0129] mAb1 inhibits CD154-induced activation in vitro and T cell-dependent activation in vivo. Inhibits antibody formation and germinal center formation.

[0130] In order to enable one skilled in the art to practice the invention, the amino acid sequences and amino acid sequences of mAb1 and mAb2 are The nucleotide sequences are provided in Table 1 below.

[0131] Other anti-CD40 mAbs known in the art include, for example, Astella, as described in U.S. Patent No. 8,568,725 B2, which is incorporated herein by reference in its entirety. ASKP1240 from s Pharma / Kyowa Hakko Kirin Co. It is.

[0132] Additional anti-CD40 mAbs known in the art are described, for example, infra. Boehri, as described in incorporated U.S. Pat. No. 8,591,900. The PCR product is BI655064 from Inger Ingelheim.

[0133] Additional anti-CD40 mAbs known in the art are described, for example, in the US Pat. As described in U.S. Patent No. 8,669,352, incorporated herein by reference, Fast Fo and FFP104 by Richard Pharmaceuticals.

[0134] Another treatment modality is the anti-CD40L-Tn3 fusion protein, AstraZeneca MEDI4920 from eca, or anti-CD40L antibody BIIB06 from Biogen 3. Dapirolizumab pegol from UCB / Biogen pegol), or letolizumab from Bristol-Myers Squibb ( letolizumab).

[0135] Antibodies with the same mode of action as the above-mentioned antibodies, so-called biosimilars, can also be developed by those skilled in the art. As will be understood, all such modifications and variations are encompassed by the present disclosure.

[0136] [Table 1-1]

[0137] [Table 1-2]

[0138] [Table 1-3]

[0139] [Table 1-4]

[0140] [Table 1-5]

[0141] [Table 1-6]

[0142] In one embodiment, the anti-CD40 antibody is an immunoglobulin comprising the amino acid sequence of SEQ ID NO:7. an immunoglobulin VH domain and an immunoglobulin VL domain comprising the amino acid sequence of SEQ ID NO:8; The present invention provides an anti-CD40 antibody comprising:

[0143] In one embodiment, the anti-CD40 antibody is selected from SEQ ID NO:1, SEQ ID NO:2 and SEQ ID NO:3. and an immunoglobulin VH domain comprising a hypervariable region as described in SEQ ID NO: 4, sequence Immunoglobulin VL domain comprising the hypervariable region depicted as SEQ ID NO:5 and SEQ ID NO:6 and an anti-CD40 antibody comprising the antibody and

[0144] In one embodiment, the anti-CD40 antibody is an immunoglobulin comprising the amino acid sequence of SEQ ID NO:7. an immunoglobulin VH domain and an immunoglobulin VL domain comprising the amino acid sequence of SEQ ID NO:8; and an Fc region of SEQ ID NO:13.

[0145] In one embodiment, the anti-CD40 antibody is an immunoglobulin comprising the amino acid sequence of SEQ ID NO:7. an immunoglobulin VH domain and an immunoglobulin VL domain comprising the amino acid sequence of SEQ ID NO:8; and an Fc region of SEQ ID NO:14.

[0146] In one embodiment, the anti-CD40 antibody comprises a silent Fc IgG1 region. D40 antibodies are provided.

[0147] In a preferred embodiment, an anti-CD40 antibody designated mAb1 is provided. mAb1 comprises the heavy chain amino acid sequence of SEQ ID NO:9 and the light chain amino acid sequence of SEQ ID NO:10. and mAb2 has a heavy chain amino acid sequence of SEQ ID NO:11 and a light chain amino acid sequence of SEQ ID NO:12. Contains arrays.

[0148] 1. Expression system For expression of the light and heavy chains, expression vectors encoding the heavy and light chains are prepared using standard techniques. Thus, the gene is transferred to the host cell. A wide variety of techniques are commonly used for the introduction of Examples include electroporation, calcium phosphate precipitation, and DEAE-dextran gene transfer. It is intended that the antibodies of the present invention be expressed in either prokaryotic or eukaryotic host cells. It is theoretically possible to express the vector in eukaryotic cells, e.g. mammalian host cells, Expression of antibodies in yeast or filamentous fungi is discussed because such eukaryotic cells, especially Mammalian cells assemble and secrete properly folded, immunologically active antibodies This is because the probability of infection is higher in bacteria than in prokaryotic cells.

[0149] In particular, the cloning or expression vector is operable with a suitable promoter sequence. The following coding sequences (a) to (b) are linked together as follows: (a) SEQ ID NO:15 and SEQ ID NO:16, which encode the full-length heavy and light chains of mAb1, respectively. or (b) SEQ ID NO:17 and SEQ ID NO:18, which encode the full-length heavy and light chains of mAb2, respectively. It may include at least one of the following:

[0150] Mammalian host cells for expressing the recombinant antibodies of the present invention include Chinese hamster ovarian tumor cells. Ovary (CHO cells) (see, e.g., RJ Kaufman and PA Sharp, 198 2 DHFR selection as described in Mol. Biol. 159:601-621 Used with possible markers, Urlaub and Chasin, 1980 Proc. dh described in Natl. Acad. Sci. USA 77:4216-4220 fr-CHO cells), CHOK1 dhfr+ cell line, NSO myeloma cells, C These include OS cells and SP2 cells. In particular, for use with NSO myeloma cells, The current system is PCT Publication International Publication No. 87 / 04462, International Publication No. 89 / 01 The GS gene shown in European Patent No. 036 and European Patent No. 0338841 It is an expression system.

[0151] When a recombinant expression vector encoding an antibody gene is introduced into a mammalian host cell, the antibody is , allowing expression of the antibody in the host cell or secretion of the antibody into the culture medium in which the host cell is grown Antibodies are produced by culturing host cells for a period of time sufficient to produce a standard tandem Proteins can be recovered from the culture medium using protein purification methods (e.g., Abhinav et al., et al.2007, Journal of Chromatography 84 8:28-37).

[0152] The host cells can be cultured under conditions suitable for the expression and production of mAb1 or mAb2. Cut.

[0153] 2. Pharmaceutical Compositions Therapeutic antibodies are typically administered in aqueous form, ready for administration, or in a suitable diluent prior to administration. The anti-CD40 antibody is formulated as a lyophilizate for reconstitution. Alternatively, it may be formulated as an aqueous composition, for example in a pre-filled syringe. The formulation is also called drug product (DP).

[0154] A suitable formulation, upon reconstitution, provides high concentrations of antibody active ingredient and low levels of The present invention provides an aqueous pharmaceutical composition or a lyophilized product capable of providing a solution with antibody aggregation. High concentrations of antibodies can thereby reduce the amount of material that must be delivered to the patient. The reduced dosage volume allows for a smaller amount of time to deliver a consistent dose to the patient. The aqueous composition of the present invention containing a high concentration of an anti-CD40 antibody is administered subcutaneously. It is particularly suitable for

[0155] Thus, the present invention provides a method for the treatment of a subject comprising administering to a subject an anti-CD40 antibody, such as mAb1 or mAb2. The present invention provides an aqueous pharmaceutical composition suitable for administration in the body, for example for subcutaneous administration.

[0156] The anti-CD40 antibody, when combined with a pharma- ceutical carrier, can be used as a pharmaceutical composition. Such compositions can be used with anti-CD40 antibodies such as mAb1 or mAb2. In addition, carriers, various diluents, fillers, salts, buffers, stabilizers, solubilizers and other agents known in the art. Other well-known ingredients may be included. The characteristics of the carrier will depend on the route of administration. The pharmaceutical composition for use in the method may be an additional therapeutic agent for the treatment of the particular disorder being targeted. Medication may also be included.

[0157] In a specific embodiment, the composition, also referred to as a drug product (DP), has a pH of 6.0. And (i) 150 mg / mL mAb1 or mAb2, (ii) 270 mM sucrose (as a stabilizer); (iii) 30 mM L-histidine (as a buffering agent), and (iv) 0.06% polysorbate 20 (as a surfactant) A lyophilized formulation prepared from an aqueous formulation comprising:

[0158] In another specific embodiment, the pharmaceutical composition, also referred to as drug product (DP), has a pH of 6.0. and (i) 150 mg / mL mAb1 or mAb2, (ii) 270 mM sucrose (as a stabilizer); (iii) 30 mM L-histidine (as a buffering agent), and (iv) 0.06% polysorbate 20 (as a surfactant) The aqueous pharmaceutical composition comprises:

[0159] 3. Combination The present invention relates to the treatment or prevention of HS in patients in need of such treatment and / or prevention. CD40 antagonists, in particular anti-CD40 antibodies, such as CFZ5, for use in prophylaxis The present invention further relates to a combination of 33 (iscalimab) with one or more additional therapeutic agents.

[0160] These additional treatments include topical treatments (creams [non-steroidal or steroidal] , cleaning agents, disinfectants), systemic treatments (e.g., with biological agents, antibiotics or chemical entities) , disinfectants, photodynamic therapy and surgical interventions (laser, drainage or incision, excision) can be done.

[0161] Anti-CD40 antagonists, such as iscalimab, are disclosed in the treatment of HS. Additional non-limiting therapeutic agents for use in combination with the disclosed CD40 antibodies are Non-limiting examples of HS agents used in systemic therapy for use with antagonists include: For this purpose, IL-17 antagonists (ixekizumab, brodalumab, secukinumab, CJ M112), as well as IL17A / F antagonists (such as bimekizumab) or I L17C antagonists (such as MOR106), tumor necrosis factor alpha (TNF-α) blockers ( Enbrel® (etanercept), Humira® (adalimumab) (infliximab), Remicade® (infliximab) and Simponi® (registered trademark) (golimumab, etc.), interleukin 12 / 23 blockers (Stelara (registered trademark) trademarks) (ustekinumab, tasocitinib, and briakinumab), IL-23 blockers (Guselkumab, Tildrakizumab, and Risankizumab, etc.) p19 inhibitors, PDE4 inhibitors complement inhibitors, such as Apremilast or Otezla®; complement pathway inhibitors, such as B Factor inhibitors (e.g., those disclosed in WO 2015 / 009616) or 4-((2S,4S)-4-ethoxy-1-((5-methoxy-7-methyl It is also known as 1H-indol-4-yl)methyl)piperidin-2-yl)benzoic acid. LNP023, also known as IFX-001, and C5a inhibitors (also known as Avacopan) CCX168, an established drug for treating IL-1 infections, and IL-1 antagonists (canakinumab, gevokizumab, riloquinoline, Nacept, Anakinra, MaBp1 (XBiotech), Inflammasome inhibitors, e.g. For example, NLRP3 inhibitors and NLRP5 inhibitors, CXCR1 / 2 inhibitors, IL-18 inhibitors, antagonist, IL-6 antagonist, IL-36 antagonist, CD20 antagonist antagonists, CTLA4 antagonists, IL-8 antagonists, B cell depleting agents (especially CD 20 antagonists, such as rituximab, as well as BAFF-R and LTA4H inhibitors agent), IL-21 antagonist, IL-22 antagonist, VEGF antagonist , CXCL antagonists, MMP antagonists and defensin antagonists (e.g. (e.g., receptor decoys, antagonist antibodies, etc.) as well as broad-spectrum oral JAK inhibitors or more specific TYK2 or JAK1, JAK2 or JAK3 inhibitors. do.

[0162] Additional embodiments for use in combination with the disclosed CD40 antagonists in the treatment of HS include, but are not limited to, HS drugs include retinoids, such as acitretin (e.g., Soriatane (registered trademark) Immune system suppressants (e.g., rapamycin, T cell blockers), and isotretinoin Drug withdrawal [e.g., Amevive® (Alefacept) and Raptiva® ( (Registered Trademark) [Efalizumab] Cyclosporine, methotrexate, mycophenolate monophosphate fetyl, mycophenolate, leflunomide, tacrolimus, etc.), hydroxyurea (e.g. For example, Hydrea®, sulfasalazine, 6-thioguanine, fumarate (e.g., dimethyl fumarate and fumaric acid esters), azathioprine, colchicine, Ritretinoin, steroids, corticosteroids, certolizumab, mometasone, Glitazone, pioglitazone, botulinum toxin, triamcinolone, IFX-1 (Inf laRx), LY-3041658 (Eli Lilly), TE-2232 (Immu nwork), NSAIDs, COX inhibitors, prescription narcotics, ketoprofen, codeine, Gabapentin, pregabalin, gentanyl, antibiotics (topical, oral) Oral, IV) (e.g., clindamycin, rifampin, tetracycline, sarsamycin, Cline, doxycycline, minocycline, lymecycline, trimethoprim-sulfamethoxazole Amethoxazole, erythromycin, ceftriaxone, moxifloxacin, methotrexate nidazole, alone or in combination), corticosteroids (injectable or oral), Antiandrogen / hormonal therapy (oral contraceptives, spironolactone, finasteride, dutasteride) Tasteride, progesterone IUD, cyproterone acetate, ethinyl estradiol, Stodden, norgestimate, desogestrel, drospirenone, spironolactone), Triamcinolone acetonide, MEDI8968, hydroxychloroquine, dapsone, These include toformin, adapalene, azelaic acid and zinc.

[0163] Preferred combinations for use in the disclosed kits, methods and uses include TNFα blockers. Other biomarkers, such as withdrawal of IL-17 or IL23 and / or IL1 and / or IL18 blockers This includes pharmaceutical preparations.

[0164] Examples of TNFα blockers for use in combination include etanercept, adalimumab, Examples of IL17 blockers are ixekizumab, brotizolam, and golimumab. Dalumab, secukinumab or CJM112. An example of an IL23 blocker is guselkumab Examples of IL1 blockers are canakinumab, gefitinib, tildrakizumab, and risankizumab. These are vokizumab, rilonacept, anakinra, and MaBp1 (XBiotech).

[0165] 4. Route of Administration Typically, the antibody or protein is administered by injection, e.g., intravenously, intraperitoneally, or subcutaneously. Methods for accomplishing this administration are known to those of skill in the art. To obtain a composition that may be administered intramuscularly or may be capable of penetrating mucosa. As will be appreciated by those of skill in the art, the particular route of administration selected may be Any suitable means of administration, as appropriate for the subject, may be used.

[0166] Examples of possible routes of administration include parenteral (e.g., intravenous (IV) or intramuscular), intramuscular (IM), intradermal, subcutaneous (SC or SC) or by injection), oral and pulmonary (e.g. , inhalation), nasal, transdermal (topical), transmucosal and rectal administration. The solutions or suspensions used for subcutaneous application may contain the following components: Diluents for bacteria, such as water for injection, saline solution, fixed oils, polyethylene glycol, Lysine, propylene glycol or other synthetic solvents, antibacterial agents such as benzyl alcohol or methylparaben, antioxidants such as ascorbic acid or sodium bisulfite, rate agents such as ethylenediaminetetraacetic acid, buffers such as acetic acid, citric acid or phosphoric acid, and agents for adjusting tonicity, e.g., sodium chloride or dextrose. pH is adjusted with hydrochloric acid or The dosage form can be prepared using an acid or base such as sodium hydroxide. Packaged in glass or plastic ampoules, disposable syringes or multi-dose vials It is possible.

[0167] Anti-CD40 therapy may involve a loading regimen or dosing of the antibody or protein of the invention in combination with anti-C D40 therapy can be initiated by administering it to a subject in need of it. A "dose" refers to an initial dose of an anti-CD40 antibody or protein of the invention administered to a subject once or several times. dosing is contemplated, where the dose of the antibody or protein of the invention administered is higher than the dose range (i.e., about 10 mg / kg to about 50 mg / kg, e.g., about 30 mg / kg (intravenous) ) or about 600 mg, about 300 mg, or about 150 mg (every week, every other week, up to 4 weeks A "loading regimen" can be a single or multiple dose regimen, e.g., a single or multiple rounds of administration. Combined as an intravenous infusion or in a "loading dose" regimen depending on disease severity. The drug can then be administered as multiple subcutaneous doses, with the first dose being followed by a "loading regimen". administering to the subject one or more additional therapeutically effective doses of an anti-CD40 antibody or protein of the invention; Thereafter, the therapeutically effective dose may be administered, for example, according to a weekly dosing schedule or once every two weeks. The dose may be administered once every two weeks (every other week), once every three weeks, or once every four weeks. Thereafter, therapeutically effective doses generally fall within the lower dosage range (i.e., about 0.003 mg / kg). kg to about 30 mg / kg, for example about 10 mg / kg, for example 10 mg / kg (IV), or Approximately 150 mg, approximately 300 mg, or Approximately 600 mg.

