Methods of treatment

Abstract

Provided are methods for treating certain diseases or disorders characterized by IL-17 and / or BAFF-mediated inflammation in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of a bispecific antibody, such as a bispecific antibody comprising two first polypeptides and two second polypeptides wherein the amino acid sequence of the first polypeptide is SEQ ID NO: 1, or a variant thereof, and the amino acid sequence of the second polypeptide is SEQ ID NO:2, or a variant thereof.

Description

Attorney Docket No. ZURAP001WO METHODS OF TREATMENT

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 636,372, filed April 19, 2024, which is incorporated herein by reference in its entirety. SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted herewith as part of the specification and is hereby incorporated by reference in its entirety. Said .xml copy, created on March 26, 2025 is named ZURAP001WO.xml, and is 9,078 bytes in size.

[0003] Hidradenitis suppurativa (HS) is a skin disorder of the apocrine glands (sweat glands found on certain parts of the body) and hair follicles in which swollen, painful, chronically inflamed lesions or lumps develop in the groin and sometimes under the arms and under the breasts. Hidradenitis suppurativa is characterized by recurrent inflamed nodules, abscesses, and fistulas, and it occurs when apocrine gland outlets become blocked by perspiration or are unable to drain normally due to incomplete gland development. Secretions trapped in the glands force perspiration and bacteria into surrounding tissue, causing subcutaneous induration, inflammation, and infection. Hidradenitis suppurativa can develop in areas of the body that contain apocrine glands. These areas are the axillae, areola of the nipple, groin, perineum, circumanal region, and periumbilical region.

[0004] There are significant unmet needs for safe, effective, and tolerable treatments for hidradenitis suppurativa and related disorders. The present disclosure satisfies these needs and provides related advantages as well. SUMMARY

[0005] Despite the relatively high prevalence and severe impact of hidradenitis suppurativa (HS) on quality of life, few treatment options are available. The bispecific antibodies described herein have been engineered to target T-cell and B-cell pathways, but have not been evaluated in patients with HS. Described herein are studies to determine and evaluate doses and dosing regimens that generate sufficient target engagement in the tissues impacted by HS. Also described herein are formulations to minimize injection site reactions, which may be particularly useful given the impact of HS on the skin.

[0006] Provided are methods for treating certain diseases or disorders characterized by IL-17 and / or BAFF-mediated inflammation in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of a bispecific antibody that specifically binds to human IL-17 and / or BAFF, or a variant of such bispecific antibody.Attorney Docket No. ZURAP001WO

[0007] Provided are methods for treating hidradenitis suppurativa in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of a bispecific antibody against interleukin 17 (IL-17) and human B cell activating factor (BAFF).

[0008] Also provided are methods of treating hidradenitis suppurativa in a human subject in need thereof, comprising administering an anti-human BAFF immunoglobulin G4 (IgG4) antibody fused with an anti-human IL-17 single-chain variable fragment (scFv) at the C- terminus of each heavy chain.

[0009] In some embodiments, the bispecific antibody comprises two first polypeptides and two second polypeptides wherein the amino acid sequence of the first polypeptide is SEQ ID NO: 1, or a variant thereof, and the amino acid sequence of the second polypeptide is SEQ ID NO:2, or a variant thereof. In some embodiments, the bispecific antibody comprises two first polypeptides and two second polypeptides wherein the amino acid sequence of the first polypeptide is SEQ ID NO: 1 and the amino acid sequence of the second polypeptide is SEQ ID NO:2.

[0010] In some embodiments, the bispecific antibody is tibulizumab, or a variant thereof. In some embodiments, the bispecific antibody is tibulizumab.

[0011] These and other aspects of the invention disclosed herein will be set forth in greater detail as the patent disclosure proceeds. BRIEF DESCRIPTION OF THE FIGURES

[0012] Figure 1 shows model-predicted percentage change from baseline of free unbound BAFF (upper panel) and IL-17 (lower panel) concentration versus time following multiple tibulizumab administrations.

[0013] Figure 2 shows the model-predicted blood tibulizumab pharmacokinetics, total & free target time course following 24-week subcutaneous administration of 150 mg Q4W with an additional dose at Week 2.

[0014] Figure 3 shows the model-predicted skin / lung tibulizumab pharmacokinetics, total and free target time course following 24-week subcutaneous administration of 150 mg Q4W with an additional Dose at Week 2.

[0015] Figure 4 shows the model-predicted blood tibulizumab pharmacokinetics, total & free target time course following 24-week subcutaneous administration of 300 mg Q4W with an additional dose at Week 2.

[0016] Figure 5 shows the model-predicted skin / lung tibulizumab pharmacokinetics, total & free target time course following 24-week subcutaneous administration of 300 mg Q4W with an additional dose at Week 2.Attorney Docket No. ZURAP001WO DETAILED DESCRIPTION

[0017] Provided are methods of treating hidradenitis suppurativa in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of a bispecific antibody against interleukin 17 (IL-17) and human B cell activating factor (BAFF).

[0018] Provided are methods of treating hidradenitis suppurativa in a human subject in need thereof, comprising administering an anti-human BAFF immunoglobulin G4 (IgG4) antibody fused with an anti-human IL-17 single-chain variable fragment (scFv) at the C-terminus of each heavy chain.

[0019] Provided are methods of treating hidradenitis suppurativa in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of a bispecific antibody, wherein the bispecific antibody comprises two first polypeptides and two second polypeptides wherein the amino acid sequence of the first polypeptide is SEQ ID NO: 1 and the amino acid sequence of the second polypeptide is SEQ ID NO:2.

[0020] In some embodiments, the bispecific antibody is administered subcutaneously.

[0021] In some embodiments, the antibody or antigen-binding fragment thereof is administered once per week, once every other week, once every two weeks, once every three weeks, once every four weeks, once every month, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every two months, once every nine weeks, once every ten weeks, once every eleven weeks or once every twelve weeks. In some embodiments, the bispecific antibody is administered once every two weeks (Q2W). In some embodiments, the bispecific antibody is administered once every four weeks (Q4W).

[0022] In some embodiments, the bispecific antibody is administered in an amount of between about 100 mg and about 500 mg, such as between about 200 mg and about 400 mg, such as about 300 mg. In some embodiments, the bispecific antibody is administered in an amount of about 100, about 110, about 120, about 125, about 130, about 140, about 150, about 160, about 170, about 175, about 180, about 190, about 200, about 210, about 220, about 225, about 230, about 240, about 250, about 260, about 270, about 275, about 280, about 290, or about 300 mg. In some embodiments, the bispecific antibody is administered in an amount of about 100, about 120, about 125, about 150, about 175, about 200, about 225, about 240, about 250, about 275, about 300, about 350, about 400, about 450, or about 500 mg.

[0023] In some embodiments, the bispecific antibody is administered by subcutaneous injections totaling about 120 mg every 2 weeks. In some embodiments, the subcutaneousAttorney Docket No. ZURAP001WO injections are in a single injector. In some embodiments, the subcutaneous injections are in two injectors. In some embodiments, the injector is an autoinjector.

[0024] In some embodiments, the bispecific antibody is administered by subcutaneous injections totaling about 240 mg every month. In some embodiments, the subcutaneous injections are in a single injector. In some embodiments, the subcutaneous injections are in two injectors. In some embodiments, the injector is an autoinjector. In some embodiments, two subcutaneous injections of 120 mg bispecific antibody each are administered together every four weeks (Q4W). In some embodiments, one subcutaneous injection of about 120 mg bispecific antibody is administered every two weeks (Q2W).

[0025] In some embodiments, the bispecific antibody is administered by subcutaneous injections of about 300 mg every 2 weeks.

[0026] In some embodiments, the bispecific antibody is administered by subcutaneous injections of about 300 mg every 4 weeks. In some embodiments, the bispecific antibody is administered by subcutaneous injections of about 300 mg every month.

[0027] In some embodiments, the bispecific antibody is administered by subcutaneous injections of about 150 mg every 2 weeks.

[0028] In some embodiments, the bispecific antibody is administered by subcutaneous injections of about 150 mg every 4 weeks. In some embodiments, the bispecific antibody is administered by subcutaneous injections of about 150 mg every month.

[0029] In some embodiments, the bispecific antibody is administered every four weeks with an additional dose administered between the first and second dose. In some embodiments, an additional dose of the bispecific antibody is administered between the first and second dose of a Q4W dosing regimen. In some embodiments, the additional dose is administered about two weeks after the first dose. In some embodiments, the additional dose is administered from about 10 days to about 18 days, such as from about 11 days to about 17 days, such as from about 12 days to about 16 days, such as from about 13 days to about 15 days, such as 14 days after the first dose. In some embodiments, the bispecific antibody is administered more frequently in the first month than in the second month. In some embodiments, an additional dose of the bispecific antibody is administered to expedite achievement of steady state.

[0030] In some embodiments, the bispecific antibody is administered in an amount of about 150 mg.

[0031] In some embodiments, the bispecific antibody is administered in an amount of about 240 mg.Attorney Docket No. ZURAP001WO

[0032] In some embodiments, the bispecific antibody is administered in an amount of about 300 mg.

[0033] In some embodiments, the bispecific antibody is administered once per week, once every other week, once every two weeks, once every three weeks, once every four weeks, or once every month.

[0034] In some embodiments, the bispecific antibody is administered in an amount of about 150 mg once every four weeks.

[0035] In some embodiments, the bispecific antibody is administered as tibulizumab 150 mg every four weeks.

[0036] In some embodiments, the method further comprises an additional administration of 150 mg tibulizumab between the first and second administration of 150 mg every four weeks.

[0037] In some embodiments, the bispecific antibody is administered in an amount of about 240 mg once every four weeks.

[0038] In some embodiments, the bispecific antibody is administered as tibulizumab 240 mg every four weeks.