[0168] Instead, in some embodiments, a "loading regimen" is followed by a subsequent therapeutically effective dose of the The anti-CD40 antibodies or proteins of the invention are administered in a "maintenance schedule" (wherein the treatment of the invention An effective dose of the antibody or protein may be administered once a month, once every six weeks, once every two months, or once every ten weeks. once every 3 months, once every 14 weeks, once every 4 months, once every 18 weeks, once every 5 months, 22 Once a week, once every 6 months, once every 7 months, once every 8 months, once every 9 months, once every 10 months once every 11 months or once every 12 months). In certain embodiments, a therapeutically effective dose of an anti-CD40 antibody or protein of the invention may be administered in a therapeutically effective amount, particularly in the form of a subsequent dose. If administered at more frequent intervals, e.g., weekly, once every 2 weeks, or once every 4 weeks, the lower dose Drug range (i.e., about 0.003 mg / kg to about 30 mg / kg, e.g., about 10 mg / kg , e.g., 10 mg / kg), or in particular, subsequent doses are administered at less frequent intervals. If doses are administered at intervals of 1–12 months, for example, subsequent doses may be administered more slowly. In the high dosage range (i.e., 10 mg / kg to 50 mg / kg, e.g., 30 mg / kg) It is within the range.

[0169] The timing of dosing is generally determined based on the time of administration of the active compound ( For example, it is measured from the day of the first administration of mAb1. However, different healthcare providers may give different Use a naming convention that:

[0170] In particular, week 0 may be considered week 1 by health care providers, while day 0 may be considered day 1 by the healthcare provider. For example, Week 3 / Day 21, Week 3 / Day 22, Week 4 / Day 23, Week 5 / Day 24, Week 6 / Day 25, Week 7 / Day 26, Week 8 / Day 27, Week 9 / Day 28, Week 10 / Day 29, Week 11 / Day 21, Week 12 / Day 22, Week 13 / Day 23, Week 14 / Day 24, Week It may be stated that a dose is given on Day 21, Week 4 / Day 22. For this purpose, the first week of dosing is considered week 0 herein, whereas the first week of dosing is considered week 1. The first day of shall be considered Day 1. However, this naming convention is merely for consistency The terms are used for the purposes of this guideline and should not be construed as limiting, i.e., a physician may refer to a particular week as " Whether referred to as "week 1" or "week 2," weekly dosing is done with anti-CD40 antibodies (e.g. For example, the provision of a weekly dose of mAb1) would be understood by one of skill in the art. Examples of dosing regimens described herein are shown in Figures 1 and 2. It will be understood that the time period does not have to be provided at the time of the scheduled date. For example, the time period may be provided at approximately the 29th day. If this is provided in the appropriate week, e.g., days 24 to 34, e.g. For example, it may be provided on the 30th day.

[0171] As used herein, the phrase "a quantity sufficient to permit delivery of [a specified dose]" means A "container having an anti-CD40 antibody" refers to a given container (e.g., a vial, a pen, A syringe) can be used to deliver the desired dose, (e.g., "anti-CD40 antibody" means that a volume of anti-CD40 antibody (as part of a composition) is disposed therein. As an example, if the desired dose is 500 mg, the clinician 2 ml from a container containing an anti-CD40 antibody formulation having a concentration of 250 mg / ml; 1 ml from a container containing an anti-CD40 antibody formulation having a concentration of 100,000 mg / ml, 0.5 ml from a container containing an anti-CD40 antibody formulation having a concentration of 0.0 mg / ml, etc. In each such case, these containers may be used to The anti-CD40 antibody has a sufficient amount to allow for the delivery of a 100 g dose.

[0172] As used herein, the phrase "enables delivery of [a specified dose] by [route of administration]" means "Formulated in a dosage for" refers to a given pharmaceutical composition that is formulated for a designated route of administration (e.g., Administer a desired dose of an anti-CD40 antibody, e.g., mAb1, via injection, sc or iv. It is used to mean that it can be used to provide a desired skin. If the lower dose is 500 mg, the clinician should administer anti-CD40 2 ml of antibody preparation, 1 ml of anti-CD40 antibody preparation having a concentration of 500 mg / ml, For example, 0.5 ml of an anti-CD40 antibody preparation having a concentration of 100 mg / ml can be used. In each of these cases, these anti-CD40 antibody formulations may be used to administer the anti-CD40 antibody subcutaneously. Subcutaneous delivery is typically in a volume of less than about 2 ml. However, it is possible to deliver a volume of about 1 ml or less, e.g., a patch / pump. A pump mechanism can be used to deliver higher volumes over time.

[0173] Disclosed herein is a pharmaceutical agent for the treatment of hidradenitis suppurativa in a patient, comprising The pharmaceutical product is formulated to include containers, each container containing at least about 75 ml of a unit dose. g, 150 mg, 300 mg, or 600 mg of an anti-CD40 antibody or antigen-binding fragment thereof (e.g., mAb1) in a sufficient amount to allow delivery of the anti-CD40 antibody. The use of anti-CD40 antibodies (e.g., mAb1) for the production of CD40 antigens.

[0174] Disclosed herein is a pharmaceutical agent for the treatment of hidradenitis suppurativa in a patient, comprising The drug product is available in doses of 75 mg, 150 mg, 300 mg or 600 mg of anti-CD4 0 Systemic delivery (e.g., i.v. or s.i.v.) of an antibody or antigen-binding fragment thereof (e.g., mAb1) .c. the manufacture of an anti-CD40 antibody formulated in a dosage to enable delivery (e.g., the use of mAb1).

[0175] 5. Kit The present disclosure relates to an anti-CD40 antibody or antigen-binding fragment thereof, such as a mAb (as the case may be). The present invention also includes a kit for treating a patient suffering from hidradenitis suppurativa, comprising: Anti-CD40 antibodies or antigen-binding fragments thereof (e.g., in liquid or lyophilized form), e.g. The present invention also includes pharmaceutical compositions comprising mAb1 or an anti-CD40 antibody (described above). The kit may include a means for administering the anti-CD40 antibody (e.g., a syringe and a vial, a plate, etc.). refilled syringes, prefilled pens, patches / pumps) and instructions for use. The instructions may include instructions for administering the anti-CD40 antibody to the patient as part of a specific dosing regimen. (e.g., mAb1). These kits can include: For example, in combination with an encapsulated anti-CD40 antibody, e.g., mAb1, for treating psoriasis. Additional therapeutic agents (as described above) for delivery may also be included.

[0176] The expression "means for administering" includes, but is not limited to, a pre-filled syringe, a vial, and syringes, pen-type injectors, autoinjectors, IV bags, pumps, patches / pumps, etc. To represent all available tools for systemically delivering drugs to patients, including These are used to allow patients to self-administer drugs (i.e. administer the drug themselves). The drug can be administered by a caregiver or physician (administered for the patient) or by a caregiver or physician. do.

[0177] Disclosed herein are a) a therapeutically effective amount of an anti-CD40 antibody or antigen-binding fragment thereof, b) a pharmaceutical composition for administering an anti-CD40 antibody or an antigen-binding fragment thereof to a patient; and c) administering the anti-CD40 antibody or antigen-binding fragment thereof to a patient in need thereof. A dose of about 3 to about 30 mg of active ingredient per kilogram for human subjects (once every other week for 3 once), followed by about 3 to about 30 mg, e.g., 10 mg, per kilogram of human subject. Monthly dosing of the active ingredient, or about 150 mg, about 300 mg, or about 600 mg (maintenance regimen) and instructions for administering the drug subcutaneously as a single dose (weekly, biweekly or monthly) during the day. A kit for treating a patient with hidradenitis.

[0178] In a specific embodiment, the present invention relates to a method for the manufacture of a medicament for the treatment of hidradenitis suppurativa, comprising: a) administering to said patient an anti-hidradenitis suppurativa antibody; a) a liquid pharmaceutical composition comprising an anti-CD40 antibody, a buffer, a stabilizer and a solubilizer, and b) an anti-CD40 Use of a means for subcutaneously administering an antibody to a patient having hidradenitis suppurativa is provided, wherein , anti-CD40 antibody, i) A dose of about 3 to about 30 mg, e.g., 10 mg, of active ingredient per kilogram of human subject is administered intravenously to patients once every other week for three doses. ii) then about 3 to about 30 mg, e.g., 10 mg, of active compound per kilogram of human subject; The composition is administered intravenously to the patient as monthly doses of the composition, wherein the anti-CD40 antibody is a) an immunoglobulin VH domain comprising the amino acid sequence of SEQ ID NO: 7 and an immunoglobulin VH domain comprising the amino acid sequence of SEQ ID NO: 8 an anti-CD40 antibody comprising an immunoglobulin VL domain comprising an amino acid sequence; b) Immunoglobulins comprising the hypervariable regions depicted as SEQ ID NO:1, SEQ ID NO:2 and SEQ ID NO:3. globulin VH domain and the high-density an anti-CD40 antibody comprising an immunoglobulin VL domain containing a frequency variable region; c) an immunoglobulin VH domain comprising the amino acid sequence of SEQ ID NO: 7 and an immunoglobulin VH domain comprising the amino acid sequence of SEQ ID NO: 8 and an anti-CD31 antibody comprising an immunoglobulin VL domain having the sequence of SEQ ID NO: 13 and an Fc region having the sequence of SEQ ID NO: 14. 40 antibodies, d) an immunoglobulin VH domain comprising the amino acid sequence of SEQ ID NO: 7 and an immunoglobulin VH domain comprising the amino acid sequence of SEQ ID NO: 8; and an anti-CD31 antibody comprising an immunoglobulin VL domain having the sequence of SEQ ID NO: 14 and an Fc region having the sequence of SEQ ID NO: 15. 40 antibodies, e) an anti-CD40 antibody comprising a silent Fc IgG1 region, and f) a heavy chain amino acid sequence of SEQ ID NO: 9 and a light chain amino acid sequence of SEQ ID NO: 10 or a light chain amino acid sequence of SEQ ID NO: 1 Anti-CD40 antibody comprising the heavy chain amino acid sequence of SEQ ID NO:1 and the light chain amino acid sequence of SEQ ID NO:12. is selected from the group consisting of:

[0179] In another specific embodiment, a method for the manufacture of a medicament for the treatment of HS comprising administering to said patient: a) an anti-CD40 a) a liquid pharmaceutical composition comprising an antibody, a buffer, a stabilizer and a solubilizer, and b) an anti-CD40 antibody, The use of a means for subcutaneous administration to a patient with HS is provided, wherein an anti-CD40 antibody teeth, i) about 150 mg of active substance, about 300 mg of active substance or about 600 mg of active substance (per dose) weekly or biweekly) to the patient subcutaneously; ii) then administering about 150 mg of the active substance, about 300 mg of the active substance, or about 600 mg of the active substance; The drug is administered subcutaneously to a patient as a weekly, biweekly or monthly (every 4 weeks) dose of a therapeutically active agent, The anti-CD40 antibody is a) an immunoglobulin VH domain comprising the amino acid sequence of SEQ ID NO: 7 and an immunoglobulin VH domain comprising the amino acid sequence of SEQ ID NO: 8 an anti-CD40 antibody comprising an immunoglobulin VL domain comprising an amino acid sequence; b) Immunoglobulins comprising the hypervariable regions depicted as SEQ ID NO:1, SEQ ID NO:2 and SEQ ID NO:3. globulin VH domain and the high-density an anti-CD40 antibody comprising an immunoglobulin VL domain containing a frequency variable region; c) an immunoglobulin VH domain comprising the amino acid sequence of SEQ ID NO: 7 and an immunoglobulin VH domain comprising the amino acid sequence of SEQ ID NO: 8 and an anti-CD31 antibody comprising an immunoglobulin VL domain having the sequence of SEQ ID NO: 13 and an Fc region having the sequence of SEQ ID NO: 14. 40 antibodies, d) an immunoglobulin VH domain comprising the amino acid sequence of SEQ ID NO: 7 and an immunoglobulin VH domain comprising the amino acid sequence of SEQ ID NO: 8; and an anti-CD31 antibody comprising an immunoglobulin VL domain having the sequence of SEQ ID NO: 14 and an Fc region having the sequence of SEQ ID NO: 15. 40 antibodies, e) an anti-CD40 antibody comprising a silent Fc IgG1 region, and f) a heavy chain amino acid sequence of SEQ ID NO: 9 and a light chain amino acid sequence of SEQ ID NO: 10 or a light chain amino acid sequence of SEQ ID NO: 1 Anti-CD40 antibody comprising the heavy chain amino acid sequence of SEQ ID NO:1 and the light chain amino acid sequence of SEQ ID NO:12. is selected from the group consisting of:

[0180] Example 2. Pharmacology 1. First Pharmacology mAb1 binds human CD40 with high affinity (K of 0.3 nM). d) to join. However, this does not bind to Fcγ receptors (including CD16) or inhibits antibody-dependent cellular cytotoxicity or mAb1 does not mediate complement-dependent cytotoxicity. 154) Inhibits induced activation of monocyte-derived dendritic cells (DCs)-induced PBMC proliferation or mAb1 does not induce cytokine production. mAb1 binds human and non-human sera with very similar affinities. It binds to proteolytic CD40.

[0181] mAb1 inhibited primary and secondary T cell-dependent antibody responses (TDAR) in vivo and Renal allograft survival in human primates can be extended (Cordoba Furthermore, mAb1 inhibits the assembly of germinal centers (GCs) in vivo. It can be collapsed.

[0182] CD40 receptor occupancy and functional activity are simultaneously assessed in vitro using human whole blood cultures Functional activity was measured by CD69 (an activation marker) expression on CD20 positive cells (B cells). CD40 occupancy was quantified via 154-induced expression using fluorescently labeled mAb1. For sufficient inhibition of rCD154-induced CD69 expression, mAb1 was required. Near complete CD40 occupancy was required.

[0183] 2. Second Pharmacology The effects of mAb1 on platelet function and hemostasis were investigated, and mAb1 induced platelet aggregation. rather, it has been shown at high concentrations to have some mild inhibitory effect on platelet aggregation. was shown.

[0184] Example 3. Nonclinical Toxicology and Safety Pharmacology Toxicity studies with mAb1 were reported in clinical trials with anti-CD154 mAbs. There was no evidence of any significant organ toxicity, including no evidence of thromboembolism when (Kawai et al 2000). In a 13-week GLP rhesus monkey study (10, Weekly dosing at 50 and 150 mg / kg) resulted in ongoing Increased lymphatic cellularity was observed, possibly due to infection. Inflammatory effects were observed in the kidneys and lungs of two animals at 50 mg / kg. Lesions were observed in both animals, including in the eyes and trachea in one of the two animals. Although a direct effect of mAb1 on the liver and lungs cannot be excluded, it is possible that it may be involved in the suppression of opportunistic pathogens. The weight of evidence, including confirmation, suggests that these findings may be secondary to mAb1-mediated immunosuppression. Considering these inflammatory findings, The no observed adverse effect level (NOAEL) for the weekly toxicity study was set at 10 mg / kg. A 26-week chronic toxicity study in monkeys found no adverse mAb1-related findings Based on these data, the NOAEL was set at 150 mg / kg (26 weeks). (all animals)C max,ss 1, 50 and 150 (NOAEL) mg / kg (SC , weekly) were 44, 3235, and 9690 μg / mL, respectively. NOAELs derived from monkey studies are most appropriate for supporting clinical dosing regimens. It is thought that.

[0185] Postmortem histological and immunohistochemical evaluation revealed that the B cell compartment of the spleen and lymphoid tissues were Recovered animals showed a reduction in GC with normal T cell areas and expanded B cell areas. We have shown several cases of increased lymph node cellularity, which may be related to GC reconstitution after withdrawal. The recovered animals had blood concentrations of mAb1 below the concentration required for sufficient receptor occupancy. The primary TDAR for keyhole limpet hemocyanin (KLH) was observed immediately after the decrease to was able to start.