[0039] In some embodiments, the method further comprises an additional administration of 240 mg tibulizumab between the first and second administration of 240 mg every four weeks.

[0040] In some embodiments, the bispecific antibody is administered in an amount of about 300 mg once every four weeks.

[0041] In some embodiments, the bispecific antibody is administered as tibulizumab 300 mg every four weeks.

[0042] In some embodiments, the method further comprises an additional administration of 300 mg tibulizumab between the first and second administration of 300 mg every four weeks. In some embodiments, the bispecific antibody is administered according to a multiple variable dose regimen.

[0043] In some embodiments, the treatment is to be carried out with a multiple- variable dose comprising a first induction dose of a bispecific antibody to a subject in need thereof such that a threshold level of the bispecific antibody is achieved within an induction phase; and at least one treatment dose of the bispecific antibody for subsequent administration within a treatment phase, such that treatment occurs.

[0044] In some embodiments, the multiple variable dose regimen comprises administering at least one loading dose and administering a treatment dose which is different than the loading dose. In some embodiments, the multiple variable dose regimen comprises a loading dose and a treatment dose that is lower than the loading dose.Attorney Docket No. ZURAP001WO

[0045] In some embodiments, a time interval between the loading dose and a first treatment dose is at least one week, at least two weeks, at least three weeks, at least four weeks, at least one month, at least five weeks, at least six weeks, at least seven weeks, at least eight weeks, at least two months, at least nine weeks, at least ten weeks, at least eleven weeks, or at least twelve weeks.

[0046] In some embodiments, a biomarker is evaluated in conjunction with the administration of tibulizumab. In some embodiments, the biomarker is selected from one or more of the following: BAFF, IL-17, interleukin-1 beta (IL-1β), interleukin-6 (IL-6), periostin (POSTN), collagen 1A1 (COL1A1), C-X-C motif chemokine ligand 1 (CXCL1), interleukin 11 (IL-11), advanced glycosylation end-product specific receptor (Ager), C-X-C motif chemokine receptor 4 (CXCR4), toll like receptor 2 (TLR2), collagen 1A2 (COL1A2), fibronectin 1 (FN1), tissue inhibitor of metalloproteinase 1 (TIMP1), connective tissue growth factor (CTGF), acetyl-CoA acetyltransferase 2 (ACTA2), transforming growth factor beta 1 (TGFβ1), vascular endothelial growth factor A (VEGFA), platelet-derived growth factor (PDGF), Nod-, LRR- and pyrin domain-containing protein 3 (NLRP3), C-C motif chemokine ligand 2 (CCL2), interleukin 8 (IL-8), chemokine ligand 3 (CXCL3), chemokine ligand 4 (CXCL4), C-C motif chemokine ligand 18 (CCL18), matrix metalloproteinase 7 (MMP7), matrix metalloproteinase 12 (MMP12), and surfactant protein D (SP-D). In some embodiments, the biomarker is CXCL1. In some embodiments, the biomarker is immunoglobulin G (IgG). In some embodiments, the biomarker is immunoglobulin 1 (IgG1). In some embodiments, the biomarker is BAFF. In some embodiments, the biomarker is IL- 17.

[0047] In some embodiments, the biomarker is a gene. In some embodiments, the biomarker is a transcript. In some embodiments, the biomarker is a protein. In some embodiments, an individual administered tibulizumab is evaluated for a reduction in one or more biomarkers. In some embodiments, an individual administered tibulizumab is evaluated for an increase in one or more biomarkers. In some embodiments, a biomarker is upregulated following administration of tibulizumab. In some embodiments, a biomarker is downregulated following administration of tibulizumab. Hidradenitis Suppurativa

[0048] In some embodiments, the hidradenitis suppurativa is moderate to severe hidradenitis suppurativa. In some embodiments, the hidradenitis suppurativa is moderate or severe hidradenitis suppurativa. In some embodiments, the hidradenitis suppurativa is moderateAttorney Docket No. ZURAP001WO hidradenitis suppurativa. In some embodiments, the hidradenitis suppurativa is severe hidradenitis suppurativa.

[0049] In some embodiments, the subject has lesions in at least two distinct anatomic areas prior to treatment.

[0050] In some embodiments, the median size of the subject’s lesions is reduced after administration of the bispecific antibody.

[0051] In some embodiments, the number of the subject’s lesions is reduced after administration of the bispecific antibody.

[0052] In some embodiments, the number of the subject’s lesions is reduced by at least 50% in the subject relative to baseline lesion count. In some embodiments, the number of the subject’s lesions is reduced by at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% in the subject relative to baseline lesion count.

[0053] In some embodiments, the lesion is selected from an abscess, nodule, inflammatory nodule, non-inflammatory nodule, tunnel or fistula, draining tunnel or draining fistula, non- draining tunnel, or pyogenic granuloma. In some embodiments, the subject’s pain associated with the subject’s lesions is reduced after administration of the bispecific antibody.

[0054] In some embodiments, the subject’s time to new lesions is increased after administration of the bispecific antibody.

[0055] In some embodiments, the subject has no increase in an abscess count and / or no increase in a draining fistula count following administration with the bispecific antibody.

[0056] In some embodiments, the hidradenitis suppurativa in the subject failed to resolve after treatment with tumor necrosis factor (TNF) alpha inhibitors. In some embodiments, the subject has not previously been administered an anti-TNF alpha therapy. In some embodiments, the anti-TNF alpha inhibitor or therapy is selected from adalimumab, certolizumab, etanercept, golimumab, and infliximab.

[0057] In some embodiments, the subject had an inadequate response to, contraindication to, recurrence after discontinuation of, or was intolerant to an oral antibiotic for the treatment of hidradenitis suppurativa.

[0058] In some embodiments, the subject is selected from a subject having an abscess and inflammatory nodule (AN) count of greater than or equal to 3 at baseline, a subject who is a female, a subject who is over 40 years old, a subject who is a smoker, or any combination thereof.

[0059] In some embodiments, the subject is selected from a subject having moderate to severe HS, a Hurley staging system category of Hurley Stage II or III, and / or a total abscessAttorney Docket No. ZURAP001WO and inflammatory count (AN) ≥ 3. In some embodiments, the subject is selected from a subject having moderate to severe HS, a Hurley staging system category of Hurley Stage II or III, and / or a total abscess and inflammatory count (AN) ≥ 5. Hurley Stage I refers to abscesses and inflammatory nodules without sinus tracts and scarring. Hurley Stage II refers to recurrent abscesses with tract formation and scarring, single or multiple and widely separated lesions. Hurley Stage III refers to diffuse or multiple interconnected sinus tracts and abscesses across the entire area.

[0060] In some embodiments, a clinical response is defined by whether or not a subject achieves an HiSCR. The term "Hidradenitis Suppurativa Clinical Response" or "HiSCR" as used herein is defined as at least a particular percentage reduction in the total inflammatory lesion (abscess and nodule) count (AN count) relative to baseline with no increase in abscess count and no increase in draining fistula count. In some embodiments, the improvement in HiSCR is at least a 50% reduction in AN count (HiSCR50). In some embodiments, the improvement in HiSCR is at least a 75% reduction in AN count (HiSCR75). In some embodiments, the improvement in HiSCR is at least a 90% reduction in AN count (HiSCR90). In some embodiments, the improvement in HiSCR is a 100% reduction in AN count (HiSCR100).

[0061] In some embodiments, a clinical response is defined as achieving an Hidradenitis Suppurativa Physician's Global Assessment (HS-PGA) score, as defined below, of clear (0), minimal (1), or mild (2), with an improvement (i.e., reduction) from baseline HS-PGA score of at least 2 grades. The baseline HS-PGA score is the HS-PGA score measured just prior to the commencement of treatment, to which the HS-PGA score obtained after a period of treatment is compared. Both the baseline HS-PGA score and the HS-PGA score obtained after a treatment period are assessed based on the system and criteria shown below.Attorney Docket No. ZURAP001WO

[0062] In some embodiments, a clinical response is defined by whether or not a subject achieves an improvement in their Hurley stage. In some embodiments, the severity of HS is determined according to the Hurley staging system. Hurley staging is based on assigning the subject having HS one of three different "Stages" depending on the disease level. More specifically, Stage I refers to abscess formation, single or multiple, without sinus tracts and cicatrisation; Stage Π refers to recurrent abscesses with tract formation and cicatrisation, as well as single or multiple, widely separated lesions; and Stage ΙΠ refers to diffuse or near- diffuse involvement, or multiple interconnected tracts and abscesses across the entire area.

[0063] In some embodiments, the subject having HS has HS lesions that are present in at least two distinct anatomic areas (e.g., left and right axilla; or left axilla and left inguinal- crural fold), one of which is at least Hurley Stage Π. In another embodiment, the subject being treated has at least one lesion that is at least a Hurley Stage II.

[0064] In some embodiments, the subject has Hurley Stage I. In some embodiments, the subject has Hurley Stage II. In some embodiments, the subject has Hurley Stage III. In some embodiments, the subject has moderate to severe HS. In some embodiments, the subject has moderate HS. In some embodiments, the subject has severe HS.

[0065] In some embodiments, treatment of HS with a bispecific antibody as described herein is determined by an improved Hurley score relative to a given baseline, e.g., the Hurley stage of the subject prior to treatment with the bispecific antibody. In some embodiments, improvement in a Hurley score indicates that the Hurley score of the subject has either improved or been maintained following treatment with the bispecific antibody as described herein. Severity of hidradenitis suppurativa may be determined according to standard clinical definitions.

[0066] In some embodiments, a clinical response is defined by whether or not a subject achieves an improvement in the Sartorius scale for treating hidradenitis suppurativa. Briefly, the following outcome variables are cited in reports based on the Sartorius scale: (1) anatomical region involved (axilla, groin, gluteal or other region or inframammary region left and / or right: 3 points per region involved); (2) number and scores of lesions (abscesses,Attorney Docket No. ZURAP001WO nodules, fistulas, scars: points per lesion of all regions involved: nodules 2; fistulas 4; scars 1; others 1); (3) the longest distance between two relevant lesions, i.e., nodules and fistulas, in each region, or size if only one lesion (< 5 cm, 2; < 10 cm, 4; > 10 cm, 8); and (4) whether all lesions are clearly separated by normal skin in each region (yes 0 / no 6). By assigning numerical scores to these variables, disease intensity can be quantified in a more clinically meaningful way on an open-ended scale. A total score as well as scores of selected regions chosen for surgical or other intervention can be calculated and followed over time.

[0067] In some embodiments, a clinical response is defined by whether or not a subject achieves an improvement in Hidradenitis Suppurativa Physician's Global Assessment (HS- PGA) score, as defined below, of clear (0), minimal (1), or mild (2), with an improvement {i.e., reduction) from baseline HS-PGA score of at least 2 grades, optionally, at the end of a treatment period. The baseline HS-PGA score is the HS-PGA score measured just prior to the commencement of treatment, to which the HS-PGA score obtained after a period of treatment is compared. The HS-PGA scoring system is a six -point score that partly depends on the presence / absence of abscesses, draining fistulas, and / or nodules (inflammatory or non- inflammatory), and, if present, the extent of such presence.

[0068] In some embodiments, a clinical response is defined by whether or not a subject achieves an improvement in Hidradenitis Suppurativa Patient’s Global Assessment (HS- PtGA) score. The HS-PtGA is a single question assessing HS-specific health-related quality of life, as reported by participants, on a 5-point scale. Participants can be asked to assess how much HS has influenced their quality of life in the past 7 days on a scale from 0 (not at all) to 4 (extremely).

[0069] In some embodiments, a clinical response is defined by whether or not a subject achieves an improvement in DLQI score. In some embodiments, the improvement in the DLQI score is determined by achieving a score, e.g., a statistically significant score, correlating with a "no" or "small impact" of the disease state on the subject. In some embodiments, the improvement in the DLQI score is determined by achieving an improvement in the DLQI score of the subject. The DLQI is an additional validated instrument used to assess dermatologic- related functional limitations. Characteristics of the DLQI include: (1) ten items on an overall scoring range of 0-30; higher scores represent greater quality of life impairment and lower scores represent lower quality of life impairment; (2) well-established properties of reliability and validity for the DLQI total score in a dermatology setting; (3) six subcategories: symptoms and feelings; daily activities; leisure; work / school; personal relationships; and treatment; and, (4) all data are observed values.Attorney Docket No. ZURAP001WO

[0070] In some embodiments, a clinical response is defined by whether or not a subject achieves an improvement in a skin pain numerical rating scale (NRS). Skin pain NRS will be evaluated by asking subjects to assign a numerical score representing the most intense skin pain due to their HS that occurred in the last 24 hours on a scale from 0 to 10, with 0 indicating no pain and 10 indicating the worst pain imaginable.

[0071] In some embodiments, a clinical response is defined by whether or not a subject achieves an improvement in the pain visual analog score (VAS). In some embodiments, the subject has an improvement of at least about 25%, 30%, 35%, 40%, 45%, or 50%.

[0072] In some embodiments, a clinical response is defined by whether or not a subject achieves an improvement in Hidradenitis Suppurativa Severity Score System (IHS4). An IHS4 score is arrived at by the number of nodules (multiplied by 1) plus the number of abscesses (multiplied by 2) plus the number of draining tunnels (multiplied by 4). A total score of 3 or less signifies mild, 4-10 signifies moderate, and 11 or higher signifies severe disease.

[0073] In some embodiments, a clinical response is defined by whether or not a subject achieves an improvement in AN count after administration of the bispecific antibody.

[0074] In some embodiments, a clinical response is defined by whether or not a subject achieves an improvement in draining tunnel count after administration of the bispecific antibody.

[0075] In some embodiments, a clinical response is defined by whether or not a subject achieves an improvement in number of flares after administration of the bispecific antibody.

[0076] In some embodiments, a flare is at least a 25% increase from baseline in AN count. In some embodiments, a flare is at least a 25% increase from baseline in AN count with an absolute increase in AN count of at least 2 relative to baseline.

[0077] In some embodiments, endpoints are stratified by baseline Hurley Stage. In some embodiments, endpoints are stratified by screening BMI (e.g., less than 38 mg / kg2 and greater than or equal to 38 mg / kg2). In some embodiments, endpoints are stratified by the presence of draining tunnels at baseline. In some embodiments, endpoints are stratified by prior use of anti-TNF alpha therapies.

[0078] In some embodiments, the subject’s Hidradenitis Suppurativa Clinical Response (HiSCR) score is improved after administration of the bispecific antibody.

[0079] In some embodiments, the subject’s Hidradenitis Suppurativa Physician's Global Assessment (HS-PGA) score is improved after administration of the bispecific antibody.Attorney Docket No. ZURAP001WO

[0080] In some embodiments, the subject’s International Hidradenitis Suppurativa Severity Score System (IHS4) score is improved after administration of the bispecific antibody.

[0081] In some embodiments, the subject’s Dermatology Life Quality Index (DLQI) is improved after administration of the bispecific antibody.

[0082] In some embodiments, the subject’s suicide risk as assessed using the Columbia- Suicide Severity Rating Scale (C-SSRS) is improved after administration of the bispecific antibody. The C-SSRS is a standardized and validated questionnaire developed to assess the severity and frequency of suicidal ideation and behavior.

[0083] In some embodiments, anti-Scl-70 antibodies are measured. In some embodiments, patients are screened for anti-Scl-70 antibodies. In some embodiments, patients positive for anti-Scl70 antibodies are selected for treatment with tibulizumab.

[0084] In some embodiments, an autoantibody is measured. In some embodiments, anti- centromere antibody is measured. In some embodiments, patients are screened for anti- centromere antibody. In some embodiments, patients negative for anti-centromere antibody are selected for treatment with tibulizumab. In some embodiments, patients positive for anti- centromere antibody are not selected for treatment with tibulizumab. In some embodiments, tibulizumab administration is discontinued in patients positive for anti-centromere antibody.

[0085] In some embodiments, acute phase reactants are measured. In some embodiments, patients are screened for acute phase reactants. In some embodiments, patients with elevated acute phase reactants are selected for treatment with tibulizumab. In some embodiments, patients with normal acute phase reactants are not selected for treatment with tibulizumab. The Bispecific Antibody

[0086] A bispecific antibody is understood to mean an immunoglobulin molecule comprising four antigen binding sites, which binds two different antigens with specificity for each antigen in the mAb-scFV format. The bispecific antibody is capable of binding each antigen alone or each antigen simultaneously.

[0087] The bispecific antibody described herein comprises two first polypeptides and two second polypeptides. In some embodiments, each of the first polypeptides forms an inter- chain disulfide bond with each of the second polypeptides, and the first polypeptide forms two inter-chain disulfide bonds with the other first polypeptide, and each of the first polypeptides forms several intra-chain disulfide bonds. In some embodiments, the relationship of the polypeptides and the disulfide bonds are shown in the following schematic:Attorney Docket No. ZURAP001WO

[0088] In some embodiments, the amino acid sequence of the first polypeptide is: QVQLQQWGAG LLKPSETLSL TCAVYGGSFS GYYWSWIRQP PGKGLEWIGE INHSGSTNYN PSLKSRVTIS VDTSKNQFSL KLSSVTAADT AVYYCARGYY DILTGYYYYF DYWGQGTLVT VSSASTKGPS VFPLAPCSRS TSESTAALGC LVKDYFPEPV TVSWNSGALT SGVHTFPAVL QSSGLYSLSS VVTVPSSSLG TKTYTCNVDH KPSNTKVDKR VESKYGPPCP PCPAPEFLGG PSVFLFPPKP KDTLMISRTP EVTCVVVDVS QEDPEVQFNW YVDGVEVHNA KTKPREEQFN STYRVVSVLT VLHQDWLNGK EYKCKVSNKG LPSSIEKTIS KAKGQPREPQ VYTLPPSQEE MTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SRLTVDKSRW QEGNVFSCSV MHEALHNHYT QKSLSLSPGG GGSGGGGTGG GGSQVQLVQS GAEVKKPGSS VKVSCKASGY KFTDYHIHWV RQAPGQCLEW MGVINPTYGT TDYNQRFKGR VTITADESTS TAYMELSSLR SEDTAVYYCA RYDYFTGTGV YWGQGTLVTV SSGGGGSGGG GSGGGGSGGG GSDIVMTQTP LSLSVTPGQP ASISCRSSRS LVHSRGETYL HWYLQKPGQS PQLLIYKVSN RFIGVPDRFS GSGSGTDFTL KISRVEAEDV GVYYCSQSTHLPFTFGCGTK LEIK (SEQ ID NO: 1).

[0089] In some embodiments, the amino acid sequence of the second polypeptide is: EIVLTQSPAT LSLSPGERAT LSCRASQSVS RYLAWYQQKP GQAPRLLIYD 50 ASNRATGI PA RFSGSGSGTD STLTI SSLEP EDFAVYYCQQ RSNWPRTFGQ 100 GTKVE I KRTV AAPSVFI FPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV 150 DNALQSGNSQ ESVTEQDSKD STYSLSNTLT LSKADYEKHK VYACEVTHQG 200 LSSPVTKSFN RGEC 214 (SEQ ID NO:2).Attorney Docket No. ZURAP001WO

[0090] In some embodiments, the inter-chain disulfide bond of each of the first polypeptides and each of the second polypeptides forms between cysteine residue 137 of SEQ ID NO: 1 and cysteine residue 214 of SEQ ID NO:2. In some embodiments, the first polypeptide forms two inter-chain disulfide bonds with the other first polypeptide. In some embodiments, the first inter-chain disulfide bond forms between cysteine residue 229 of the first polypeptide of SEQ ID NO: 1 and cysteine residue 229 of the other first polypeptide of SEQ ID NO: 1. In some embodiments, the second inter-chain disulfide bond forms between cysteine residue 232 of the first polypeptide of SEQ ID NO: 1 and cysteine residue 232 of the other first polypeptide of SEQ ID NO: 1.