[0186] Due to the complete inhibition of T cell-dependent antibody responses (TDAR), KLH, i.e., mAb1 Anti-drug antibodies (ADA) are not expected to form against the If these drugs are maintained at pharmacological levels for .

[0187] Tissue cross-reactivity studies have demonstrated that CD40 is not only present on immune cells but also in various tissues. It has been shown that CD40 is also present on endothelial and epithelial cells (where CD40 is expressed signaling, such as responding to wound healing processes, upregulation of viral defenses and inflammation Its expression on the inflammatory mediators involved in inflammation-related inflammation is due to its antagonistic activity, such as mAb1. The anti-CD40 monoclonal antibody is not expected to contribute to the inflammatory process, which is , which was confirmed by in vitro studies using human umbilical vein endothelial cells (HUVEC).

[0188] No reproductive toxicity studies have been conducted to date that fully comply with the guidelines. , dose range finding in rabbits to confirm rabbits as an appropriate reproductive toxicology species; Embryo-fetal development (EFD) studies have been conducted. No effects on embryo-fetal development have been observed. There were no treatment-related external fetal malformations in any group.

[0189] In conclusion, this preclinical data supports the studies in patients with hidradenitis suppurativa.

[0190] Example 4. Non-clinical Pharmacokinetics and Pharmacodynamics 1. Pharmacokinetics (PK) As is typical for IgG immunoglobulins, the primary route of elimination of mAb1 is through plasma equilibrium. This is likely mediated by proteolytic catabolism occurring at the site of the condition. Binding and internalization of Ab1-CD40 complexes results in a rapid, saturable clearance pathway. This is a nonlinear mAb1 serum concentration-dependent change that shows an inflection point at approximately 10-20 μg / mL. Time profiles of CD40-mediated clearance versus total clearance The contribution of lance was determined by the levels of CD40 expression, internalization and receptor turnover rates together with mAb1 Concentration dependent. Linear kinetics are predicted for serum concentrations of mAb1 >10-20 μg / mL. whereas at lower concentrations nonlinear kinetics become evident.

[0191] 2. Pharmacodynamics (PD) In a PK / PD study in cynomolgus monkeys, the inflection point in the PK profile (approximately 10 (μg / mL) is CD40 as determined in an independent lymphocyte target saturation assay This inflection point was therefore related to the level of CD40 saturation. These are considered evidence of all markers and target engagement.

[0192] The relationship between CD40 occupancy and pharmacodynamic activity was examined in rhesus monkeys immunized with KLH. Further demonstrated, monkeys were immunized three times with KLH (the first immunization was approximately 3 weeks before dosing and the second immunization was approximately 3 weeks before dosing). The second was 2 weeks after administration of mAb1, and the third was after complete washout of mAb1. The plasma concentration of mAb1 at the time of the second KLH vaccination was >40 μg / mL. CD40 occupancy by mAb1 completely prevented recall antibody responses. All animals mounted sufficient memory antibody responses to the third KLH. This suggests that the function of pre-existing memory B cells was not affected. After successful clearance, immunization with tetanus toxoid (TTx) produced anti- inflammatory responses similar to those in untreated animals. TTx-IgG / IgM titers and sufficient TDAR was restored after mAb1 withdrawal This demonstrated that:

[0193] 3. Immunogenicity As expected for an immunosuppressant, immunogenicity data in rhesus monkeys (single dose) Consistent with the results from the KLH-TDAR experiment, the CD40 occupancy rate was sufficient with mAb1. These results suggest that immune responses to mAb1 may not be initiated in these patients.

[0194] 4. Treatment Regimen Pharmacokinetic and pharmacodynamic profile of mAb1 and preclinical and clinical studies of mAb1 Based on the results of the studies, the following treatment regimens can be used:

[0195] In one embodiment (see FIG. 1), the mAb1 treatment regimen includes: , 8th (2nd week), 15th (3rd week), 22nd (4th week) and 29th (5th week) The study consisted of weekly loading doses of 600 mg mAb1 (2 × 2 mL) administered sc at 4 °C. After 5 weeks, patients were randomized to receive weekly (or semi-weekly) doses on days 43 (week 7), 57 (week 9), etc. Receive a maintenance dose of 600 mg (2 x 2 mL per week) of scmAb1.

[0196] In one embodiment (see FIG. 2A, 1), the mAb1 treatment regimen comprises two doses. A loading dose consisting of two doses of 600 mg mAb1 administered one week apart; followed by maintenance dosing consisting of 600 mg mAb1 administered every 2 weeks (Q2W). The 600 mg dose preferably comprises two doses of 2 mL of drug product (150 mg / mL). It is administered subcutaneously via injection.

[0197] In another embodiment (see FIG. 2A, 2), the mAb1 treatment regimen comprises 600 mg of A loading dose consisting of a first administration of 300 mg mAb1 and a second administration of 300 mg mAb1 ( where the second dose is administered one week after the first dose) and then every two weeks thereafter (Q2 W) maintenance dosing consisting of administration of 600 mg mAb1 administered at a dose of 300 mg. is preferably administered subcutaneously via a single injection of 2 mL drug product (150 mg / mL). The 600 mg dose is preferably administered as two injections of 2 mL of drug product (150 mg / mL). It is administered subcutaneously via injection.

[0198] In yet another embodiment (see Figures 2A, 3), the mAb1 treatment regimen comprises 6 The loading dose consisted of a first dose of 0.00 mg mAb1 and a second dose of 150 mg mAb1. drug (wherein the second dose is administered one week after the first dose), followed by every two weeks Maintenance dosing consisted of administration of 600 mg mAb1 administered Q2W. The dose is preferably administered via a single injection of 1 mL of drug product (150 mg / mL). Instead, the drug was administered subcutaneously via a single injection of 2 mL of half-diluted drug product (75 mg / mL). The 600 mg dose is preferably administered twice as a 2 mL dose of the drug product (150 mg / mL). It is administered subcutaneously via injection.

[0199] In one embodiment (see FIG. 2B, 1), the mAb1 treatment regimen comprises two doses. A loading dose consisting of two doses of 600 mg mAb1 administered one week apart; followed by maintenance dosing of 300 mg mAb1 administered every 2 weeks (Q2W). The 600 mg dose preferably comprises two doses of 2 mL of drug product (150 mg / mL). It is administered subcutaneously via injection. The 300 mg dose is preferably administered in 2 mL of drug product (150 The drug is administered subcutaneously via a single injection of 10 mg / mL.

[0200] In another embodiment (see FIG. 2B, 2), the mAb1 treatment regimen comprises 600 mg of A loading dose consisting of a first administration of 300 mg mAb1 and a second administration of 300 mg mAb1 ( where the second dose is administered one week after the first dose) and then every two weeks thereafter (Q2 W) maintenance dosing consisting of administration of 300 mg mAb1 at 300 mg dose is preferably administered subcutaneously via a single injection of 2 mL drug product (150 mg / mL). The 600 mg dose is preferably administered as two injections of 2 mL of drug product (150 mg / mL). It is administered subcutaneously via injection.

[0201] In yet another embodiment (see Figure 2B, 3), the mAb1 treatment regimen comprises 6 The loading dose consisted of a first dose of 0.00 mg mAb1 and a second dose of 150 mg mAb1. drug (wherein the second dose is administered one week after the first dose), followed by every two weeks Maintenance dosing consisted of administration of 300 mg mAb1 administered Q2W. The dose is preferably administered via a single injection of 1 mL of drug product (150 mg / mL). Instead, the drug was administered subcutaneously via a single injection of 2 mL of half-diluted drug product (75 mg / mL). The 600 mg dose is preferably administered twice as a 2 mL dose of the drug product (150 mg / mL). The 300 mg dose is preferably administered subcutaneously via injection of 2 mL of drug product (15 The drug is administered subcutaneously via a single injection of 0.0 mg / mL.

[0202] In one embodiment (see FIG. 2C, 1), the mAb1 treatment regimen comprises two doses. A loading dose consisting of two doses of 600 mg mAb1 administered one week apart; followed by maintenance dosing consisting of 150 mg mAb1 administered every 2 weeks (Q2W). The 600 mg dose preferably comprises two doses of 2 mL of drug product (150 mg / mL). It is administered subcutaneously via injection. The 150 mg dose is preferably administered in 1 mL of drug product (150 Instead, 2 mL of the drug product (75 mg / mL) was administered via a single injection of 1:2 diluted The drug is administered subcutaneously via a single injection of 100 mg / mL.

[0203] In another embodiment (see FIG. 2C, 2), the mAb1 treatment regimen comprises 600 mg of A loading dose consisting of a first administration of 300 mg mAb1 and a second administration of 300 mg mAb1 ( where the second dose is administered one week after the first dose) and then every two weeks thereafter (Q2 W) maintenance dosing consisting of administration of 150 mg mAb1 administered at a dose of 300 mg. is preferably administered subcutaneously via a single injection of 2 mL drug product (150 mg / mL). The 600 mg dose is preferably administered as two injections of 2 mL of drug product (150 mg / mL). The 150 mg dose is preferably administered subcutaneously via injection into a 1 mL drug product (150 ml Instead, 2 mL of the drug product (75 mg / mL) was administered via a single injection of 1 / 2 diluted The drug is administered subcutaneously via a single injection of 100 mg / mL.

[0204] In yet another embodiment (see Figure 2C, 3), the mAb1 treatment regimen comprises 6 The loading dose consisted of a first dose of 0.00 mg mAb1 and a second dose of 150 mg mAb1. drug (wherein the second dose is administered one week after the first dose), followed by every two weeks Maintenance dosing consisted of administration of 150 mg mAb1 administered Q2W. The dose is preferably administered via a single injection of 1 mL of drug product (150 mg / mL). Instead, the drug was administered subcutaneously via a single injection of 2 mL of half-diluted drug product (75 mg / mL). The 600 mg dose is preferably administered twice as a 2 mL dose of the drug product (150 mg / mL). The 300 mg dose is preferably administered subcutaneously via injection of 2 mL of drug product (15 The drug is administered subcutaneously via a single injection of 0.0 mg / mL.

[0205] The advantage of having a treatment regimen separated into a loading and maintenance dosing portion is that it provides optimal The aim of this study is to enable a more effective treatment.

[0206] For all treatment regimens described herein, the goal of the loading dose is to achieve target saturation (4 0 μg / mL plasma concentration), and therefore the onset of therapeutic effect, The purpose of sustained dosing is to provide sustained efficacy.

[0207] Example 5. Human Safety and Tolerability Data The safety, tolerability, PK and PD activity of mAb1 were evaluated in healthy subjects and in patients with rheumatoid arthritis (RA). An ongoing, randomized, double-blind, placebo-controlled study of mAb1 in patients with It is being evaluated in a single ascending dose study of 100 mg / kg / day ... Thirty-six healthy subjects received a single dose of mAb1 up to 3 mg / kg (IV or SC) and 12 patients with RA (6 of whom received a single dose of 10 mg / kg (IV) Overall, the results showed that the mAb1 doses up to 3 mg / kg in healthy volunteers were Single doses of up to mAb1 and a single 10 mg / kg mAb1 in RA patients were safe. The treatment was overall and well tolerated, with no suspected serious adverse events (SAEs). A study of the 30 mg / kg (IV) dose is ongoing in RA patients. As treatment is still ongoing, all clinical data are preliminary in nature and may be of limited use in RA patients. The findings are based on an interim analysis of doses up to 10 mg / kg in

[0208] Example 6. Human Pharmacokinetics and Pharmacodynamics (Healthy Volunteers and Rheumatoid Arthritis Patients) In healthy subjects and patients with rheumatoid arthritis after a single IV or SC administration, CFZ5 33 The PK profile was consistent with target-mediated elimination, with CD40 receptor occupancy If decreased below approximately 90%, non-linear PK profile and more rapid clearance was brought about.

[0209] Although there was some interindividual variability in the PK profile from Chinese subjects, The elimination of CFZ533 in Chinese subjects was generally similar to that in non-Chinese subjects, with Target engagement after 1 / kg(IV) CFZ533 was similar (approximately 4 weeks). The plasma free CFZ533 profile, free CD40 and total CD40 at each dose level The CD40 occupancy rate on peripheral B cells and the total CD40 concentration in plasma were measured. A similar PK / PD profile was observed.

[0210] Following SC administration in healthy subjects, CFZ533 was rapidly absorbed and exhibited bioavailability characteristics typical of humans. The distribution was consistent with that expected for a typical IgG1 antibody. CFZ533 generally peaked 3 days after dosing (7 days in two subjects). After one week of dosing, plasma concentrations were in the same range as after IV dosing. , the duration of target engagement was still approximately 4 weeks.

[0211] In patients with rheumatoid arthritis receiving 10 mg / kg (IV), whole blood As measured by free CD40 on B cells and total sCD40 profile in plasma At 30 mg / kg (IV), sufficient CD40 occupancy was generally maintained for 8 weeks. K and plasma total sCD40 profiles were consistent with the 16-week period of target engagement. I was doing it.

[0212] In healthy subjects, CD40 engagement by CFZ533 increased the expression of free C on B cells. Tracking CD40 occupancy on B cells as measured by CD40 generally reveals that peripheral This resulted in approximately a 50% reduction in total CD40 on B cells upon binding to CFZ533. This is likely due to internalization and / or shedding of membrane-bound CD40. No reduction in total CD40 on peripheral B cells was observed in patients with rheumatoid arthritis.

[0213] CFZ533 in plasma and CD40 occupancy on whole blood B cells (free CD40 on B cells) The relationship between the concentration of CFZ533 and whole blood B cells was revealed. was associated with adequate (defined as ≥ 90%) CD40 occupancy.

[0214] More generally, non-specific and specific elimination pathways have been identified for CFZ533. The nonspecific high-capacity pathway mediated by the FcRn receptor generally involves the uptake of endogenous I Specific target-mediated elimination of CFZ533 is consistent with subsequent lysosomal CFZ is partially internalized (with inflammasome degradation) and / or shed from the membrane The target-mediated process resulted in the formation of CFZ533-CD40 complexes. The formation of CFZ533-CD40 complexes was associated with a dose-dependent and nonlinear elimination of The effect was concentration-dependent, with saturation occurring at high concentrations of CFZ533.

[0215] Overall, the disappearance of CFZ533 contributed approximately 100% to the total clearance of CFZ533. Depends on the relative contribution of specific (target-mediated) and non-specific elimination pathways. CFZ53 When the 3 concentration was lower than the target concentration, a nonlinear PK behavior was observed, whereas the CD40 receptor At concentrations higher than receptor saturation, the nonspecific pathway prevails and CFZ533 is eliminated. It was linear.

[0216] A typical IgG1 antibody that targets a membrane-bound receptor and shows target-mediated elimination As expected, the extent of CFZ533 exposure (AUClast) decreased more rapidly with increasing dose than with increasing dose. Thus, this is consistent with the results of the study, which showed that the CFZ533 This is predicted to be associated with a decrease in the volume of distribution and clearance of

[0217] One subject received 1 mg / kg (IV) CFZ533 (1 week, sufficient CD40 occupancy) The results showed that the plasma concentration of CFZ533 was quantifiable. It is necessary to ensure that the CD40 pathway is below the threshold and blocks any CD40 pathway-related effects in tissues. Anti-drug antibodies (ADA) in this subject were detected 6 weeks after the initial The presence of ) did not impair exposure and was not associated with immune-related safety signals. This corresponds to a 2% incidence of ADA in this study.

[0218] A single dose of CFZ533 at 3 mg / kg (IV and SC) was well tolerated (≥90%). At the CFZ533 concentration corresponding to the total body occupancy rate, the anti-KLH reaction to the first KLH immunization was The primary anti-KLH response was suppressed temporarily (approximately 3 to 4 weeks) at CFZ533 concentrations was detected in all subjects, with a concomitant decrease in receptor occupancy. , and a second KLH immunization (administered after the predicted loss of receptor occupancy) The reaction was then initiated.

[0219] Data show that CD40 engagement by CFZ533 is enhanced by recombinant CFZ533 in human whole blood. These results suggest that it prevents human CD154 (rCD154)-mediated B cell activation. rCD154-induced CD69 expression on B cells generally corresponds to sufficient CD40 occupancy on B cells. The functional activity of rCD154 was suppressed during the period of CD40 occupancy. Sexuality was restored.