[0091] In some embodiments, within the scFV, an engineered intra-chain disulfide bond is formed between cysteine residue 507 of SEQ ID NO: 1 and cysteine residue 707 of SEQ ID NO: 1. Also, In some embodiments, an intra-chain disulfide bond is formed between cysteine residue 625 of SEQ ID NO: 1 and cysteine residue 695 of SEQ ID NO: 1. In some embodiments, within the mAb, intra-chain disulfide bonds that normally occur in an IgG4 antibody are formed between cysteine residue 22 of SEQ ID NO: 1 and cysteine residue 95 of SEQ ID NO: 1, between cysteine residue 150 of SEQ ID NO: 1 and cysteine residue 206 of SEQ ID NO: 1, between cysteine residue 264 of SEQ ID NO: 1 and cysteine residue 324 of SEQ ID NO: 1, between cysteine residue 370 of SEQ ID NO: 1 and cysteine residue 428 of SEQ ID NO: 1, between cysteine residue 485 of SEQ ID NO: 1 and cysteine residue 559 of SEQ ID NO: 1, between cysteine residue 23 of SEQ ID NO:2 and cysteine residue 88 of SEQ ID NO:2, and between cysteine residue 134 of SEQ ID NO:2 and cysteine residue 194 of SEQ ID NO:2.

[0092] In some embodiments, the first polypeptide comprises a first heavy chain variable region (HCVR1), a heavy chain constant region (CH), a second heavy chain variable region (HCVR2) and a second light chain variable region (LCVR2). In some embodiments, the second polypeptide comprises a first light chain variable region (LCVRl) and a light chain constant region (CL). In some embodiments, the HCVR and LCVR regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with framework regions (FR). Each HCVR and LCVR is composed of three CDRs and four FRs, arranged from amino- terminus to carboxyl-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.

[0093] The 3 CDRs of HCVR1 can be referred to as CDRHl-1, CDRHl-2, and CDRHl-3 and the 3 CDRs of HCVR2 are referred to as CDRH2-1, CDRH2-2, and CDRH2-3 and the 3Attorney Docket No. ZURAP001WO CDRs of LCVRl are referred to as CDRLl-1, CDRLl-2 and CDRLl-3 and the 3 CDRs of LCVR2 are referred to as CDRL2-1, CDRL2-2 and CDRL2-3.

[0094] In some embodiments, the CH is fused to HCVR2 by an amino acid linker (LI). HCVR2 is fused to LCVR2 by an amino acid linker (L2).

[0095] In some embodiments, the relationship of the various regions and linkers is as follows:

[0096] Significant problems associated with chemical and physical stability were encountered when constructing a bispecific antibody in the mAb-scFv format with the anti- IL-17 binding portion in the scFv configuration. Chemical modifications were made in the CDRL2-1 and CDRH2-2 portions of the bispecific antibody that improved physical stability and reduced concentration-dependent aggregation. Extensive protein stability and solubility studies identified chemically unstable residues in CDRL2-1 and CDRH2-2. These labile residues were replaced with charge neutral amino acids using targeted libraries constructedAttorney Docket No. ZURAP001WO by codon depletion. Additionally, the electrostatic surface of the bispecific antibody was calculated and charged patches were identified. Disruptions of these charged patches in the scFv led to a decrease in protein self-association. However, a mutation was identified in the CDRH2-1 portion of the bispecific antibody that rebalanced the surface electrostatic distribution, and improved physical stability and solubility at high concentrations. None of the above issues were encountered in the parental single antibodies. These problems were encountered only in the context of constructing a bispecific antibody in the mAb-scFv format, suggesting that the local environment around the mutated areas of the single antibody differed in the context of a bispecific antibody.

[0097] Further chemical modifications were made to stabilize the HCVR2 / LCVR2 interface in the IL-17 portion of the bispecific antibody, and to reduce bispecific antibody aggregation. Studies conducted to determine the aggregation showed that the observed protein self- association was not driven by conformational instability of the individual HCVR2 or LCVR2 domains, but rather by the opening or breathing of the HCVR2 / LCVR2 interface, leading to intermolecular protein interactions. Thus, various intra-chain disulfide bonds were introduced into the HCVR2 / LCVR2 interface of the IL- 17 portion of the bispecific antibody. One such intra-chain disulfide bond occurs in each of the first polypeptides between cysteine residue 507 of SEQ ID NO: 1 and cysteine residue 707 of SEQ ID NO: 1. This disulfide bond covalently connects the HCVR2 / LCVR2 interface in the IL-17 portion of the bispecific antibody, which stabilizes the HCVR2 / LCVR2 interface and reduces intermolecular protein interactions that can lead to physical instability and unfavorable formulation limitations. Out of the nine different disulfide bonds tested, 8 of which expressed functional protein, the magnitude of affinity loss ranged from about 2 to about 35-fold. The intra-chain disulfide bond in each of the first polypeptides between cysteine residue 507 of SEQ ID NO: 1 and cysteine residue 707 of SEQ ID NO: 1 best stabilized the HCVR2 / LCVR2 interface while maintaining optimal binding affinity for IL-17.

[0098] In addition, studies indicated that linker length for LI affected binding kinetics. Kinetic analysis (by surface plasmon resonance) showed that a 10 amino acid linker caused a 2-fold slower Kon rate compared to 15 amino acid and 20 amino acid linkers. Thus, in some embodiments, a linker length of > 10 amino acids is used. In some embodiments, the linker length is between 15 amino acids and 20 amino acids. In some embodiments, the linker length is 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acids. In some embodiments, a linker length of 15 is used.Attorney Docket No. ZURAP001WO

[0099] The bispecific antibodies described herein bind both human BAFF and human IL-17. The bispecific antibodies described herein can inhibit IL-17 in the presence and absence of BAFF in vitro. The bispecific antibodies described herein can inhibit both soluble and membrane-bound BAFF in the presence or absence of IL-17 in vitro. The bispecific antibodies described herein are further characterized as having a binding affinity for human BAFF in the range of 150 pM to 1 pM and human IL-17 in the range of 50 pM to 1 pM. The bispecific antibodies have a binding affinity for human IL-17A / F heterodimer of about 90 pM.

[0100] The bispecific antibodies effectively neutralize soluble as well as membrane- bound BAFF and this neutralization is not affected by the presence of saturating amounts of human IL-17. The bispecific antibodies effectively neutralize human IL-17 and this neutralization is not affected by the presence of saturating amounts of human BAFF.

[0101] In some embodiments, the bispecific antibody is tibulizumab. In some embodiments, the bispecific antibody comprises components of tabalumab combined with components of ixekizumab.

[0102] Expression vectors capable of directing expression of genes to which they are operably linked are well known in the art. Expression vectors can encode a signal peptide that facilitates secretion of the polypeptide(s) from a host cell. The signal peptide can be an immunoglobulin signal peptide or a heterologous signal peptide. The first polypeptide and the second polypeptide may be expressed independently from different promoters to which they are operably linked in one vector or, alternatively, the first polypeptide and the second polypeptide may be expressed independently from different promoters to which they are operably linked in two vectors - one expressing the first polypeptide and one expressing the second polypeptide.

[0103] A host cell includes cells stably or transiently transfected, transformed, transduced or infected with one or more expression vectors expressing a first polypeptide, a second polypeptide or both a first polypeptide and a second polypeptide described herein.

[0104] Creation and isolation of host cell lines producing a bispecific antibody described herein can be accomplished using standard techniques known in the art. In some embodiments, mammalian cells are used as the host cells for expression of bispecific antibodies. Particular mammalian cells are HEK 293, NSO, DG-44, and CHO. In some embodiments, the bispecific antibodies are secreted into the medium in which the host cells are cultured, from which the bispecific antibodies can be recovered or purified.Attorney Docket No. ZURAP001WO

[0105] It is well known in the art that mammalian expression of antibodies results in glycosylation. Typically, glycosylation occurs in the Fc region of the antibody at a highly conserved N-glycosylation site. N-glycans typically attach to asparagine. In some embodiments, each of the first polypeptides is glycosylated at asparagine residue 300 of SEQ ID NO: l.