[0220] There was no evidence of any effect of CFZ533 on the immunophenotyping data.

[0221] Example 7. CFZ533, a blocking, non-cell-depleting anti-CD40 monoclonal antibody Characterization of in vitro and in vivo properties 1. Method Surface plasmon resonance analysis of the affinity of CFZ533 for CD40 Binding analysis of recombinant CFZ533 was performed using HBS-EP+ as running buffer for 2 h. A typical binding assay cycle involves three steps: (i) immobilizing the antibody on the chip surface; (ii) capture of the antibody via a specific protein A, and (iii) binding of the captured anti-CD40 antibody to the CD40 antibody. 40 antigen binding, and (iii) regeneration of the protein A surface. To determine the kinetic rate constant of the binding interaction, double-reference the response from a blank injection. Binding curves were analyzed using the Biacore T100 Evaluati The kinetic rate constants were locally fitted using the 1:1 interaction model in the ON software. The equilibrium dissociation constant (KD) was calculated as the ratio of the rate constant kd / ka. All binding measurements were performed in two independent experiments.

[0222] Surface plasmon resonance analysis of the affinity of CFZ533 for FcγRIIIA 4-amino acid purification tag (4APP; Novartis) and Avi biotin-labeled tag ( Human FcγRII tagged with GLNDIFEAQKIEWHE (Avidity) Geneart the extracellular domain of IA: human FcγRIIIA (CD16a) 158V (Uniprot: P08637, 17-199), human FcγRIIIA 158F( Uniprot: P08637, 17-199) and incubated in HEK293 cells. The receptor was expressed in Escherichia coli and purified using anti-4APP affinity chromatography. Bis-linked to a leptoavidin sensor chip (General Electric) Equilibrium binding of different Abs using site-specific biotin labeling with rA (Avidity) Levels were measured using surface plasmon resonance (T100, General Electric) as described. The equilibrium dissociation was analyzed by electrochemical analysis (Warncke et al. 2012). Constant (K D ) was calculated using a 1:1 model.

[0223] Human leukocyte culture Whole blood buffy coats were collected from healthy volunteers (Blutspendezentrum, Basel, Switzerland) or Swiss Human Resea Nordworch Act and the Ethics Committee (Ethikkommission Nordworch) In accordance with the approval of the European Commission (EKNZ), Human tonsillar was obtained from whole blood collected from healthy volunteers who provided informed consent. Peach samples were obtained from Ergolz Klinik (Liestal, Switzerland) Research Protocol No. 1000244 v.03;Ethikkommission b eider Basel; approved by EKBB) and Kantonspit al (Liestal, Switzerland) (research protocol no. TRI014 9 v.01; approved by EKNZ). For detailed methods, please see the supplementary materials. Briefly, whole blood was isolated. PBMCs, in vitro derived monocytic DCs or human tonsillar B cells were used at a single concentration or The cells were incubated with increasing amounts of CFZ533 or appropriate control antibodies. These cultures were treated with an EC80 concentration of recombinant human CD154 (5 μg / ml) and I The in vitro assay readout included thymidine L-4 (75 ng / ml). Import ( 3 H-TdR), and expression of the activation molecule CD69 on B cells. Current flow cytometry-based assessment and cytokines assessed by ELISA Similar assays were used for NHP whole blood and PBMCs. In some human whole blood experiments, fluorescently tagged CFZ533 was used to identify CD40 receptor markers. Body occupancy was also examined. Where appropriate, GraphPad Prism® software was used IC50 values ​​were estimated using curve fitting based on linear regression in

[0224] In vitro cell depletion assay See supplementary material for detailed methods. Briefly, CFZ533 binds CD2 0 pos The ability of IL-1 to mediate B cell depletion was compared to the B cell depleting antibody rituximab after 3 days. CDC was monitored in human whole blood over a period of 10 days. Rituximab was incubated with RAJI B cells in the presence or absence of rabbit complement. Cell lysis was assessed by luminescence.

[0225] Internalization of CFZ533 Internalization of fluorescently tagged CFZ533 and rCD154 was measured in the human B cell line RI- 1 (Th'ng et al., 1987) was used to evaluate in vitro. 3. CD40 Dependence of Internalization was Assessed Using the CD40 Knockout RI-1 Cell Line Internalization was monitored using an Amnis® Image flow cytometer according to the manufacturer's instructions. image flow cytometer (Merck KHaA, Dar The data were evaluated using ImageStream® X Sof The data were analyzed using software.

[0226] In vivo studies A single-dose pharmacokinetic / pharmacodynamic (PK / PD) study was conducted in subjects aged 7.5–8.5 years (6.5 ± 2. 6kg) from Siconbrec, Makati City, Philippines Biologic-naïve cynomolgus monkeys (Maca fascicularis) bred in captivity in the Pines The handling, care, medication and blood of the animals were Fluid collection is carried out in accordance with the Swiss Federal Law on Animal Welfare ( Animal License BS #1900, BS#1495). For recall immunization experiments, The inventors are affiliated with Covance Laboratories GmbH, Muenster The study used animals from a toxicity study conducted in Germany (manuscript in preparation). , in strict compliance with national legal regulations regarding animal welfare laws and recognised animal welfare standards. The procedures were performed in accordance with the approved study protocol and local standard operating procedures.

[0227] In PK studies, CFZ533 had 16.2 (5532), 18.5 (5531) and 2 Three animals were administered a calculated single dose of 0 (5530) mg / kg. 3 Serum concentration, peripheral T and B lymphocyte counts, and CD4 on peripheral B cells by CFZ533 For the recall TDAR experiment, animals were placed in the study Alum on days 8 (priming) and 43 (recall; during CFZ533 treatment), respectively. The mice were immunized with keyhole limpet hemocyanin (KLH) in the presence of 100 mM NaCl. Sera were collected 1 day before and 7, 14, and 21 days after immunization with Cole. The gM / IgG titers were measured using cynomolgus monkey anti-KLH IgM / IgG standard serum as a standard. PK evaluation was performed as described above. For additional details of the PK and TDAR experiments, please see the Supplementary Material.

[0228] Histological analysis of germinal centers Formalin-fixed, paraffin-wax-embedded (FFPE) spleen and lymph nodes (axillary Sections of the nasal cavity (fossa, mandible and mesentery) were stained with hematoxylin and eosin and the following markers: Anti-CD20 antibody (M0755, Dako), anti-CD8 antibody (RM-9116-SO, Me Indirect immunoperoxidase using Ki67 (M7240, Dako) and Ki67 (M7240, Dako) All slides were evaluated and stained according to the staining method (HRP+DAB by Dako). In addition, all immunohistochemical staining in the tissues was graded according to intensity (negative to strong). The staining pattern and distribution of stained cells was also described.

[0229] 2.Results CFZ533 binds human CD40 and induces rCD154 in multiple CD40-expressing cell types Inhibits sexual activation. Table 2 shows the KD of CFZ533 for recombinant human CD40 by surface plasmon resonance. The antibody titer was determined to be 0.3 nM, and thus is comparable to the wild-type IgE of its parent antibody HCD122 (CFZ533). gG1 version).

[0230] [Table 2]

[0231] FIG. 3A shows human whole blood cultures from multiple donors (5, 32, and 6 donors, respectively). , rCD154- and IL-4-mediated proliferation of PBMC and isolated tonsillar B cells (3H- The effect of CFZ533 on TdR is shown. Data are shown as normalized cpm. (rCD154+IL-4=100; dotted line). Figure 3B shows that CFZ533 inhibited the IL-4 expression of CD154 after overnight culture. Figure 3C shows that rCD154-stimulated moDCs suppressed TNF-α production. We found that delayed addition of CFZ533 inhibited rCD154+IL-4-mediated proliferation of human PBMCs. 1 hour before, at the same time, or 2 and 6 hours after stimulation with rCD154+IL-4. CFZ533 was then added to human PBMCs, and proliferation (3H-Td R) was evaluated (dotted and dashed lines represent rCD154+IL-4 and cell+medium controls). For all data, the mean and SD of rCD154-induced stimulation readings are The results are plotted as a function of log-transformed CFZ533 concentration. IC50 values ​​were reported where appropriate. , determined using a linear regression-based curve fit. The relationship between 0 occupancy and pathway blockade is shown. Human whole blood from 10 donors was treated with escalating doses of CFZ5. The degree of pathway activation (%CD on B cells) was measured by incubation with rCD154 overnight in the presence of 33. 69pos) and the degree of CD40 occupancy (CFZ533 with AlexaFlour 488 labeling The white and black circles indicate the Cs occupied by CFZ533, respectively. The proportion of D40 and the proportion of CD69pos expressing cells on CD20pos B cells were calculated using logarithmic The results are shown as a function of the CFZ533 concentration converted (mean and SD are shown). rCD154-induced CD69 expression and cells + media normalized across all donors Control cultures are represented.

[0232] Figure 3A shows that CFZ533 inhibits the expression of IgG in human whole blood cultures, PBMCs, and purified IgG from multiple donors. The rCD154-induced proliferation of tonsillar B cells was measured using 0.024 μg / ml (0.16 nM), 0.017 μg / ml (0.12 nM) and 0.071 μg / ml (0.47 nM). The inventors further demonstrated that CFZ completely inhibited the NF-α signaling pathway with a potency (IC50 value) of 100 μM. 533 inhibited rCD154-induced TNF production by primary monocyte-derived dendritic cells (moDCs) We were able to demonstrate complete inhibition with an IC50 of 0.04 μg / ml (0.27 nM). It arrived (Figure 3B).

[0233] As previously reported, CFZ533 inhibits rCD1 expression in PBMCs from cynomolgus monkeys. 54-induced proliferation (Cordoba et al., 2015). 3. rCD154-induced augmentation of PBMCs from humans, rhesus monkeys, and cynomolgus monkeys The proliferation of the 20-kDa β-lactams was inhibited with similar potency (IC50 of 0.02, 0.03, and 0.01 μg / ml, respectively). and had an EC50 value of approximately 0.2 μg / ml with CD40 on B cells from these species. (See Table 3).

[0234] [Table 3]

[0235] The above cell data shows that CFZ533 was added before or simultaneously with rCD154. These results were obtained from experiments carried out using the antibody, which showed that it was able to block the binding of endogenous ligands. We also found that up to 6 hours after initiation of leukocyte cultures containing rCD154 Addition of CFZ533 at 100 ng / mL resulted in complete inhibition of cell activation with minimal loss of titer. We were able to demonstrate that CFZ533 releases endogenous ligands from CD40. This shows that it can be removed and replaced (Figure 3C).

[0236] We have demonstrated a relationship between the degree of CD40 occupancy by CFZ533 and the degree of pathway inhibition. To do so, we have developed a method to assess the relationship between genomic DNA fragments from multiple donors. In whole blood, CFZ533-induced CD40 receptor occupancy and rCD154-induced CD6 9 were evaluated simultaneously. Figure 3D shows that CFZ533 inhibited at least 90% of the CD40 receptor Receptor occupancy was required for complete blockade of CD40 pathway activation. A similar relationship between occupancy and pathway inhibition was observed in CD23 and CD40 as readouts of pathway activation. and CD54 (data not shown).

[0237] CFZ533 exhibits minimal stimulatory potential in vitro The ability of CFZ533 to stimulate activation of human leukocytes was examined by measuring activation of B cells in whole blood. The proliferation and upregulation of the molecule CD69 were evaluated. Figure 4A shows data on i. Human whole blood from multiple donors (n=13) was infused with escalating doses of CFZ533. After incubation, the cells were grown for 3 days ( 3 ii. Multiple donors Human PBMCs from 144 patients (n=26) were incubated with increasing doses of CFZ533 and cultured in 1000 mL of 1 ... After 3 days of incubation, the growth 3 H-TdR) was evaluated. For both graphs, the data were The mean and SD of normalized cpm are shown as a function of log-transformed CFZ533 concentration. (rCD154+IL-4=100; dotted line, cells+medium=0; dashed line). Showing that CFZ533 does not induce human PBMC proliferation in the presence of additional stimuli. BMC were administered at 200 mg / kg in the presence of IL-4 (i) or anti-IgM F(ab')2 (ii). Stimulation with increasing doses of CFZ533 for 3 days. Mean and SD of 3H-TdR (cpm) are shown as logarithmic plots. In Figure 4C, human whole blood (41 donors) is shown as a function of CFZ533 concentration. However, no stimulation, no CFZ533 stimulation, no isotype control stimulation, or no rCD154 stimulation were performed overnight. How were they cultured and how CD69 expression on B cells was assessed by FACS? Each point represents data from a single donor, and the mean %CD69 values ​​are Indicated by a flat red line.

[0238] FIG. 4A shows that CFZ533, in contrast to rCD154, inhibits the expression of rCD154 in human whole blood (1:10 dilution) or CFZ533 was not able to induce thymidine incorporation by PBMCs. The inability to induce was abrogated by the addition of additional costimulatory substances such as IL-4 or anti-IgM. The inventors found that CFZ533 was also in contrast to rCD154. Conversely, we were unable to induce upregulation of CD69 on B cells in whole blood from multiple donors. Finally, we were able to demonstrate that CFZ533 inhibited the expression of CD40 in Cytokine production by monocyte-derived DCs or human umbilical vein endothelial cells (HUVECs) could not be induced (data not shown).

[0239] CFZ533 does not mediate cell depletion CFZ533 is a marker that blocks FcγR binding and is unable to mediate antibody-dependent cellular cytotoxicity (ADCC). The antibody was engineered to contain the N297A mutation, which has previously been shown to result in the absence of CFZ533 binds FcγRIIIA and (Table 4) and we hypothesize that this lack of binding is due to the fact that CFZ533 is unable to bind to cells. We wanted to see how this might affect their ability to mediate depletion.

[0240] [Table 4]

[0241] FIG. 5A shows the effect of CFZ533 at 72 h in the presence of escalating doses or 50 μg / ml rituximab. Data are shown from human whole blood cultures incubated for 1 h. B cell counts were determined using lymphocyte FS Determined based on CD45pos and CD19pos events falling within the C / SSC gate The results for individual antibody concentrations were compared with the residual B cell counts for untreated samples. (percentage) and graphed as a function of log-transformed antibody concentration (10 (The values ​​were corrected to 0% and shown as dotted lines.) Data are the mean and SD of eight independent donors. FIG. 5B shows the results of the analysis of the CFZ533-Rituximab and rabbit complement inhibitors at different concentrations. Results from Raji B cells incubated with IgG are shown. Viable death was analyzed after 2 hours, where cell viability was determined using luciferase The results were measured as a function of the log-transformed antibody concentration. and expressed as relative luciferase units (RLU) normalized to isotype control. show.

[0242] Figure 5A shows that the depleting anti-CD20 antibody rituximab inhibits approximately 80% of B cells in human whole blood. was able to eliminate CFZ533, whereas CFZ533 failed to mediate any cell depletion. Furthermore, in contrast to rituximab, CFZ533 inhibited the proliferation of Raji B cells. were unable to mediate complement-dependent cytotoxicity (CDC) (Fig. 5B ).

[0243] CFZ533 is internalized by B cells in a CD40-dependent manner We next investigated whether CFZ533 inhibits C-terminal endothelial cell proliferation in the human B cell line RI-1. We wanted to examine whether it could be internalized by D40. rCD154 was internalized under permissive conditions (37°C) compared to nonpermissive conditions (4°C). Here, we show that weak staining of rCD154 could be observed on the plasma membrane. CFZ533 was also internalized, but there did appear to be residual membrane staining at 37°C. FIG 6B shows that the extent of rCD154 internalization was significantly greater than that observed for CFZ533. We showed that CD40 knockout RI-1 Using B cell lines, CFZ533 (Figure 6C) and rCD154 (data not shown), It could be demonstrated that binding and internalization of is CD40 dependent.