[0106] A particular DNA polynucleotide sequence encoding the first polypeptide having an amino acid sequence of SEQ ID NO: 1 is: CAGGTGCAACTACAGCAGTGGGGCGCAGGACTGTTGAAGCCTTCGGAGACCCTG TCCCTCACCTGCGCTGTCTATGGTGGGTCCTTCAGTGGTTACTACTGGAGCTGGAT TCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGGAAATCAATCATAGTGG AAGCACCAACTACAACCCGTCCCTCAAGAGTCGAGTCACCATATCAGTAGACAC GTCCAAGAACCAGTTCTCCCTGAAACTGAGCTCTGTGACCGCCGCGGACACGGCT GTGTATTACTGTGCGAGAGGGTATTACGATATTTTGACTGGTTATTATTACTACTT TGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCCTCCACCAAGGGC CCATCGGTCTTCCCGCTAGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCG CCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAA CTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCA GGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGA AGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGA GAGTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCCT GGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATC TCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCC GAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACA AAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACC GTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAAC AAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCC CGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAAC CAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGG AGTGGGAAAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGC TGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAG GTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAAC CACTACACACAGAAGAGCCTCTCCCTGTCTCCTGGAGGCGGAGGATCCGGGGGA GGGGGTACCGGAGGAGGGGGCTCGCAGGTGCAGCTGGTGCAGTCTGGGGCTGAG GTGAAGAAGCCTGGGTCCTCAGTGAAGGTTTCCTGCAAGGCATCTGGTTACAAGTAttorney Docket No. ZURAP001WO TCACTGACTACCATATTCATTGGGTGCGACAGGCCCCTGGACAATGCCTTGAGTG GATGGGAGTAATTAATCCTACTTATGGTACTACTGACTACAATCAGCGGTTCAAA GGCCGTGTCACCATTACCGCGGACGAATCCACGAGCACAGCCTACATGGAGCTG AGCAGCCTGAGATCTGAGGACACGGCCGTGTATTACTGTGCGAGATATGATTACT TTACTGGGACGGGTGTGTACTGGGGCCAAGGAACCCTGGTCACCGTCTCCTCAGG TGGCGGAGGATCTGGTGGAGGTGGCTCAGGAGGTGGCGGAAGCGGCGGAGGTG GAAGTGATATTGTGATGACTCAGACTCCACTCTCCCTGTCCGTCACCCCTGGACA GCCGGCCTCCATCTCCTGCAGATCTAGTAGGAGCCTTGTACACAGTCGTGGAGAA ACCTATTTACATTGGTATCTGCAGAAGCCAGGCCAATCTCCACAGCTCCTAATTT ATAAAGTTTCCAACCGGTTTATTGGGGTCCCAGACAGATTCAGCGGCAGTGGGTC AGGCACAGATTTCACACTGAAAATCAGCAGGGTGGAGGCCGAAGATGTTGGGGT TTATTACTGCTCTCAAAGTACACAT CTTCCATTCACGTTTGGCTGCGGGACCAAGCTGGAGATCAAA SEQ ID NO:3.

[0107] A particular DNA polynucleotide sequence encoding the second polypeptide having an amino acid sequence of SEQ ID NO:2 is: GAAATTGTGTTGACGCAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGGAAAGAG CCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCCGCTACTTAGCCTGGTACCA GCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGATGCATCCAACAGGGCC ACTGGCATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGACTCCACTCTCA CCATCAGCAGCCTAGAGCCTGAAGATTTTGCAGTTTATTACTGTCAGCAGCGTAG CAACTGGCCTCGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGAACTGT GGCGGCGCCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCCGGA ACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTAC AGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAG AGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAACACCCTGACGCTGAGCA AAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCC TGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGC SEQ ID NO:4.

[0108] Medium, into which a bispecific antibody has been secreted, may be purified by conventional techniques. For example, the medium may be applied to and eluted from a Protein A or G column using conventional methods. Soluble aggregate and multimers may be effectively removed by common techniques, including size exclusion, hydrophobic interaction, ion exchange, or hydroxyapatite chromatography. The product may be immediately frozen, for example at -70°C, or may be lyophilized.Attorney Docket No. ZURAP001WO

[0109] There may be a need to reduce the level of misfolded bispecific antibody present in the medium. Misfolded bispecific antibody is also known as diabody. Misfolding results when one or more disulfide bonds form incorrectly, either inter or intra chains. The misfolded bispecific antibody may be purified by conventional techniques. For example, the medium containing the misfolded bispecific antibody may be applied to and eluted from strong cation exchange resin. For example, SP-Sepharose HP strong cation exchange resin is used to purify correctly folded bispecific antibody from diabody. The pH of the medium containing the diabody is adjusted to pH 8 using 1M Tris Base. The medium is loaded onto an SP-Sepharose HP column, washed with 2 column volumes of 20mM Tris, pH 8 and eluted with 20mM Tris, 100mM NaCl, pH8 over 30 column volumes (0-70 mM NaCl). The collected pools can be assessed for high molecular weight versus main peak. A typical result is an improvement from 10% diabody to 1% diabody with 71% recovery.

[0110] In another example, Poros HS 50 strong cation exchange resin is used to purify correctly folded bispecific antibody from diabody. The pH of the medium containing the diabody is adjusted to pH 8 using 1M Tris Base. The medium is loaded onto an SP- Sepharose HP column and eluted with 20mM Tris, 100mM NaCl, pH8 over 15 column volumes (15-50 mM NaCl). The collected pools can be assessed for high molecular weight versus main peak. A typical result is an improvement from 10% diabody to 1% diabody with 57% recovery.

[0111] The bispecific antibody of the example of expression and demonstration of properties described herein comprises two first polypeptides having amino acid sequences of SEQ ID NO: l and two second polypeptides having amino acid sequences of SEQ ID NO:2 wherein each of the first polypeptides forms an inter-chain disulfide bond with each of the second polypeptides between cysteine residue 137 of SEQ ID NO: l and cysteine residue 214 of SEQ ID NO:2, and the first polypeptide forms two inter-chain disulfide bonds with the other first polypeptide between cysteine residue 229 first polypeptide of SEQ ID NO: 1 and cysteine residue 229 of the other first polypeptide of SEQ ID NO: 1 and between cysteine residue 232 first polypeptide of SEQ ID NO: 1 and cysteine residue 232 of the other first polypeptide of SEQ ID NO: 1, and each of the first polypeptides forms an intra-chain disulfide bond between cysteine residue 22 and cysteine residue 95 of SEQ IDNO: l, between cysteine residue 150 of SEQ ID NO: l and cysteine residue 206 of SEQ ID NO: 1, between cysteine residue 264 of SEQ ID NO: 1 and cysteine residue 324 of SEQ ID NO: 1, between cysteine residue 370 of SEQ ID NO: 1 and cysteine residue 428 of SEQ ID NO: l, between cysteine residue 485 of SEQ ID NO: l and cysteine residue 559 of SEQ ID NO: l, betweenAttorney Docket No. ZURAP001WO cysteine residue 507 of SEQ ID NO: l and cysteine residue 707 of SEQ ID NO: 1, and between cysteine residue 625 of SEQ ID NO: 1 and cysteine residue 695 of SEQ ID NO: l, and each of the second polypeptides forms an intra-chain disulfide bond between cysteine residue 23 of SEQ ID NO:2 and cysteine residue 88 of SEQ ID NO:2, and between cysteine residue 134 of SEQ ID NO:2 and cysteine residue 194 of SEQ ID NO:2, and wherein each of the first polypeptides is glycosylated at asparagine residue 300 of SEQ ID NO: l. The ratio of correctly folded bispecific antibody to misfolded diabody is on the order to 90: 10. Variants

[0112] A “variant” antibody refers herein to a molecule which differs in amino acid sequence from a “parent” antibody amino acid sequence by virtue of addition, deletion and / or substitution of one or more amino acid residue(s) relative to the parent antibody sequence. In some embodiments, the variant antibody comprises at least one amino acid (e.g., from one to about ten, and such as 2, 3, 4, 5, 6, 7 or 8) addition, deletion and / or substitution in the CDR regions of the parent antibody. Identity or homology with respect to the variant antibody sequence is defined herein as the percentage of amino acid residues in the variant antibody sequence that are identical with the parent antibody residues after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity. The variant antibody retains the ability to bind the antigen, or in some embodiments, the epitope, to which the parent antibody binds. In some embodiments, the variant antibody has at least one property or bioactivity that is superior to that of the parent antibody. For example, in some embodiments, the variant antibody has stronger binding affinity, slower off-rate, lower IC50 and / or enhanced ability to inhibit an antigen bioactivity than the parent antibody. In some embodiments, the variant antibody displays at least about 2-fold, such as at least about 5-fold, 10-fold or 20-fold enhancement in a property or bioactivity when compared to the parent antibody. In some embodiments, the variant antibody has at least 75%, 80%, 85%, 90%, 95%, 97%, 98%, or 99% amino acid sequence identity with the parent antibody. In some embodiments, the variant antibody has at least 75%, 80%, 85%, 90%, 95%, 97%, 98%, or 99% amino acid sequence identity with the parent antibody heavy or light chain variable domain sequences. In some embodiments, the variant antibody has at least 75%, 80%, 85%, 90%, 95%, 97%, 98%, or 99% amino acid sequence identity with the parent antibody heavy chain variable domain sequence. In some embodiments, the variant antibody has at least 75%, 80%, 85%, 90%, 95%, 97%, 98%, or 99% amino acid sequence identity with the parent antibody light chain variable domain sequence. In some embodiments, the variant antibodyAttorney Docket No. ZURAP001WO has at least 75%, 80%, 85%, 90%, 95%, 97%, 98%, or 99% amino acid sequence identity with SEQ ID NO: 1. In some embodiments, the variant antibody has at least 75%, 80%, 85%, 90%, 95%, 97%, 98%, or 99% amino acid sequence identity with SEQ ID NO: 2. In some embodiments, the variant antibody has at least 75%, 80%, 85%, 90%, 95%, 97%, 98%, or 99% amino acid sequence identity with SEQ ID NO: 3. In some embodiments, the variant antibody has at least 75%, 80%, 85%, 90%, 95%, 97%, 98%, or 99% amino acid sequence identity with SEQ ID NO: 4. In some embodiments, the sequence identity is calculated without reference to the cysteine residues, i.e., the sequence of the variant antibody can be varied except for cysteines required for maintaining the conformation of the bispecific antibody.

[0113] In some embodiments, the “parent” antibody herein is one which is encoded by an amino acid sequence used for the preparation of a variant antibody. The parent antibody may have framework sequence of murine origin, but in some embodiments, the framework sequence is entirely or substantially of human origin. The parent antibody may be a murine, chimeric, humanized or human antibody.