[0244] FIG. 6A shows the results of the analysis of rCD154 or CFZ533 labeled with AlexaFlour 488. Representative images of individual RI-1 B cells cultured together for 3 h at 37° C. or 4° C. are shown. 6B. Relative internalization erosion of CFZ533 and rCD154 under permissive conditions (non-permissive erosion) Each point represents data from an individual experiment, and the population mean is Figure 6C. Alexa488-labeled CFZ533 at 37°C. Representative images of individual CD40-expressing or CD40-knockout RI-1 cells cultured for 3 h at 4°C. In all experiments, cells were incubated with AlexaF Co-staining was performed with lour 647-labeled CD45.

[0245] Pharmacokinetic properties of CFZ533 in non-human primates Figure 7A.16.2 (5532), 18.5 (5531) and 20 (5530) mg / k CFZ in three cynomolgus monkeys after single-dose administration at the calculated dose of 1000 mg (intravenous) 533 serum concentration. Figure 7B. CD40 occupancy: Available CD40 (percent) (i (ii) C. Peripheral B / T cells: Peripheral blood B cells after a single dose Day 0 is when CFZ533 was administered.

[0246] The data above show that CFZ533 binds to NHP CD40 and inhibits rCD1 in NHP B cells. 54-induced activation was inhibited with similar potency to that of the cytoplasmic β-lactamase inhibitor 54. In vivo study in horse and rhesus monkeys to investigate the relationship between CFZ533 PK and PD The data in Figure 7A suggest that CFZ533 may be a suitable species for single intravenous Three crabeaters after intravenous administration (calculated doses of 16.2, 18.5 and 20 mg / kg) The PK profile of the monkey is shown. This is typical of monoclonal antibodies (Mager et al. 2006 and Ng et al. 2010). 006), the time course of CFZ533 concentration showed a clear target-mediated loss of activity, with a nonlinear P The PK profile and concentration-dependent clearance rate and half-life were obtained. The inflection point observed in the profile is a marker of target engagement and is This is associated with an increased contribution of CD40 to the overall clearance of Z533 and a shorter half-life. Furthermore, the inflection point in the PK profile corresponds to the time at which a decrease in CD40 saturation is observed. This was consistent with the results shown in Fig. 7B, i, which indicates that CFZ533 was more rapidly eliminated. In all animals, CD40 receptors on cells were detected There was no loss of somatic expression (Figure 7B, ii). Furthermore, CFZ533 was Despite some observed variability throughout, no significant differences were observed in peripheral blood B cells (Figure 7C) or T cells ( (data not shown) was not depleted.

[0247] CFZ533 inhibits recall T cell-dependent antibody production Figure 8A shows the experimental design for evaluating the effect of CFZ533 on recall TDAR. A schematic diagram is shown. Arrows below the x-axis highlight primary and secondary KLH immunizations. Single dose The timing of administration of 10 mg / kg CFZ533 is shown above. Asterisks indicate anti-KLH The time points at which IgG and / or CFZ533 concentrations were measured are shown in FIG. Anti-KLH IgG (filled symbols) and plasma CFZ533 concentrations (logarithmic scale) for each animal The mean anti-KLH IgG levels from control animals (open symbols) are shown for comparison. Figure 8C. CFZ533 at 1 mg / kg / week subcutaneously Germinal centers (Ki67) in mLN from rhesus monkeys obtained from repeated dosing (26-week study) Histological analysis of the staining. Representative mLN sections from six animals are shown in (i) control images, (ii) nascent images, (iii) histological images, (iv) histological images, (v) histological images, (vi ... ii). iii. Average steady-state C over the dosing period from individual animals at the end of the treatment period The results are shown together with FZ533 serum concentrations.

[0248] The predicted targeted PD effect of CD40 blockade is inhibition of TDAR (Kawabe et al. 1994). CFZ533 was a potent marker for the expression of IFN-γ in NHPs and humans. Next we inhibit TDAR and examine the effect of this antibody on TDAR recall. We also hoped to study the effect of oxidative stress on the function of the oxidative stress pathway in the pulmonary circulation. The experimental design is outlined in Figure 8A. The subjects received a single intravenous dose of CFZ533 at 10 mg / kg on Study Day 1 and On day 1 (priming), the mice were immunized with KLH in Alum, followed by a second immunization on day 15 of the study. 2 KLH immunizations were performed.

[0249] FIG. 8B shows the results of the immunized control (without CFZ533) and the control (without CFZ533) in each of the four animals. We show the effect of CFZ533 on anti-KLH IgG recall responses compared with the data from The PK profile of CFZ533 showed interanimal variability, with animals #1 and #2 showing A more rapid clearance of CFZ533 was observed in animals #2 and #3. Higher plasma concentrations were observed for longer periods. Interestingly, these animals Complete suppression of anti-KLH IgG (and IgM; data not shown) recall responses at 15 days (It was noted that all animals initiated primary TDAR to KLH. In contrast, animals with more rapid clearance of CFZ533 (compared to animal #1) In animal #3, the serum CFZ533 concentration was significantly higher than that of the second KLH immunization. If the anti-KLH IgG response is less than approximately 40 μg / ml at the time of vaccination, (albeit with a delay of 100 years) was observed. 5) and non-transplanted (Figure 7B) animals. As observed in previous studies, peripheral B cell depletion was not observed (data not shown).

[0250] The above results indicate that complete inhibition of recall TDAR in NHPs requires approximately 40 μg / mL The present inventors have demonstrated that CFZ533 serum concentrations greater than 1 ml are required for CFZ533 therapy. To further explore the relationship between Z533 exposure and CD40 pathway-related tissue pharmacodynamic effects At the end of a 26-week toxicity study with CFZ533 (subcutaneous) at 1 mg / kg / week, We performed histological and molecular analysis of GC in mesenteric lymph nodes (mLN). FIG. 8C(i) shows that the present inventors found that 3 out of 6 animals administered We could observe complete suppression of GC in the mLN of the remaining animals, whereas the mLN of the remaining animals was still suppressed. Figure 8C(iii) shows that GC was observed at a plasma concentration of at least 38 μg / mL. Serum concentrations (average steady-state concentrations over the dosing period) in the cortical B cell regions of lymph nodes was accompanied by complete suppression of GC development, whereas whole blood CD20 pos Sufficient C on B cells Despite D40 occupancy (animals 26842 and 26772; data not shown), GC Incomplete inhibition (animal 26842) or no inhibition (animals 26772 and 26837) were observed in 2 The results show that the IL-18-related inflammatory bowel disease was observed at serum concentrations of <0 μg / mL. There was no evidence of peripheral B cell depletion. There was no (data not shown).

[0251] Consideration CFZ533 inhibits solid organ transplantation and It is being developed as a potential treatment for autoimmune diseases. Functional characterization of CFZ533 in CD40 pathway-related in vitro and in vivo model systems To describe the characteristics and explore the relationship between CFZ533 exposure and PD efficacy.

[0252] CFZ533 binds CD40 and expresses CD40 on various human immune cell types, including B cells and DCs. Furthermore, CFZ533 was able to completely block rCD154-induced pathway activation in requires >90% CD40 occupancy to completely block pathway activation in whole blood Taken together, these data suggest that once sufficient receptor occupancy is achieved, We hypothesize that CFZ533 may mediate CD40 pathway-dependent effector functions regardless of cell type. Our data suggest that CFZ may be able to block inflammatory responses in PBMCs. 533 displaces prebound rCD154 from CD40 We also demonstrated that the epitopes of the mAb and physiological ligands may overlap. suggesting that this is a concept that is still in the exploration stage in structural research.

[0253] Single-dose PK studies demonstrated that CFZ533 exhibited concentration-dependent clearance in vivo The PK profile was consistent with that observed in patients with CD40 receptor expression who had a CFZ This suggests that low CFZ533 concentrations (i.e. incomplete clearance of In the CFZ533 ELISA, the contribution of CD40 to the overall clearance of CFZ533 was increased and the half The decline time was somewhat shorter than that typically observed for IgG1-type antibodies. At higher concentrations, corresponding to total (and full functional pathway inhibition), CFZ533 cleared This limited the receptor's contribution to the overall response and increased the half-life of CFZ533. Clearance was observed in vitro in relation to the CD40-mediated internalization of CFZ533 ( This was consistent with subsequent lysosomal degradation of the complex.

[0254] Additional findings from PK / PD studies demonstrated that CFZ533 can deplete peripheral B cells in vivo. As mentioned above, the CFZ The inability of 533 to deplete CD40-expressing cells is due to N-linked glycosylation within the hinge region. to cause the loss of FcγRIIIA binding or to mediate ADCC or CDC. This is due to the presence of the N297A mutation in the antibody, which prevents it from mediated by CD40-expressing cells. The broad tissue distribution of this receptor on immune and non-immune cell types, especially under inflammatory conditions, is of particular interest. To prevent depletion of Fc (which is thought to be a factor in the pathogenesis of CFZ533), we performed Fc-silencing of CFZ533.

[0255] In addition to its efficacy in NHP kidney transplantation (Cordoba et al. 2015), The results in the literature showed that CFZ533 completely inhibited recall TDAR. These results suggest that memory B cell responses to T cell-dependent antigens are related to the CD40-CD154 The extent of inhibition of recall responses was significantly dependent on the interaction between the CF and The effect appears to be related to the concentration of Z533, which is 30–40% (at least 1 week after the boost). Serum levels of >μg / ml are required for sufficient suppression of antigen-specific antibody responses. This relationship between serum concentrations and tissue PD readouts related to the CD40 pathway was consistent with the association of mesenteric phosphorylation with This was also applied to investigate the effect of CFZ533 on nodal GC, where the mean steady-state A minimum threshold of total serum CFZ533 concentration was required for complete inhibition of GC. The data provide insight into peripheral drug exposure and target-related PD in tissues to inform dosing strategies. These results point to the importance of establishing the relationship between the effects of the CD40-CD154 costimulatory pathway. Several biologics targeting thrombosis are being developed for various autoimmune diseases. Despite the possible risk of thrombosis (Boumpas et al., 2003), In addition to anti-CD40 mAbs such as FZ533, anti-CD154 mAbs continue to be used in clinical trials. Recent results have demonstrated that Fc silencing and PEGylated F(ab')2 approaches can mediate the expression of CD1 These results suggest that the thromboembolic tendency of antibodies targeting 54 can be eliminated. However, there are reports that Fc-silent anti-CD154 mAbs may be less effective. To date, there have been adverse reactions associated with the administration of several anti-CD40 antibodies in preclinical models or in clinical trials. There is no evidence of thromboembolism.

[0256] In conclusion, our data indicate that CFZ533 has minimal agonistic properties. Demonstrated to be a pathway-blocking, non-cell-depleting anti-CD40 antibody. Sufficient and pharmacologically relevant exposure CFZ533 completely inhibits recall TDAR without depleting CD40-expressing cell types These data support the preclinical efficacy of EGFR-1 in kidney transplantation. Clinical trials of CFZ533 in selected autoimmune diseases and solid organ transplantation, in combination with This study provides a solid scientific rationale for the potential clinical benefits.

[0257] Example 8. CD40 Pathway Inhibition and Hidradenitis Suppurativa Analysis of skin samples from human HS patients showed that, compared to healthy skin, the target of CFZ533 ( CD40) and its ligand (CD40LG) at both the RNA and protein levels. Furthermore, experiments have shown that CD40 expression is abundant in the major components of skin (keratinocytes). In cell types that constitute the dermal tumour cells (i.e., sarcoidocytes and dermal fibroblasts), disease-associated cytokines (TNFR) F, IFNG) and subsequent CD40LG induction We show that the signaling pathway of HS is reflected in tertiary germinal centers. Lymphoid tissue-like structures were formed in the affected tissues, and autoantibodies were detected in the sera from HS patients. Taken together, this evidence supports the idea that the CD40 pathway is active and that CD40 pathway inhibition is disease-associated and therefore may benefit HS patients This suggests that...

[0258] 1. Materials and Methods Transcriptomics Transcriptomic analysis of 19 HS skin biopsies versus 8 healthy skin biopsies It was obtained as follows: from flash frozen skin tissue, using a Qiagen RNeasy mini kit. Homogenates were prepared using the buffers recommended by the manufacturer. The cDNA of the samples was extracted from the same starting amount of RNA using Hi gh capacity cDNA reverse transcription K The samples were prepared using CiTo Affymetrix HG_U133_Plus2 was identified by xLAB France. The data were processed using the microarray. The RMA-normalized data were then analyzed using GeneSpring 11.5.1(Agilent Technologies,Santa Clara ,CA) and the results were analyzed using Illumina BaseSpace Correlation. Interpretation was performed using the Qiagen IPA and the ELISA engine software. First, the data were subjected to standard QC controls by CiToxLAB and to GeneSpri ng (PCA, hybridization control). This was then used for further analysis. A prognosis greater than the 20th percentile in 100% of samples in any one of the preceding conditions The subset was screened for expression levels.

[0259] To generate a list of differentially expressed genes, unpaired t-test and Benjamin i p < 0.05 was used for Hochberg FDR to evaluate the significance of the differences between groups (i.e., healthy Probe sets with greater than 2× and significant differences in the markers (lesions vs. tumors) were selected.

[0260] Organizational Diagnosis Twenty-seven skin biopsies (16 lesional and 11 non-lesional) from 11 HS patients and healthy controls were included. Three skin biopsies from healthy volunteers were included in a non-interventional biomarker study (EKNZ As part of the TRI1270397 approved by the University Hospital al Basel,Department of Plastic,Reconstru ctive&Aesthetic Surgery and Hand Surgery (Basel, Switzerland).

[0261] Paraffin sections of 3 μm thickness were cut and stained with CD40 (polyclonal rabbit anti-CD40 antibody). Body:E3702,Lot:130507MD,Spring Bioscience,U SA) and CD40L (polyclonal goat anti-CD40 ligand / TNFSF5:AF6 17,Lot:BFW0314021,R&D,UK), Ventana XP Staining was performed using an immunohistochemistry apparatus (Roche Diagnostics, Switzerland). In addition, CD3 (clone: ​​SP7, NeoMark) was used to stain T cells. ers Inc., USA), CD20 for B cells (clone L26, Dako, D enmark), CD68 for macrophages (clone KP-1, Dako, De Specific isotype controls were used as negative controls. All biopsies were recorded using a ScanScope XT slide with a ×20 or ×40 objective. Scanner (Aperio, Leica Biosystems, Switzerland) The images were digitized using the Digital Imaging System (DIS) (DIS 10000).

[0262] 2.Results Analysis of HS transcriptomes from patients and comparison with levels in non-diseased or healthy tissues The mRNA message levels of both CD40 and CD40LG in HS lesions were The results are shown in Figure 9, where CD40 (Figure 9A) and CD40L (Figure 9B) The expression intensity of was clearly stronger in HS lesion samples than in HS non-lesion samples and healthy samples. I understand.

[0263] As shown in Figure 10, immunohistochemical staining revealed that the tertiary lymphoid tissue-like structures containing germinal centers CD20 positive B cells in the dermis and CD68 positive macrophages (including multinucleated giant cells) in the dermis Furthermore, CD40L staining was predominantly Germinal centers of tertiary lymphoid tissue-like structures (where CD3 (T cell marker) staining was observed) ) The scale bar indicates 100 μm.

[0264] In data not shown, the inventors have demonstrated that TNF and IFN-γ (both of which Using cytokines such as keratinocytes and epidermal cells, which are also abundant in the lesions of HS patients, CD40 mRNA (by RT-PCR) and protein (FA We found that CD40LG stimulation could induce the expression of CS. Subsequent transcriptomic analysis of cells stimulated in this way demonstrated that HS-lesioned tissues We also showed upregulation of genes that were elevated in the control group.

[0265] Additional data (not shown) indicate that HS patients have elevated levels of autoantibodies, This suggests that the increased numbers of CD40 positive B cells and ectopic germinal centers may have functional significance for patients. It indicates that it has.

[0266] Thus, the disclosed CD40 antagonists and compounds according to any one of the embodiments The compound (such as CFZ533) can be used in vitro, ex vivo, or The compositions can be incorporated into pharmaceutical compositions and administered in vivo to treat HS patients (e.g., human patients). can be treated.