[0114] A murine monoclonal antibody or a human antibody (produced e.g., in a transgenic mouse) raised against IL-17 and / or BAFF may be a parent antibody. A parent antibody may be further altered to create a chimeric or humanized form of the antibody or other variant form of the antibody using methods available in the art, e.g., PCR mutagenesis. Such chimeric, humanized, or otherwise variant antibodies, may serve as parent antibodies for further variation or mutagenesis. Parent antibodies may be mutagenized, e.g., within the CDR domain(s) to create variant antibodies that may be screened for presence of a property of interest, e.g., binding affinity (lower KD), IC50, specificity, preferential binding, etc. In some embodiments, the property of interest in the variant antibody is an improvement over that property in the parent antibody. In some embodiments, an amino acid substitution variant antibody has at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid residue(s) of the parent antibody molecule removed and a different residue inserted in its place. The site of greatest interest for substitutional mutagenesis is one or more CDR regions, but FR alterations are also contemplated. Conservative amino acid substitutions are typically used; although, for more substantial changes, non-conservative amino acid changes may be introduced and the resulting antibodies screened for the property of interest.

[0115] A convenient way for generating substitution variants of a parent antibody is affinity maturation using phage display. Briefly, a polynucleotide molecule encoding a parent antibody is mutated within one or more CDR regions to generate all possible amino acidAttorney Docket No. ZURAP001WO substitutions at each amino acid residue at which a substitution is desired. The antibody variants thus generated are displayed in a monovalent fashion from filamentous phage particles as fusions to the gene III product of M13 packaged within each particle. The phage- displayed variant antibodies are then screened for their biological activity (e.g., binding affinity, specificity, IC50). In order to identify candidate CDR region sites for modification, alanine scanning mutagens can be performed to identify CDR region residues contributing significantly to antigen binding.

[0116] Alternatively, or in addition, it may be beneficial to analyze a crystal structure of the antigen-antibody complex to identify contact points between the antibody and IL-17 or BAFF. Such contact residues and neighboring residues are candidates for substitution according to the techniques elaborated herein or known in the art. Alternatively, or in addition, random mutagenesis or point mutagenesis may be performed, on one or more polynucleotide molecules encoding at least one CDR. The mutagenesis may be performed, at one or more positions, either while the CDR is operably linked to the framework region within the variable region or while the CDR is independent of other variable region sequence and then the altered CDR returned to the variable region using recombinant DNA technology. Once such variant antibodies are generated the panel of variants is subjected to screening for a property or activity of interest and antibodies with superior properties in one or more relevant assays may be selected for further development.

[0117] Any cysteine residue not involved in maintaining the proper conformation of the antibody may be substituted, generally with serine, to improve the oxidative stability of the molecule and prevent aberrant crosslinking. Conversely, cysteine bond(s) may be added to the antibody to improve its stability (particularly where the antibody is an antibody fragment such as an Fv fragment).

[0118] Another type of amino acid variant of the antibody alters the original glycosylation pattern of the antibody. In some embodiments, altering is deleting one or more carbohydrate moieties found in the antibody, and / or adding one or more glycosylation sites that are not present in the parent antibody. Glycosylation of antibodies is typically either N-linked or O- linked. N-linked refers to the attachment of the carbohydrate moiety to the side chain of an asparagine residue. The tripeptide sequences asparagine-X-serine and asparagine-X- threonine, where X is any amino acid except proline, are the recognition sequences for enzymatic attachment of the carbohydrate moiety to the asparagine’s side chain. Thus, the presence of either of these tripeptide sequences in a polypeptide creates a potential glycosylation site. O-linked glycosylation refers to the attachment of one of the sugars N-Attorney Docket No. ZURAP001WO aceylgalactosamine, galactose, or xylose to a hydroxyamino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine may also be used.

[0119] Addition of glycosylation sites to the antibody is conveniently accomplished by altering the amino acid sequence such that it contains one or more of the above-described tripeptide sequences (for N-linked glycosylation sites). The alteration may also be made by the addition of, or substitution by, one or more serine or threonine residues to the sequence of the original antibody (for O-linked glycosylation sites).

[0120] In some embodiments, the parent antibody is the polypeptide having SEQ ID NO: 1. In some embodiments, the parent antibody is the polypeptide having SEQ ID NO: 2. In some embodiments, the parent antibody is the bispecific antibody comprising two first polypeptides and two second polypeptides wherein the amino acid sequence of the first polypeptide is SEQ ID NO: 1 and the amino acid sequence of the second polypeptide is SEQ ID NO:2. Pharmaceutical Compositions

[0121] A bispecific antibody described herein can be incorporated into a pharmaceutical composition suitable for administration to a patient. Such pharmaceutical compositions are designed to be appropriate for the selected mode of administration, and pharmaceutically acceptable diluents, carrier, and / or excipients such as dispersing agents, buffers, surfactants, preservatives, solubilizing agents, isotonicity agents, stabilizing agents and the like are used as appropriate. Said compositions can be designed in accordance with conventional techniques disclosed in, e.g., Remington, The Science and Practice of Pharmacy, 19thEdition, Gennaro, Ed., Mack Publishing Co., Easton, PA 1995 which provides a compendium of formulation techniques as are generally known to practitioners. Suitable carriers for pharmaceutical compositions include any material which, when combined with a bispecific antibody described herein, retains the molecule's activity and is non-reactive with the patient's immune system. A pharmaceutical composition described herein comprises a bispecific antibody and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0122] A pharmaceutical composition comprising a bispecific antibody described herein can be administered to a patient at risk for or exhibiting diseases or disorders as described herein using standard administration techniques.

[0123] A pharmaceutical composition described herein contains an effective amount of a bispecific antibody described herein. An effective amount refers to an amount necessary (at dosages and for periods of time and for the means of administration) to achieve the desired therapeutic result. An effective amount of the bispecific antibody may vary according toAttorney Docket No. ZURAP001WO factors such as the disease state, age, sex, and weight of the individual, and the ability of the antibody or antibody portion to elicit a desired response in the individual. An effective amount is also one in which any toxic or detrimental effect of the bispecific antibody, are outweighed by the therapeutically beneficial effects.

[0124] In some embodiments, the pharmaceutical composition comprises tibulizumab.

[0125] In some embodiments, the pharmaceutical composition is formulated for injection.

[0126] In some embodiments, the pharmaceutical composition is formulated for subcutaneous injection.

[0127] In some embodiments, the pharmaceutical composition is formulated for intravenous injection.

[0128] In some embodiments, the pharmaceutical composition is in a liquid formulation.

[0129] In some embodiments, the pharmaceutical composition comprises a buffer. In some embodiments, the pharmaceutical composition comprises a buffering agent. In some embodiments, the pharmaceutical composition comprises buffer system. In some embodiments, the pharmaceutical composition comprises a stabilizer. In some embodiments, the pharmaceutical composition comprises a tonicity agent. In some embodiments, the pharmaceutical composition comprises a surfactant. In some embodiments, the pharmaceutical composition comprises water for injection.

[0130] In some embodiments, the pharmaceutical composition does not comprise citrate. In some embodiments, the pharmaceutical composition does not comprise sodium citrate dihydrate. In some embodiments, hypersensitivity reactions are evaluated following administration. In some embodiments, injection site reactions are evaluated following administration. In some embodiments, the injection site reaction is selected from pain, a nodule, erythema or redness, and induration or swelling. In some embodiments, the injection site reaction is mild (Grade 1), moderate (Grade 2), severe (Grade 3), or potentially life- threatening (Grade 4). In some embodiments, the risk of injection site reaction is reduced compared to the administration of ixekizumab with citrate. In some embodiments, the buffer does not comprise citrate.

[0131] In some embodiments, the pharmaceutical composition comprises histidine. In some embodiments, the buffer is histidine.

[0132] In some embodiments, the pharmaceutical composition is lyophilized. In some embodiments, the pharmaceutical composition has not been lyophilized.

[0133] In some embodiments, the pharmaceutical composition comprises sucrose. In some embodiments, the stabilizer is sucrose. In some embodiments, the tonicity agent is sucrose.Attorney Docket No. ZURAP001WO

[0134] In some embodiments, the pharmaceutical composition comprises polysorbate. In some embodiments, the solubilizer is polysorbate. In some embodiments, the polysorbate is polysorbate 80 (PS80). In some embodiments, the concentration of polysorbate is about 0.01, 0.02, 0.025, 0.03, 0.04, or 0.05% of the pharmaceutical composition.

[0135] In some embodiments, the pharmaceutical composition has a pH of about 5-6. In some embodiments, the pH is about 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, or 6.0. In some embodiments, the pH is about 5.4. In some embodiments, the pH is about 5.5. In some embodiments, the pH is about 5.6.

[0136] In some embodiments, the pharmaceutical composition is isotonic. In some embodiments, the pharmaceutical composition is isotonic with patient tissue impacted by disease. In some embodiments, the pharmaceutical composition is isotonic with the injection site for a patient with hidradenitis suppurativa. In some embodiments, the pharmaceutical composition has a pH close to that of human skin. In some embodiments, the pharmaceutical composition has a pH close to that of patient skin impacted by hidradenitis suppurativa.

[0137] In some embodiments, the isoelectric point of the pharmaceutical composition is about 8-9 under denaturing conditions. In some embodiments, the isoelectric point of the pharmaceutical composition is about 8.5 under denaturing conditions. In some embodiments, the isoelectric point of the pharmaceutical composition is about 8.6 under denaturing conditions. In some embodiments, the isoelectric point of the pharmaceutical composition is about 8.7 under denaturing conditions. In some embodiments, the isoelectric point of the pharmaceutical composition is about 8.8 under denaturing conditions.