[0267] 3. CD40 pathway inhibition A recent Cochrane review of controlled HS trials The median duration of treatment was 16 weeks (Ingram et al 2016). A similar placebo-controlled phase 2 study was conducted with adalimumab, which was recently approved for the treatment of HS. This was also the period of the study (Kimball et al 2012), but another placebo-controlled trial The study was conducted in a very similar HS population with a maximum duration of 24 weeks (Tzanetakou et al., 2013). t al 2016). Placebo treatment may have some effect on the disease. This may be due to natural history, regression to the mean effect, or other factors that may be due in part to concomitant drug therapy. reflects the more stringent clinical management of subjects. Short-term (<2 weeks) antibiotics (for skin infections) if medically justified If medically justified, subjects may be , and will be eligible for additional treatment (according to standard of care) during the safety follow-up period. If the lesion requires incision or limited excision for relief, this will be acknowledged and recorded. The information must be recorded.

[0268] HS subjects, who exhibit a hyperinflammatory state likely accompanied by high CD40 expression, therefore Iscalimab was administered sc in conditions where CD40 expression in the blood is likely to be elevated. If this is the case, a loading phase is warranted to overcome the efficient CD40-mediated elimination of iscalimab. It will be turned into.

[0269] This has been demonstrated in study CCFZ533X2203 in pSS subjects. In cohort 1 of that study (sc regimen; data not shown), most subjects , possibly in the interstitium, lymphatic capillaries and / or lymph nodes, before being circulated throughout the body. Lower than expected PK profile due to D40-mediated elimination The figure shows the results.

[0270] The CD40 receptor has been reported to be upregulated in the parenchyma in inflamed tissues. Therefore, elevated levels of CD40 receptors may be a key factor in efficient CD40 uptake before iscalimab is distributed throughout the body. 40 This is likely the origin of target-mediated elimination. Iscalimab is not subject to target-mediated elimination. If the CD40 receptor is not fully saturated, increased CD40 expression may be a predictor of iscalimab Associated with high exclusion rates.

[0271] In HS subjects, the 600 mg sc weekly regimen during the loading period was This is expected to provide rapid and complete blockade of the CD40-CD40L pathway in targeted tissues. do.

[0272] In study CCFZ533X2203, the sc regimen was administered in cohort 2 (v regimen (data not shown), and To demonstrate that iscalimab had the ability to overcome CD40-mediated elimination Cohort 3 was enrolled: 4 doses of 600 mg sc weekly (loading), followed by 9 doses 300 mg sc weekly (maintenance; data not shown). Preliminary data suggest that This regimen was shown to be safe and well tolerated.

[0273] During the maintenance phase of the study disclosed in Example 9 (Day 43 (Week 7) to Day 99 (Week 15)) Iscalimab will be administered at 600 mg sc every other week (Q2W; 5 doses). .

[0274] The 600mg Q2W maintenance regimen was designed to achieve a steady-state trough blood plasma concentration of approximately 160-170μg / mL. The plasma concentrations of 100 mg / kg / day of CCF in pSS subjects were predicted to be 100 mg / kg / day (Figure 11). Z533X2203-Cohort 2 (10 mg / kg IV regimen) In study CCFZ533X2203-Cohort 2, 100-120 μg Steady-state iscalimab trough plasma concentrations of 0.001 mg / mL were Clinical improvement of disease activity indicators and biologically relevant biomarker CXCL13 (chemokine Clinical efficacy, such as inhibition of in-CXC ligand 13 protein (a marker of germinal center activity) was accompanied by.

[0275] HS (deep skin nodules / tumors (in skin with apocrine glands) and abscesses) In the case of follicular dermatosis accompanied by psoriasis, the tissue penetration of iscalimab is key, and it is more effective than pSS. It is likely that these drugs will require greater plasma exposure.

[0276] 4.Hidradenitis suppurativa HS primarily affects the skin in the axillary, groin, submammary, genito-anal and perineal areas of the body. Three diagnostic criteria establish the diagnosis of HS: Typical lesions (initial first lesions are deep painful nodules [mouthless] swellings) primary or secondary lesions include abscesses, draining sinuses, connected scars, and "tombstone" open comedones); typical Typical tissue distribution (axilla, groin, genitals, perineum and perianal area, buttocks and submammary and breast and chronicity and relapse (Margesson and Danby (2014) The physical extent of HS is determined by the Hurley clinical stage classification (Hurley 2006), shown in Table 2 below. To classify patients at baseline using Ley's clinical staging This can be done.

[0277] [Table 5]

[0278] HS consists of follicular plugs, ductal disruption, and secondary inflammation. Patients first experience blockage of the ducts, which over time leads to leakage of the ducts and horizontal tears into the dermis. If repair of the hair follicle-pilosebaceous gland (FPSB) fails, hair follicle fragments may initiate the HS disease process. The first is the inflammatory response triggered by the innate immune system. The second reaction is inflammation and tissue destruction, resulting in a foreign body reaction and extensive scarring. The response is stem cells derived from FPSB units that survived the destruction caused by the inflammatory response. The third type of inflammatory cell-containing gastrointestinal tract is the epithelium-lined sinus, which may arise from the inflammatory process. In most cases, an invasive proliferative gelatinous mass consisting of granules occurs, as described above. It is hypothesized to be a precursor of the encrusted elements (Margesson and Danby (20 14). As used herein, the phrase "slowing HS disease progression" refers to " slows the progression of any of the above-mentioned aspects of the HS disease process, especially the inflammatory response. In some embodiments of the present disclosure, treatment with an anti-CD40 antibody reduces HS Slows disease progression.

[0279] Recurrences of HS in patients include papules, pustules or inflammatory nodules, pain and pruritus, abscesses, As used herein, "H" refers to the development of purulent discharge, purulent purulence, and any combination thereof. "S erythema" (etc.) is abscess and inflammatory lesions with minimal increase in 2AN over baseline. Defined as at least a 25% increase in nodule number (AN).

[0280] In some embodiments of the present disclosure, treatment with an anti-CD40 antibody according to the disclosed methods provides Preventing S erythema, reducing the severity of HS erythema, and / or reducing the frequency of HS erythema In some embodiments, when a population of HS patients is treated according to the disclosed methods, Less than 5%, 10%, 15%, or 20% of patients experienced erythema during the first 16 weeks of treatment. Try it.

[0281] As used herein, the phrase "reducing the severity of HS erythema" and the like refers to reducing the severity of HS erythema. Reducing the intensity of plaques, e.g., the number and / or size of abscesses and / or inflammatory nodules reducing the intensity of certain erythema components (e.g., abscesses and / or It reduces the number, size, thickness, etc. of inflammatory nodules, and reduces skin irritation (itching, pain, etc.) The extent to which the erythema (or its components) persists It means to decrease the amount.

[0282] As used herein, the phrase "reducing the frequency of HS erythema" and the like refers to reducing the frequency of HS erythema. reducing the incidence of abscesses and / or inflammatory nodules; By reducing the frequency of HS flares, patients will experience fewer HS recurrences. The incidence of erythema was assessed by monitoring patients over time to see if the prevalence of erythema decreased. It can be evaluated by making a judgment.

[0283] As used herein, the phrase "preventing HS erythema" refers to preventing future HS erythema and and / or excludes the erythema component.

[0284] The efficacy of HS treatment can be assessed by a variety of known methods for measuring HS pathology and / or HS clinical response. Some examples include, for example, Hurley et al. Stage classification, severity assessment scoring system (SAHS), Sartorius stage Core, modified Sartorius score, HS Physician Global Assessment (HS-PGA) score, skin A visual analogue scale (VAS) or a numeric rating scale ( NRS), Dermatology Life Quality Index (DLQI), H based on the sum of abscesses and inflammatory nodules S Clinical Response (HiSCR), Simplified HiSCR, EuroQuol-5D (EQ5D), Disease Scales of anxiety and depression in the causes, medical resource utilization, Hidradenitis Suppurativa Severity Index (HSSI), Work Productivity Index (WPI), Inflamed Body Surface Area (BSA), Acne Severity Index (AISI) ) (For example, Deckers and Prens (2016) Dru gs 76:215-229;Sartorius et al.(2009)Br.J .Dermatol 161:831-39;Chiricozzi et al.(2 015) See Wounds 27(10):258-264. In an embodiment, the efficacy of the methods disclosed herein is evaluated using a HS Physician Global Rating (HS- PGA), severity assessment score (SAHS), score numerical rating scale (NR S), Dermatology Life Quality Index (DLQI), and HS clinical outcomes based on the sum of abscesses and inflammatory nodules. The results can be evaluated by HiSCR and / or simplified HiSCR. In general, the efficacy of the HS treatments disclosed herein is based on the combined H The clinical response can be assessed by the HiSCR and / or the simplified HiSCR.

[0285] In some embodiments, HS patients achieve HiSCR in response to HS treatment. In some embodiments, a population of HS patients may experience at least at least 30%, at least 40%, at least 50%, at least 60% or at least 70% achieve HiSCR by week 16 of treatment.

[0286] In other embodiments, the efficacy of the HS treatments disclosed herein is measured by the 16th week of treatment. , the proportion of responders among treated patients (i.e., to HS treatment with the compounds of the present invention) , patients achieving a HiSCR response) and the proportion of responders in placebo-treated patients In some embodiments, the difference between the The difference in the proportion of responders when is also 30% or at least 35%.

[0287] The preferred scoring system for treatment response is the HiSCR, simplified HiSCR, or N RS (especially NRS30), Severity Assessment Scoring System (SAHS), HS-PGA , inflammatory lesion count (number of abscesses, inflammatory nodules and / or draining fistulas) and DLQI.

[0288] The Hidradenitis Suppurativa Clinical Response (HiSCR) is a measure of clinical response to HS treatment. The HiSCR response to treatment (compared to baseline) was as follows: 1) abscess and at least a 50% reduction in inflammatory nodules, and 2) no increase in the number of abscesses, and 3) no increase in the number of abscesses. No increase in the number of fistulas. R' is a modified version that does not include abscess counts relative to baseline when assessing disease progression. In a preferred embodiment, the HS patient has a simple HiSCR in response to the HS treatment. In some embodiments, a population of HS patients achieves SCR according to the disclosed methods. If treated, at least 40%, at least 50%, at least 60% or 70% achieve simplified HiSCR by the 16th week of treatment.

[0289] Pain can be assessed using a numeric rating scale (NRS). In embodiments, HS patients achieve an improvement in NRS in response to HS treatment. NRS30 is At least 30% reduction in pain in patients with a baseline score of 3 or greater A small difference from baseline in the Patient Global Assessment (PGA) of cutaneous pain from baseline In some embodiments, the HS patient is treated with HS and is defined as a decrease of at least one unit in the HS response rate. In some embodiments, a population of HS patients responds to the disclosed At least 25%, at least 30%, at least 40% when treated according to the method At least 50% or at least 60% will achieve NRS30 by the 16th week of treatment. In a preferred aspect of this embodiment, a population of HS patients is treated according to the disclosed methods. At least 30% of patients achieve NRS30 by the 16th week of treatment. In some embodiments, in response to treatment according to the claimed methods, patients experience a decrease in serotonin levels as early as one week after the first dose. Afterwards, patients experience a rapid reduction in pain as measured by VAS or NRS.

[0290] The Symptom Assessment Scoring System (SAHS) was developed by Hessam S and Scholl. As described by L, Sand M, et al (2018), the severity of HS is To this end, the following items can be assessed by the SAHS score: Number of areas treated (left axilla, right axilla, left submammary, right submammary, intermammary or chest, abdomen, mons pubis, Left groin, right groin, genitals, perianal or perineal area, left buttock, right buttock and other areas [e.g., cervical (front, back, ear) and the number of inflammatory and / or painful lesions other than fistulas (ILOF) and the number of fistulas These physician-rated items were then supplemented by two patient-reported items. Patients were asked to report the number of new tumors or flares of existing tumors in the past 4 weeks. The patient is asked about the number and frequency of activities during a range of daily activities (e.g., sitting, moving, or working). The current severity of pain in the most symptomatic lesion was assessed on a numeric rating scale (NRS). The SAHS score is a composite score of all the collected information above. Mild cases of S are defined by a SAHS score of 4 or less. Moderate S is defined by a SAHS score of 5-8. severe cases of HS were defined by a SAHS score of ≥ 9. will be done.

[0291] In some embodiments, the HS patient achieves an improvement in SAHS score in response to the HS treatment. In some embodiments, the HS patient responds to the HS treatment by achieving a SAHS score of In another embodiment, the HS Patients were required to respond to HS treatment by achieving an increase of at least 2 points from baseline in their SAHS score. Preferably, the SAHS score is reduced by at least 3 points. , was at least 4 at baseline before treatment with anti-CD40 antibodies.

[0292] The DLQI is the most established dermatological quality of life measure. It measures It consists of questions about the impact of the skin condition on emotions and other aspects of daily living activities. The questions are scored from 0 (not at all) to 3 (very much). 0 points is the maximum score, where 0-1 means no impact on the patient's life, 2 means no impact on the patient's life, and ~5 is small, 6~10 is medium, 11~20 is very large, and 21~30 is very large. is considered to be a very large effect (Finlay and Khan (1994) in Exp Dermatol 19:210-16). In embodiments, HS patients achieve an improvement in DLQI in response to HS treatment.

[0293] In some embodiments, in response to treatment according to the claimed methods, a patient may experience as little as a first After one week of dosing, CRP levels were measured using either a standard CRP assay or a high-sensitivity CRP (hsCRP) assay. As used herein, "C-reactive protein" and and "CRP" stands for serum C-reactive protein, an indicator of the acute phase response to inflammation. CRP is a plasma protein commonly used in the treatment of diabetes. CRP levels can be expressed in various indicators. Standard assays, such as radial immunodiffusion, electroimmunoassay, immunoturbidimetric assay, ELISA A. It can be measured by turbidimetry, fluorescence polarization immunoassay and laser nephelometry. Testing for CRP can be done using standard CRP tests or high-sensitivity CRP (hs-CRP) tests. P) test (i.e., using laser nephelometry to measure low levels of CRP in a sample) A highly sensitive test (which can detect CRP levels) can be used. Kits are available from various companies, such as Calbiotech, Inc., Cayman Chem. ical, Roche Diagnostics Corporation, Abazy me, DADE Behring, Abnova Corporation, Aniar a Corporation, Bio-Quant Inc., Siemens Hea It can be purchased from ithcare Diagnostics, etc.

[0294] The Sartorius HS score (also called the HS score or HSS) is The lesions are scored by counting the affected areas, nodules and sinus tracts in the sarcoma. torius et al.(2003)Br J Dermatol 149:211 The modified Sartorius HS score has some simplifications that make it more practical to use. simplification, e.g., including fewer specific lesions in the score, This is a revised version of the original HSS by making changes to the number of points that can be obtained ( In some embodiments, the HS patient achieves improved modified Sartorius HS in response to HS treatment.

[0295] The HS Physician Global Assessment (HS-PGA) is a HS lesion (i.e., abscess, drainage fistula, inflammatory small intestine, etc.) A 6-item rating scale (score range 0-5) based on the number of nodules (nodules and non-inflammatory nodules) It is. (Kimball AB,Kerdel F,Adams D et al A dalimumab for the treatment of moderate to severe hidradenitis suppurativa:a par allel randomized trial.Ann Intern Med 20 12;157:846-855). In some embodiments, the HS patient is refractory to the HS treatment. In response, improved modified HS-PGA is achieved. In some embodiments, the HS patient is A reduction of at least 2 points from baseline in HS-PGA score in response to treatment Preferably, the HS-PGA score is at least 0.05 mg / kg / day before treatment with the anti-CD40 antibody. There was at least a 3 in the line.

[0296] In some embodiments, when a population of HS patients is treated according to the disclosed methods, Patients who responded to treatment by Week 16 (e.g., HiSCR or simplified HiSCR by Week 16) At least 40%, at least 50%, at least 60%, or at least 70% of patients achieving CR At least 70%, at least 80%, or at least 90% are still alive 3 months after the end of treatment, or Responses were sustained 6 months after the end of treatment or 12 months after the end of treatment. In another embodiment of the present invention, patients who have responded to treatment by week 16 (e.g., patients who have HiS by week 16) are At least 40% or at least 50% of patients who achieve CR or simplified HiSCR Response was sustained 3 months after the end of treatment. Preferably, response was achieved by week 16. The number of patients who achieved HiSCR or simplified HiSCR by week 16 was low. At least 70% maintained a response 3 months after the end of treatment. The term "sustained" refers to the fact that an outcome or goal (e.g., pain relief, inflammation reduction) continues for a given period of time. This means that the standard is substantially maintained.