[0138] In some embodiments, the concentration of tibulizumab in the pharmaceutical composition is about 25-100 mg / ml. In some embodiments, the concentration of tibulizumab in the pharmaceutical composition is about 45-75 mg / ml. In some embodiments, the concentration of tibulizumab in the pharmaceutical composition is about 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg / ml. In some embodiments, the concentration of tibulizumab in the pharmaceutical composition is about 75 mg / ml. In some embodiments, the concentration of tibulizumab in the pharmaceutical composition is about 100 mg / ml.

[0139] In some embodiments, the pharmaceutical composition comprises tibulizumab, a buffer, a stabilizer or tonicity agent, and a solubilizer.

[0140] In some embodiments, the pharmaceutical composition is a subcutaneous injection in a liquid formulation comprising tibulizumab, histidine, sucrose, and polysorbate.

[0141] In some embodiments, the pharmaceutical composition comprises tibulizumab and has a pH of about 5.5.Attorney Docket No. ZURAP001WO

[0142] In some embodiments, the pharmaceutical composition comprises about 75 mg / mL tibulizumab and has a pH of about 5.5.

[0143] In some embodiments, the pharmaceutical composition comprises about 75 mg / mL tibulizumab and histidine.

[0144] In some embodiments, the pharmaceutical composition has a pH of about 5.5 and comprises histidine.

[0145] In some embodiments, the pharmaceutical composition has a pH of about 5.5 and does not comprise citrate.

[0146] In some embodiments, the pharmaceutical composition has a pH of about 5.5 and comprises histidine.

[0147] In some embodiments, the pharmaceutical composition has a pH of about 5.5 and does not comprise citrate.

[0148] In some embodiments, the pharmaceutical composition comprises about 75 mg / mL tibulizumab and does not comprise citrate.

[0149] In some embodiments, the pharmaceutical composition comprises about 75 mg / mL tibulizumab; about 20 mM histidine; about 270 mM sucrose; and polysorbate.

[0150] In some embodiments, the pharmaceutical composition comprises about 75 mg / mL tibulizumab; about 20 mM histidine; about 270 mM sucrose; and polysorbate; and has a pH of about 5.5.

[0151] In some embodiments, the polysorbate is polysorbate 80.

[0152] In some embodiments, the pharmaceutical composition has a viscosity of about 10- 20 centiPoise. In some embodiments, the pharmaceutical composition has a viscosity of about 15-20 centiPoise. In some embodiments, the pharmaceutical composition has a viscosity of about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 centiPoise. In some embodiments, the pharmaceutical composition has a viscosity of about 15 centiPoise. In some embodiments, the pharmaceutical composition has a viscosity of about 16 centiPoise. In some embodiments, the pharmaceutical composition has a viscosity of about 17 centiPoise. In some embodiments, the pharmaceutical composition has a viscosity of about 18 centiPoise. In some embodiments, the pharmaceutical composition has a viscosity of about 19 centiPoise. In some embodiments, the pharmaceutical composition has a viscosity of about 20 centiPoise. In some embodiments, the pharmaceutical composition has a viscosity of less than about 30, 25, or 20 centiPoise.

[0153] In some embodiments, the pharmaceutical composition is stored at about 0 to about 10 degrees Celsius. In some embodiments, the pharmaceutical composition is stored at aboutAttorney Docket No. ZURAP001WO 2 to about 8 degrees Celsius. In some embodiments, the pharmaceutical composition is stored at about 5 degrees Celsius. In some embodiments, the pharmaceutical composition is stored at about 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 degrees Celsius. In some embodiments, the pharmaceutical composition is allowed to come to room temperature prior to administration.

[0154] In some embodiments, about 2, 3, 4, 5, or 6 mL of pharmaceutical composition is delivered per administration. In some embodiments, about 2 mL of pharmaceutical composition is delivered per administration. In some embodiments, about 4 mL of pharmaceutical composition is delivered per administration. In some embodiments, the 2, 3, 4, 5, or 6 mL per administration is delivered in more than one injection.

[0155] In some embodiments, the pharmaceutical composition is delivered in one injection per administration. In some embodiments, the pharmaceutical composition is delivered in two injections per administration. In some embodiments, the pharmaceutical composition is delivered in three injections per administration.

[0156] In some embodiments, the pharmaceutical composition is delivered in three or less injections per administration. In some embodiments, the pharmaceutical composition is delivered in two or less injections per administration. In some embodiments, the pharmaceutical composition is delivered in one injection per administration.

[0157] In some embodiments, 100 mg tibulizumab is in each of two vials for an administration. In some embodiments, 100 mg tibulizumab is in each of three vials for an administration. In some embodiments, 200 mg tibulizumab is in a single vial for an administration. In some embodiments, 120 mg tibulizumab is in each of two vials for an administration. In some embodiments, 240 mg tibulizumab is in a single vial for an administration. In some embodiments, 125 mg tibulizumab is in each of two vials for an administration. In some embodiments, 250 mg tibulizumab is in a single vial for an administration. In some embodiments, 150 mg tibulizumab is in each of two vials for an administration. In some embodiments, 300 mg tibulizumab is in a single vial for an administration. In some embodiments, each vial contains about 1, 1.25, 1.5, 1.75, or 2 mL of pharmaceutical composition. In some embodiments, each vial contains 1.5 mL of pharmaceutical composition. In some embodiments, each vial contains 2.0 mL of pharmaceutical composition. In some embodiments, each vial contains about 100, 125, 150, 175, or 200 mg of bispecific antibody. In some embodiments, each vial contains about 125 mg of bispecific antibody. In some embodiments, each vial contains about 150 mg of bispecific antibody.Attorney Docket No. ZURAP001WO

[0158] In some embodiments, the pharmaceutical composition is in an autoinjector. In some embodiments, the pharmaceutical composition is administered by autoinjector.

[0159] As used in the present specification, the following words and phrases are generally intended to have the meanings as set forth herein.

[0160] PREVENT, PREVENTING, OR PREVENTION: As used herein, the term “prevent,” “preventing”, or “prevention,” such as prevention of a particular disorder or the occurrence or onset of one or more symptoms associated with the particular disorder and does not necessarily mean the complete prevention of the disorder. For example, the term “prevent,” “preventing” and “prevention” means the administration of therapy on a prophylactic or preventative basis to an individual who may ultimately manifest at least one symptom of a disease or condition but who has not yet done so. Such individuals can be identified on the basis of risk factors that are known to correlate with the subsequent occurrence of the disease. Alternatively, prevention therapy can be administered without prior identification of a risk factor, as a prophylactic measure. Delaying the onset of at least one symptom can also be considered prevention or prophylaxis.

[0161] TREAT, TREATING, OR TREATMENT: As used herein, the term “treat,” “treating”, or “treatment” means the administration of therapy to an individual who already manifests at least one symptom of a disease or condition or who has previously manifested at least one symptom of a disease or condition. For example, “treating” can include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition. For example, the term “treating” in reference to a disorder means a reduction in severity of one or more symptoms associated with that particular disorder. Therefore, treating a disorder does not necessarily mean a reduction in severity of all symptoms associated with a disorder and does not necessarily mean a complete reduction in the severity of one or more symptoms associated with a disorder.

[0162] TOLERATE: As used herein, an individual is said to “tolerate” a dose of a compound if administration of that dose to that individual does not result in an unacceptable adverse event or an unacceptable combination of adverse events. One of skill in the art will appreciate that tolerance is a subjective measure and that what may be tolerable to one individual may not be tolerable to a different individual. For example, one individual may notAttorney Docket No. ZURAP001WO be able to tolerate headache, whereas a second individual may find headache tolerable but is not able to tolerate vomiting, whereas for a third individual, either headache alone or vomiting alone is tolerable, but the individual is not able to tolerate the combination of headache and vomiting, even if the severity of each is less than when experienced alone.

[0163] INTOLERANCE: As used herein, “intolerance” means significant toxicities and / or tolerability issues that led to a reduction in dose or discontinuation of the medication. “Intolerance” can be replaced herein with the term “unable to tolerate.”

[0164] ADVERSE EVENT: As used herein, an “adverse event” is an untoward medical occurrence that is associated with treatment with the active agent.

[0165] IN NEED OF TREATMENT and IN NEED THEREOF: As used herein, “in need of treatment” and “in need thereof” when referring to treatment are used interchangeably to mean a judgment made by a caregiver (e.g., physician, nurse, nurse practitioner, etc.) that an individual requires or will benefit from treatment. This judgment is made based on a variety of factors that are in the realm of a caregiver’s expertise, but that includes the knowledge that the individual is ill, or will become ill, as the result of a disease, condition or disorder that is treatable by the compounds described herein. Accordingly, the compounds described herein can be used in a protective or preventive manner; or compounds described herein can be used to alleviate, inhibit or ameliorate the disease, condition or disorder.

[0166] INDIVIDUAL: As used herein, “individual” means any human. In some embodiments, a human individual is referred to a “subject” or “patient.” In some embodiments, the patient is a human with a disease, disorder or condition that would benefit from a decreased level of BAFF and / or IL-17 or decreased bioactivity of BAFF and / or IL- 17.

[0167] DOSE: As used herein, “dose” means a quantity of a bispecific antibody described herein, given to the individual for treating or preventing the disease or disorder at one specific time.

[0168] THERAPEUTICALLY EFFECTIVE AMOUNT: As used herein, “therapeutically effective amount” of an agent, compound, drug, composition or combination is an amount which is nontoxic and effective for producing some desired therapeutic effect upon administration to a subject or patient (e.g., a human subject or patient). The precise therapeutically effective amount for a subject may depend upon, e.g., the subject’s size and health, the nature and extent of the condition, the therapeutics or combination of therapeutics selected for administration, and other variables known to those of skill in the art. The effective amount for a given situation is determined by routine experimentation and is withinAttorney Docket No. ZURAP001WO the judgment of the clinician. In some embodiments, the therapeutically effective amount is the standard dose.