[0297] Lesion-associated pruritus can be assessed by patient surveys. Patients were asked to rate their itching from 0 (no itching) to 10 (worse itching possible). In some embodiments, a population of HS patients is treated according to the disclosed methods. In this case, the pruritus score is improved by at least 2 points, preferably by at least 3 points. Furthermore, when comparing with the placebo group, the difference between the treated group and the placebo group is at least It's 3 points.

[0298] The odor caused by the drainage of the lesion can be assessed by a patient survey. Patients were asked to rate the odor caused by the drainage of the lesion from 1 (no odor), 2 (a little odor), Participants were asked to rate the odor from 3 (moderate odor) to 4 (severe odor). In one embodiment, when a population of HS patients is treated according to the disclosed methods, the pruritus scores are: At least 1 point improvement, preferably at least 2 points improvement. When comparing the difference between the treated and placebo groups, the difference is at least 1 point.

[0299] The impact of HS on the ability to complete tasks can be assessed by patient surveys. Patients were asked to rate the extent to which HS affected their ability to complete tasks from 1 (not at all) to Please rate it on a scale of 2 (a little), 3 (moderately), 4 (a lot) and 5 (not able to work at all). In some embodiments, a population of HS patients is treated according to the disclosed methods. If so, the pruritus score should be at least 1 point, preferably at least 2 points. Furthermore, when compared to the placebo group, the difference between the treated and placebo groups was small. At least one point.

[0300] Example 9. Efficacy and safety of CFZ533 drug in patients with moderate to severe hidradenitis suppurativa A randomized, subject- and investigator-blinded, placebo-controlled study to evaluate efficacy and safety. Multicenter study Provided below is a clinical trial to demonstrate the efficacy of the anti-CD40 antibody CFZ533. These are design details.

[0301] By blinding the subjects and investigators, the number of HS lesions or the total HS-PGA score were This will enable unbiased evaluation of subjective readings such as adverse events and outcomes.

[0302] Several studies, including the anti-CD40 antibody CFZ533, have been reported in subjects with moderate to severe HS. Randomized, controlled trials were conducted to evaluate the efficacy, safety, and tolerability of the active therapeutic compound. A multicenter, investigator-blinded, placebo-controlled, parallel-group study will be conducted. After the cleaning period, a 16-week treatment period was planned, with approximately 12 weeks of safety follow-up. Subjects were subsequently treated with iscalimab, 600 mg (2 mL injections; weekly, then (every other week) (sc) or its corresponding placebo (2 × 2 mL) (sc) .

[0303] Subjects included in this study had to have been diagnosed with recurrent inflammatory lesions for at least 12 months. The subjects of this study were adult men and women aged 18 to 65 years with moderate to severe HS. The requirement for inclusion in the study was that subjects had at least five inflammatory lesions. Line evaluations were performed on the first day of treatment to allow for completion of evaluations on Day -1 prior to treatment on Day 1. Treatment can begin on day 7. All baseline safety assessments are available prior to dosing. Randomization will be centralized. This is done using an interactive response technology (IRT) system.

[0304] The primary clinical outcome measure chosen will be the simplified HiSCR (Hidradenitis Suppurativa Clinical Trials Response) score after 16 weeks of treatment. reaction).

[0305] On Day 113 (Week 17), after safety and other evaluations were performed, all subjects If medically justified, and if not, will undergo a follow-up period in which the patient is free of any medication. If no potential safety concerns are identified (after discussion with the sponsor), the subject During the follow-up period, patients will be able to receive medication that was previously prohibited.

[0306] Safety and efficacy evaluations were performed at follow-up on Day 141 (Week 21) and Day 197 (Week 29). Follow-up visits will be conducted. Pharmacokinetics (PK) and pharmacodynamics (PD) will be collected. Blinding of the animals will be maintained until study end. End-of-Study Visit on Day 197 (Week 29) (This will include an evaluation at the completion of the study and subsequent release from the study).

[0307] Approximately 45 subjects will be randomized to 30 active and 15 placebo. Day 1 The patients were randomly assigned to receive 600 mg of iscalimab or a matching placebo (2 mL injections) in a 1-week period. The drug will be administered by subcutaneous injection (sc) by on-site personnel. Clinical evaluation and PK, PD, IG, Biomarker and safety assessments will be performed. Subjects will be Subjects will be released from the facility on the condition that there are no health concerns. After the first dose, subjects will Immediate injection site reactions were monitored at the facility for at least 1 hour, or longer at the investigator's discretion. It should be observed.

[0308] The subjects were those who were examined on the 8th (2nd week), 15th (3rd week), 22nd (4th week) and 29th ( Week 5) 600 mg iscalimab (same as received on day 1) or matching placebo The subjects then returned to the study center to receive weekly sc doses of

[0309] After the fifth week, subjects were examined on days 43 (week 7), 57 (week 9), and 71 (week 11). , 600 mg every other week on days 85 (Week 13) and 99 (Week 15; final dose) Received sc iscalimab.

[0310] Safety and selected efficacy assessments were performed during these visits and were reviewed in a PK / PD / IG / BAC format. Iomarker samples are collected.

[0311] The primary objective was to evaluate the efficacy and safety of anti-CD40 antibody C compared with placebo in subjects with HS after 16 weeks of treatment. The objective of this study was to demonstrate the preliminary efficacy of treatment with FZ533. After a 16-week treatment period, the efficacy persistence was To observe whether the survival potential could be maintained or increased after 16 weeks of treatment, A follow-up period of one week will be included.

[0312] Based on the fact that subjects have limited exposure to the placebo while choosing exposure to the active ingredient A 2:1 randomization will be planned based on the randomized control group.

[0313] This study will include multiple clinical trials to better characterize these selected endpoints. Includes evaluation items.

[0314] The primary outcome of this study was the simplified HiSCR (Kimball 2014). The simplified HiSCR was selected without any increase in draining fistulas. is defined as a 50% reduction in the total number of abscesses + inflammatory nodules.

[0315] Inflammatory lesions of HS are characterized by discrete lesions (inflammatory nodules, abscesses, and In addition to the count, a comprehensive assessment scale (Hidradenitis suppurativa - Physician Overall score or HS-PGA) and composite score (Hidradenitis Suppurativa Severity Assessment Score or S AHS) is used.

[0316] Several patient-reported outcomes were reported, including the Dermatology Life Quality Index (DLQI). Finally, from the subject's perspective, skin-related pain is the most important symptom, and pain is A numeric rating scale (NRS) for each symptom is included.

[0317] 1. Additional information regarding clinical evaluation: HS-PGA (Hidradenitis Suppurativa - Physician Global Assessment): This score is used to assess HS. Used for exploratory purposes, Kimball AB, Kerdel F, Adams D, et al (2012).

[0318] The SAHS score is a composite score (Hessam S, Scholl L, San d M, et al (2018)), inflammatory lesion count, fistula count, and NRS pain score In addition, the anatomical area and any new or recurrent existing tumors are identified. Collected in both cohorts.

[0319] Cutaneous Pain - NRS (Numeric Rating Scale for Pain): NRS for skin-related pain RS has been used in adalimumab studies (Kimball et al. (2 016), and skin or HS-related pain is one of the greatest burdens for patients (Mat This is used because of the findings of the study (Usiak et al. (2017)). Pain is recorded as the average for the past 24 hours and at its worst (in the past 24 hours).

[0320] Other patient-reported outcomes (PROs) included pruritus, fatigue, and work disability. Modalities and quality of life in skin diseases using validated scores available in many countries and languages These include the Skin Disease-Related Quality of Life Index (DLQI) and Skin Disease-Related Quality of Life (QoL) tools. Patient global assessment is included.

[0321] 2. Research objectives and evaluation items

[0322] [Table 6]

[0323] [Table 7]

[0324] 3. Main Selection Criteria - 18-65 years of age with clinically diagnosed HS at least 12 months prior to screening Men and subjects A total of at least 5 inflammatory lesions, i.e. abscesses and / or inflammatory nodules, and At most 10 fistulas, and At least two anatomical regions must be involved with the HS lesion. Subjects must have a minimum weight of 50kg (inclusive)

[0325] 4. Main Exclusion Criteria At the time of screening or within 30 days or 5 half-lives after registration or until the predicted pharmacodynamic effect has returned to baseline (whichever is longer); or longer periods of study drug use if required by local regulations. -IL such as ustekinumab or guselkumab within the past 6 months prior to randomization / first treatment 12 and the use of IL23-blocking biologics. - B-cell-targeting or B-cell-depleting chemotherapy, such as rituximab or belimumab, within 12 months use of anti-inflammatory drugs or similar; for patients who received these drugs earlier, B cell counts Must be within normal range. Randomization / 3 months or 5 half-lives (whichever is longer) prior to first treatment Biologic immunomodulators other than those listed above (e.g., adalimumab, secukinumab, etanercept use of rifabutin, infliximab, etc.; Use of rituximab or belimumab within the last 12 months; Any systemic treatment for HS (e.g., retinoids or other) in the past 4 weeks prior to randomization immunomodulatory therapy (e.g. methotrexate, cyclosporine A, corticosteroids) use. Use of cyclophosphamide within the past 6 months Use of systemic antibiotics for HS in the past week prior to randomization / first treatment Spironolactone or other antiandrogens (e.g. finasteride, cyproterone acetate) If used (for HS), a stable dose must be used for the past 3 weeks and continued for the duration of the study. Only patients who are planned to undergo treatment with EDTA were eligible. Surgical treatment for HS in the past 4 weeks prior to randomization / first treatment. Surgical treatments include: This does not include excisional biopsies of tumors. Receipt of any high-infusion corticosteroid bolus (>1mg / kg) within 3 months the law of nature

[0326] 5.Treatment The investigational drug, iscalimab, and its matching placebo were licensed by Novartis. The drugs will be prepared in a double-blind drug treatment kit and delivered to the research facility. Requirements and details regarding administration of study treatment, as well as subject numbering, prescription / dispensing and The instructions to be followed for the adoption of research treatments are given in the Site Operations Manual. This is summarized in the Pharmacy Manual.

[0327] For iscalimab, the drug dosage form supplied is “CFZ533 Concentrate for Injection (BA).” It is a "ready-to-use" aqueous, sterile buffer solution also known as a "liquid in a vial." The solution contains 150 mg / ml iscalimab and the excipients L-histidine, sucrose, and and polysorbate 20 (pH 6.0 ± 0.5). The placebo control is a solution containing a matching composition of inert excipients.

[0328] Subjects were randomized to receive iscalimab, 600 mg (2 mL injections; weekly, then every other week) (s .c.) or their matching placebo (2 × 2 mL) (sc).

[0329] Subjects will be randomized in a 2:1 ratio to the investigational treatment arm or its matching placebo. The treatment period will not exceed 16 weeks.

[0330] Enumeration of embodiments 1. A method for treating hidradenitis suppurativa in a human subject, comprising administering a therapeutically effective dose of CD40 administering to said subject an antagonist.

[0331] 2. CD40 antagonists are a) an immunoglobulin VH domain comprising the amino acid sequence of SEQ ID NO: 7 and an immunoglobulin VH domain comprising the amino acid sequence of SEQ ID NO: 8 an anti-CD40 antibody comprising an immunoglobulin VL domain comprising an amino acid sequence; b) Immunoglobulins comprising the hypervariable regions depicted as SEQ ID NO:1, SEQ ID NO:2 and SEQ ID NO:3. globulin VH domain and the high-density an anti-CD40 antibody comprising an immunoglobulin VL domain containing a frequency variable region; c) an immunoglobulin VH domain comprising the amino acid sequence of SEQ ID NO: 7 and an immunoglobulin VH domain comprising the amino acid sequence of SEQ ID NO: 8 and an anti-CD31 antibody comprising an immunoglobulin VL domain having the sequence of SEQ ID NO: 13 and an Fc region having the sequence of SEQ ID NO: 14. 40 antibodies, d) an immunoglobulin VH domain comprising the amino acid sequence of SEQ ID NO: 7 and an immunoglobulin VH domain comprising the amino acid sequence of SEQ ID NO: 8; and an anti-CD31 antibody comprising an immunoglobulin VL domain having the sequence of SEQ ID NO: 14 and an Fc region having the sequence of SEQ ID NO: 15. 40 antibodies, and e) Anti-CD40 antibodies containing silent Fc IgG1 regions 2. The method of embodiment 1, wherein the anti-CD40 antibody is selected from the group consisting of:

[0332] 3. The antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 9 and a light chain amino acid sequence of SEQ ID NO: 10, or The embodiment comprises a heavy chain amino acid sequence of SEQ ID NO:11 and a light chain amino acid sequence of SEQ ID NO:12. 3. The method of treatment according to claim 1 or 2.

[0333] 4. The antibody is administered subcutaneously or intravenously, or a combination of subcutaneously or intravenously; 2. The method according to any of the above embodiments.

[0334] 5. The antibody is administered at a dose of about 3 mg to about 30 mg of active ingredient per kilogram of human subject. 20. The method of any of the above embodiments, wherein the administration is

[0335] 6. The dosage is about 10 mg of active ingredient per kilogram of human subject, embodiment 5. The method according to

[0336] 7. The antibody is about 150 mg to about 600 mg of active ingredient, for example about 300 mg of active ingredient. 2. The method of any of the above embodiments, wherein the administration is

[0337] 8. Doses are 150 mg active ingredient, 300 mg active ingredient or 600 mg active ingredient 8. The method of embodiment 7, wherein

[0338] 9. The method of any of the above embodiments, wherein the antibody is administered in a loading dose and a maintenance dose. Law.

[0339] 10. The loading dose is administered via subcutaneous injection of a first dose and the maintenance dose is administered via subcutaneous injection of a second dose. 10. The method of embodiment 9, wherein the dose is administered via subcutaneous injection.

[0340] 11. The first dose is from about 150 mg to about 600 mg of the active ingredient, for example about 300 mg. and the second dose is from about 150 mg to about 600 mg of the active ingredient, e.g., about The method of embodiment 10, wherein the amount is 300 mg of active ingredient.

[0341] 12. The first dose is 150 mg, 300 mg, or 600 mg of active ingredient, and The second dose is 150 mg, 300 mg, or 600 mg of active ingredient. The method according to

[0342] 13. The loading dose includes at least two subcutaneous injections and the maintenance dose is weekly (Q1W ), every other week (Q2W) or every month (Q4W) by subcutaneous injection. The method according to any one of the above.

[0343] 14. The method of embodiment 13, wherein at least two subcutaneous injections of the loading dose are of different doses. Method of posting.

[0344] 15. The method of any of the above embodiments, wherein the antibody is administered with one or more pharma- ceutically acceptable carriers. Any method as described above.

[0345] 16. Patients meet the following criteria: a) Patients have moderate to severe HS, b) the patient is an adult; c) the patient is an adolescent; d) Patients have an HS-PGA score of ≥ 3 prior to treatment with a CD40 antagonist. , e) Patients must have at least three inflammatory lesions prior to treatment with a CD40 antagonist. and / or f) The patient did not have extensive scarring as a result of HS prior to treatment with the CD40 antagonist. (<10 fistulas) 3. The method according to any of the above embodiments, wherein the method is selected according to one of the following:

[0346] 17. The patient has, by week 16 of treatment, one of the following: a) Simple HiSCR, b) Reduction in HS erythema, c) NRS30, d) a decrease of ≦6 as measured by DLQI, and / or e) Improve DLQI 4. The method according to any of the above embodiments, wherein the method achieves at least one of the following:

[0347] 18. When used to treat a population of patients with moderate to severe HS, At least 40% of patients achieve a simplified HiSCR by week 16 of treatment. The method according to any one of the above aspects.

[0348] 19. When used to treat a population of patients with moderate to severe HS, In one embodiment, at least 25% of patients achieve an NRS30 response by week 16 of treatment. The method according to any one of claims 1 to 11.

[0349] 20. When used to treat a population of patients with moderate to severe HS, The method of any of the above embodiments, wherein less than 15% of patients experience HS erythema during 16 weeks of treatment. Method of posting.

[0350] 21. The patient will be treated with a CD40 antagonist for at least 16 weeks, 2. The method according to any of the above embodiments.

[0351] 22. Patients will receive one of the following as early as one week after the first dose of CD40 antagonist: a) a rapid reduction in pain as measured by VAS or NRS, and b) A rapid decrease in CRP as measured using a standard CRP assay 4. The method according to any of the above embodiments, comprising at least one of:

[0352] 23. The patient will be evaluated for inflammatory lesion counts, hidradenitis suppurativa clinical response (HIDR) 3 months after the end of treatment. iSCR), Numeric Rating Scale (NRS), Modified Sartorius HS Score, Suppuration Hidradenitis Glandularis-Physician Global Assessment (HS-PGA) or Dermatology Life Quality Index (DLQI) The method of any of the above embodiments, wherein the method achieves a sustained response as measured by

[0353] 24. The patient is assessed by simplified HiSCR (sHiSCR) 3 months after the end of treatment. 24. The method of embodiment 23, which achieves a sustained response as measured.

[0354] 25. Anti-CD40 antibodies, buffer solutions, for the manufacture of medicines for the treatment of hidradenitis suppurativa Use of a liquid pharmaceutical composition comprising a stabilizer and a solubilizer and administering an anti-C to a patient with hidradenitis suppurativa A means for subcutaneously administering an anti-CD40 antibody, comprising: a. A first loading dose, b. Thereafter, a second maintenance dose is administered subcutaneously, wherein the anti-CD40 antibody is An immunoglobulin VH domain comprising the amino acid sequence of SEQ ID NO: 7 and the amino acid sequence of SEQ ID NO: 8 an anti-CD40 antibody comprising an immunoglobulin VL domain comprising the sequence Immunoglobulins comprising the hypervariable regions depicted in SEQ ID NO:1, SEQ ID NO:2 and SEQ ID NO:3 Brin VH domain and the frequent nucleotide sequences depicted as SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6. an anti-CD40 antibody comprising an immunoglobulin VL domain comprising a variable region; An immunoglobulin VH domain comprising the amino acid sequence of SEQ ID NO: 7 and the amino acid sequence of SEQ ID NO: 8 Anti-CD40 comprising an immunoglobulin VL domain comprising the sequence and an Fc region of SEQ ID NO: 13. antibody, An immunoglobulin VH domain comprising the amino acid sequence of SEQ ID NO: 7 and the amino acid sequence of SEQ ID NO: 8 Anti-CD40 comprising an immunoglobulin VL domain comprising the sequence and an Fc region of SEQ ID NO: 14. antibody, an anti-CD40 antibody comprising a silent Fc IgG1 region, and The heavy chain amino acid sequence of SEQ ID NO: 9 and the light chain amino acid sequence of SEQ ID NO: 10 or SEQ ID NO: 11 An anti-CD40 antibody comprising a heavy chain amino acid sequence and a light chain amino acid sequence of SEQ ID NO:12. The use and means are selected from the group consisting of:

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Cordoba F,Wieczorek G,Audet M,Roth L,Sch neider MA,Kunkler A et al.A novel,blocki ng,Fcsilent anti-CD40 monoclonal antibod y prolongs nonhuman primate renal allogr aft survival in the absence of B cell de pletion.Am J Transplant 2015;15(11):2825 . Deckers IE,Kimball AB(2016)The Handicap of Hidradenitis Suppurativa.Dermatol Cli n p.17-22. Dessinioti C,Zisimou C,Tzanetakou V,et a l(2016)Oral clindamycin and rifampicin c ombination therapy for hidradenitis supp urativa:a prospective study and 1-year f ollow-up.Clin.Exp.Dermatol.p.852-857. Esmann S,Jemec GB(2011)Psychosocial impa ct of hidradenitis suppurativa:a qualita tive study.Acta Derm.Venereol.p.328-32. Fimmel S,Zouboulis CC(2010)Comorbidities of hidradenitis suppurativa(acne invers a).Dermatoendocrinol p.9-16. Garg A,Wertenteil S,Baltz R,et al(2018)P revalence Estimates for Hidradenitis Sup purativa among Children and Adolescents in the United States:A Gender- and Age-A djusted Population Analysis.J.Invest.Der matol.. Giuseppe P,Nicola P,Valentina C,et al(20 18)A Case of Moderate Hidradenitis Suppu rativa and Psoriasis Treated with Secuki numab.Ann Dermatol p.462-464. Hessam S,Scholl L,Sand M,et al(2018)A No vel Severity Assessment Scoring System f or Hidradenitis Suppurativa.JAMA Dermato l p.330-335. Ingram JR,Woo PN,Chua SL,et al(2016)Inte rventions for hidradenitis suppurativa:a Cochrane systematic review incorporatin g GRADE assessment of evidence quality.B r.J.Dermatol.p.970-8. Janse IC,Deckers IE,van der Maten AD,et al(2017)Sexual health and quality of lif e are impaired in hidradenitis suppurati va:a multicentre cross-sectional study.B rJDermatol.p.1042–1047. Jemec GB(2012)Clinical practice.Hydraden itis suppurative.N.Engl.J.Med.p.158-64. Jemec GB,Kimball AB(2015)Hydradenitis su ppurative:Epidemiology and scope of the problem.J.Am.Acad.Dermatol.p.S4-7. Jorgensen AR,Yao Y,Thomsen SF(2018)Thera peutic Response to Secukinumab in a 36-Y ear-Old Woman with Hidradenitis Suppurate iva.Case Rep Dermatol With p.8685136. Canni T, Zenker O, Habel M, et al(2018)Comp lement activation in hydradenitis suppur ativa:a new pathway of pathogenesis?Br.J .Dermatol. Kawabe T, Naka T, Yoshida K, Tanaka T, Fujiw ara H,Suematsu S et al.The immune response ses in CD40-deficient mice:impaired immun noglobulin class switching and germinal center formation.Immunity 1994;1(3):167-167. 178. Kelly G,Sweeney CM,Tobin AM,et al(2014)H idradenitis suppurativa:the role of immu ne dysregulation.Int.J.Dermatol.p.1186-9 6. Kimball AB,Kerdel F,Adams D,et al(2012)A dalimumab for the treatment of moderate to severe Hidradenitis suppurativa:a par allel randomized trial.Ann.Intern.Med.p. 846-55. Kimball AB,et al(2014)Assessing the vali dity,responsiveness and meaningfulness o f the Hidradenitis Suppurativa Clinical Response(HiSCR)as the clinical endpoint for hidradenitis suppurativa treatment.B ritish Journal of Dermatology 171,p.1434 -1442. Kimball AB,Okun MM,Williams DA,et al(201 6)Two Phase 3 Trials of Adalimumab for H idradenitis Suppurativa.N.Engl.J.Med.p.4 22-34. Lima AL,Karl I,Giner T,et al(2016)Kerati nocytes and neutrophils are important so urces of proinflammatory molecules in hi dradenitis suppurativa.Br.J.Dermatol.p.5 14-21. Mager DE.Target-mediated drug dispositio n and dynamics.Biochem Pharmacol 2006;72 (1):1-10. Margesson and Danby(2014)Best Practices and Res.Clin.Ob.And Gyn 28:1013-1027. Matusiak et al(2017)Increased interleuki n(IL)-17 serum levels in patients with h idradenitis suppurativa:Implications for treatment with anti-IL-17 agents.J Am A cad Dermatol;76:670-5. Mehling et al(2001)Overexpression of CD4 0 Ligand in Murine Epidermis Results in Chronic Skin Inflammation and Systemic A utoimmunity.J.Exp.Med.Vol 194,Number 5,p .615-628. J.Musilova,A.Malara,S.Kirthi,R.Hambly,R. Hughes,B.Kirby(2018)Patients with hidrad enitis suppurativa have abnormalities in circulating B cell subsets(abstract htt ps: / / onlinelibrary.wiley.com / doi / full / 10 .1111 / exd.13538) Ng CM,Stefanich E,Anand BS,Fielder PJ,Va ickus L.Pharmacokinetics / pharmacodynamic s of nondepleting anti-CD4 monoclonal an tibody(TRX1)in healthy human volunteers. Pharm Res 2006;23(1):95-103. Sartorius et al.(2009)Br.J Dermatol.161: 831-839 Schuch A,Fischer T,Boehner A,et al(2018) Successful Treatment of Severe Recalcitr ant Hidradenitis Suppurativa with the In terleukin-17A Antibody Secukinumab.Acta Derm.Venereol.p.151-152. Shah A,Alhusayen R,Amini-Nik S(2017)The critical role of macrophages in the path ogenesis of hidradenitis suppurativa.Inf lamm.Res.p.931-945. Sharon VR,Garcia MS,Bagheri S,et al(2012 )Management of recalcitrant hydradenitis suppurative with ustekinumab.Act Derm. Venereol.p.320-1. Th'ng KH,Garewal G,Kearney L,Rassool FM elo JV,White H et al.Establishment and c haracterization of three new malignant l ymphoid cell lines.Int J Cancer 1987;39( 1):89-93. Thorlacius L,Theut Rice P,Jemec GBE(2017). )Severe suppurative hydradenitis respond ing to treatment with secukinumab:a case report.Br.J.Dermatol. Tzanetakou V,Kanni T,Giatrakou S,et al(2). 016)Safety and Efficacy of Anakinra in S evere Suppurative Hydradenitis:A Random zed Clinical Trial.JAMA Dermatol p.52-59 . . . . Warncke M,Calzascia T,Coulot M,Balke N,T ouil R,Kolbinger F et al.Different adapt ations of IgG effector function in humans and nonhuman primates and implications for therapeutic antibody treatment.J Imm unol 2012;188(9):4405-4411. Weber P,Seyed Jafari SM,Yawalkar N,et al (2017)Apremilast in the treatment of mod erate to severe hidradenitis suppurativa :A case series of 9 patients.J.Am.Acad.D ermatol.p.1189-1191. Zouboulis CC,Desai N,Emtestam L,et al(20 15)European S1 guideline for the treatme nt of hidradenitis suppurativa / acne inve rsa.J Eur Acad Dermatol Venereol p.619-4 4.

Claims

1. A CD40 antagonist for use in the treatment of hidradenitis suppurativa.

2. The CD40 antagonist for use according to claim 1 which is an anti-CD40 antibody.

3. The anti-CD40 antibody is an anti-CD40 antibody having suppressed ADCC activity. A CD40 antagonist for use according to item 1.

4. a. an immunoglobulin VH domain comprising the amino acid sequence of SEQ ID NO: 7 and an immunoglobulin VH domain comprising the amino acid sequence of SEQ ID NO: 8 an anti-CD40 antibody comprising an immunoglobulin VL domain comprising an amino acid sequence; b. Immunoglobulins comprising the hypervariable regions set forth as SEQ ID NO:1, SEQ ID NO:2 and SEQ ID NO:

3. globulin VH domain and the high-density an anti-CD40 antibody comprising an immunoglobulin VL domain containing a frequency variable region; c. An immunoglobulin VH domain comprising the amino acid sequence of SEQ ID NO:7 and the amino acid sequence of SEQ ID NO:

8. and an anti-CD31 antibody comprising an immunoglobulin VL domain having the sequence of SEQ ID NO: 13 and an Fc region having the sequence of SEQ ID NO:

14. 40 antibodies, d. An immunoglobulin VH domain comprising the amino acid sequence of SEQ ID NO: 7 and the amino acid sequence of SEQ ID NO:

8. and an anti-CD31 antibody comprising an immunoglobulin VL domain having the sequence of SEQ ID NO: 14 and an Fc region of SEQ ID NO:

15. 40 antibodies, and e. Anti-CD40 antibodies comprising silent Fc IgG1 regions The CD4 antibody for use according to claim 1 is an anti-CD40 antibody selected from the group consisting of 0 antagonist.

5. The heavy chain amino acid sequence of SEQ ID NO: 9 and the light chain amino acid sequence of SEQ ID NO: 10 or SEQ ID NO: 11 and a light chain amino acid sequence of SEQ ID NO:

12. Antibodies for.

6. The route of administration is subcutaneous or intravenous or a combination of subcutaneous and intravenous. An antibody for use according to any one of 1 to 3.

7. The dosage is about 3 mg to about 30 mg of active ingredient per kilogram of human subject. An antibody for use according to any one of items 1 to 4.

8. 6. The method of claim 5, wherein the dosage is about 10 mg of active ingredient per kilogram of human subject.

4. An antibody compound for use in

9. The dosage is from about 150 mg to about 600 mg of active ingredient, for example about 300 mg of active ingredient. The antibody for use according to any one of claims 1 to 6.

10. The doses may be 150 mg of active ingredient, 300 mg of active ingredient or 600 mg of active ingredient.

8. The antibody compound for use according to claim 7,

11. The use according to any one of claims 1 to 8, which is administered via a loading dose and a maintenance dose. Antibodies for.

12. The loading dose is administered via subcutaneous injection of the first dose, and the maintenance dose is administered via subcutaneous injection of the second dose.

10. The antibody for use according to claim 9, which is administered via subcutaneous injection.

13. The first dose may contain from about 150 mg to about 600 mg of the active ingredient, for example about 300 mg of the active ingredient. and the second dose is from about 150 mg to about 600 mg of active ingredient, e.g., about 300 mg.

11. The antibody for use according to claim 10, which is an active ingredient of 0.1 mg.

14. The first dose is 150 mg, 300 mg or 600 mg of active ingredient and the second dose is 12. The method according to claim 10 or 11, wherein the dosage is 150 mg, 300 mg or 600 mg of active ingredient.

2. An antibody for use as described in claim 1.

15. The loading dose comprises at least two subcutaneous injections, and the maintenance dose comprises weekly (Q1 The method according to any one of claims 10 to 12, comprising subcutaneous injections every other week (Q2W), every other week (Q2W) or every month (Q4W). An antibody for use according to any one of claims 1 to 4.

16. 14. The use according to claim 13, wherein at least two subcutaneous injections of the loading dose are of different doses. Antibodies for.

17. Patients with hidradenitis suppurativa are classified as having the following criteria: a) the patient has moderate to severe HS; b) the patient is an adult; c) the patient is an adolescent; d) the patient has an HS-PGA score of ≧3 prior to treatment with said CD40 antagonist. thing, e) the patient has at least three inflammatory lesions prior to treatment with said CD40 antagonist; or f) the patient had extensive scarring as a result of HS prior to treatment with said CD40 antagonist; Not to do (<10 fistulas) The antibody for use according to any one of claims 1 to 14, selected according to one of the following:

18. By the 16th week of treatment, hidradenitis suppurativa patients had the following: a. Simple HiSCR, b. Reduction in HS erythema; c. NRS30; d. A decrease of ≦6 as measured by DLQI, and / or e. Improvement of DLQI The antibody for use according to any one of claims 1 to 14, which achieves at least one of the following: 。

19. By week 16 of treatment, at least 40% of patients achieved a simple HiSCR or at least 25% of said patients achieve an NRS30 response, or at least 15% of said patients achieve an NRS30 response The antibody for use according to any one of claims 1 to 14, wherein less than 10% of patients experience HS erythema. 。

20. Patients will receive the following as early as one week after the first administration of the CD40 antagonist: a. A rapid reduction in pain as measured by VAS or NRS, and b. A rapid decrease in CRP as measured using a standard CRP assay The antibody for use according to any one of claims 1 to 14, having at least one of the following:

21. Patients were followed up 3 months after the end of treatment for inflammatory lesion counts, hidradenitis suppurativa clinical response (HiSCR), and , Numeric Rating Scale (NRS), Modified Sartorius HS Score, Hidradenitis Suppurativa - Physician Global Assessment (HS-PGA) or Dermatology Life Quality Index (DLQI) For the use according to any one of claims 1 to 14, in order to achieve a sustained response when antibodies.

22. Patients will be assessed by simple HiSCR (sHiSCR) 3 months after the end of treatment. The use of an anti-cancer drug according to any one of claims 1 to 14, which achieves a sustained response in cases body.

23. A therapeutically effective amount of an antibody for use according to any one of claims 1 to 20 and one or more and a pharma- ceutically acceptable carrier.

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