[0169] CLINICAL RESPONSE: As used herein, a "clinical response" refers to an indicator of therapeutic effectiveness of an agent.

[0170] PHARMACEUTICAL COMPOSITION: As used herein, “pharmaceutical composition” means a composition comprising at least one active ingredient, such as a bispecific antibody described herein, whereby the composition is amenable to investigation for a specified, efficacious outcome. Those of ordinary skill in the art will understand and appreciate the techniques appropriate for determining whether an active ingredient has a desired efficacious outcome based upon the needs of the artisan.

[0171] When an integer is used in a method disclosed herein, the term “about” can be inserted before the integer.

[0172] Throughout this specification, unless the context requires otherwise, the word “comprise”, or variations such as “comprises” or “comprising” will be understood to imply the inclusion of a stated step or element or integer or group of steps or elements or integers but not the exclusion of any other step or element or integer or group of elements or integers.

[0173] Throughout this specification, unless specifically stated otherwise or the context requires otherwise, reference to a single step, composition of matter, group of steps, or group of compositions of matter shall be taken to encompass one and a plurality (i.e., one or more) of those steps, compositions of matter, groups of steps, or groups of compositions of matter.

[0174] Each embodiment described herein is to be applied mutatis mutandis to each and every other embodiment unless specifically stated otherwise.

[0175] Those skilled in the art will appreciate that the invention(s) described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention(s) includes all such variations and modifications. The invention(s) also includes all the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations or any two or more of said steps or features unless specifically stated otherwise.

[0176] The present invention(s) is not to be limited in scope by the specific embodiments described herein, which are intended for the purpose of exemplification only. Functionally equivalent products, compositions, and methods are clearly within the scope of the invention(s), as described herein.

[0177] It is appreciated that certain features of the invention(s), which are, for clarity, described in the context of separate embodiments, can also be provided in combination in aAttorney Docket No. ZURAP001WO single embodiment. Conversely, various features of the invention(s), which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination. For example, a method that recites prescribing and / or administering a bispecific antibody described herein can be separated into two methods; one method reciting prescribing a bispecific antibody described herein and the other method reciting administering a bispecific antibody described herein. In addition, for example, a method that recites prescribing a bispecific antibody described herein and a separate method of the invention reciting administering a bispecific antibody described herein can be combined into a single method reciting prescribing and / or administering a bispecific antibody described herein.

[0178] Further embodiments include the embodiments disclosed in the following Examples, which is not to be construed as limiting in any way.Attorney Docket No. ZURAP001WO EXAMPLES Example 1: Bispecific Antibodies

[0179] The bispecific antibody can be expressed and purified essentially as follows. A glutamine synthetase (GS) expression vector containing the DNA of SEQ ID NO:3 (encoding the first polypeptide having amino acid sequence of SEQ ID NO: 1) and SEQ ID NO:4 (encoding the light chain amino acid sequence of SEQ ID NO:2) is used to transfect the Chinese hamster cell line, CHOK1SV (Lonza Biologies PLC, Slough, United Kingdom) by electroporation. The expression vector encodes an SV Early (Simian Virus 40E) promoter and the gene for GS. Expression of GS allows for the biochemical synthesis of glutamine, an amino acid required by the CHOK1SV cells. Post-transfection, cells undergo bulk selection with 50μΜ L-methionine sulfoximine (MSX). The inhibition of GS by MSX is utilized to increase the stringency of selection. Cells with integration of the expression vector cDNA into transcriptionally active regions of the host cell genome can be selected against CHOK1 SV wild type cells, which express an endogenous level of GS. Transfected pools are plated at low density to allow for close-to-clonal outgrowth of stable expressing cells. The masterwells are screened for bispecific antibody expression and then scaled up in serum-free, suspension cultures to be used for production. Clarified medium, into which the bispecific antibody has been secreted, is applied to a Protein A affinity column that has been equilibrated with a compatible buffer, such as phosphate buffered saline (pH 7.4). The column is washed to remove nonspecific binding components. The bound bispecific antibody is eluted, for example, by pH gradient (such as 0.1 M sodium phosphate buffer pH 6.8 to 0.1 M sodium citrate buffer pH 2.5). Bispecific antibody fractions are detected, such as by SDS-PAGE or analytical size-exclusion, and then are pooled. Soluble aggregate and multimers may be effectively removed by common techniques, including size exclusion, hydrophobic interaction, ion exchange, or hydroxyapatite chromatography. The bispecific antibody may be concentrated and / or sterile filtered using common techniques. The purity of the bispecific antibody after these chromatography steps is greater than 98%. The

[0180] Binding affinity and binding stoichiometry of the bispecific antibody to human IL-17 and human BAFF is determined using a surface plasmon resonance assay on a Biacore 2000 instrument primed with HBS-EP+ (GE Healthcare, 10 mM Hepes pH7.4 + 150 mM NaCl + 3 mM EDTA + 0.05% surfactant P20) running buffer and analysis temperature set at 25 °C. A CM5 chip containing immobilized protein A (generated using standard NHS-EDC amine coupling) on all four flow cells (Fc) is used to employ a capture methodology. Antibody samples are prepared at 10 mcg / mL by dilution into running buffer. Human IL-17 or humanAttorney Docket No. ZURAP001WO BAFF are prepared at final concentrations of 20.0, 10.0, 5.0, 2.5, 1.25 and 0 (blank) nM by dilution into running buffer. Each analysis cycle consists of (1) capturing antibody samples on separate flow cells (Fc2, Fc3, and Fc4), (2) injection of 250 mcL (300-sec) of human IL- 17 or human BAFF over all Fc at 50 mcL / min, (3) return to buffer flow for 20 min to monitor dissociation phase, (4) regeneration of chip surfaces with a 5 mcL (30-sec) injection of glycine, pH1.5, (5) equilibration of chip surfaces with a 10 mcL (60-sec) injection of HBS- EP+. Data are processed using standard double-referencing and fit to a 1 : 1 binding model using Biacore 2000 Evaluation software, version 4.1, to determine the association rate (kon, M'Y1units), dissociation rate (kof¾ s"1units), and Rmax (RU units). The equilibrium dissociation constant (¾) is calculated as from the relationship ¾ = k0ff / kon, and is in molar units. Binding affinity to human IL-17 and human BAFF by the bispecific antibody

[0181] These results demonstrate that the bispecific antibody described herein binds human IL-17 and human BAFF.

[0182] BIAcore 2000 instrument is used to determine whether human IL- 17 and human BAFF can bind to the bispecific antibody simultaneously. Except as noted, all reagents and materials are purchased from BIAcore AB (Upsala, Sweden). All measurements are performed at 25°C. HBS-EP+ buffer (150 mM sodium chloride, 3 mM EDTA, 0.05 % (w / v) surfactant P-20, and 10 mM HEPES, pH7.4) is used as the running buffer and sample buffer. Protein A is immobilized on flow cells 1 and 2 of a CM4 sensor chip using an amine coupling kit. The bispecific antibody is first captured on flow cell 2, followed by injection of human IL-17 at 20 nM for 5 min to saturate IL-17 binding site. After binding of IL-17, human BAFF at 20 nM is then injected for 5 min. and additional binding signal is observed. Chip surface is then regenerated using l0 mM Glycine pH 1.5. The same process is repeated except with a different order of human IL-17 and human BAFF. The stoichiometry is calculated to ensure complete saturation of human IL-17 or human BAFF to the bispecific antibody. The stoichiometry of human IL-17 to the bispecific antibody is typically at -1.3 based on a kinetic binding experiment. Similarly, the stoichiometry of human BAFF to the bispecific antibody isAttorney Docket No. ZURAP001WO typically at ~ 1.0 based on a kinetic binding experiment. Control BAFF Ab is 4A5-3.1.1-B4 of US7,317,089.

[0183] Control IL-17 Ab is Fab 126 of US7,838,638. Table 2: Simultaneous binding of human IL-17 and human BAFF to the bispecific antibody.

[0184] These results demonstrate that the bispecific antibody described herein can bind human IL-17 and human BAFF simultaneously as shown by the increase in response units (Δ RU) from the two ligands binding to the bispecific antibody.

[0185] HT-29 cells are human colorectal adenocarcinoma epithelial cells that naturally express the IL-17 receptor. Incubation of HT29 cells with human IL-17 results in the production of CXCL1, which can be measured using a commercially available ELISA.

[0186] A dose range of the bispecific antibody from 41200 to 2.64 pM is evaluated (final concentration based on monomeric MW of bispecific antibody (=100 kDa)). Each test concentration of bispecific antibody is then added (50 mcl) to wells containing recombinant IL-17 (final IL-17 concentration in the well is 3.75 nM (based on monomeric MW of IL-17 (=16 kDa)). Testing is carried out in triplicate wells per treatment. Assay medium is used for "medium alone" and "IL-17 alone" controls. An IL-17 neutralizing antibody (Fab 126 of US7, 838,638) is used as positive control in the assay. Plates containing IL-17 and antibody mixtures are incubated for 60 to 90 minutes at 37°C, 95% relative humidity, 5% C02 in the inner wells of tissue-culture treated 96 well plates. In a variation of this assay, a saturating concentration of human BAFF is added (1.25 nM final concentration based on monomeric MW of BAFF (=20 kDa)), with the goal to determine if bispecific antibody would still be able to neutralize IL-17 when simultaneously bound to BAFF. HT-29 cells are routinely cultured in assay medium (McCoy's 5A containing10% FBS, penicillinG (0.2 U / mL) and streptomycin (0.2 mcg / mL)). On the day of the assay, the cells are rinsed with HBSS and detached from the culture flasks with trypsin + EDTA. The trypsin is inactivated with assay medium. HT-29 cells are then centrifuged at 500Xg for 5 minutes at RT. The cell pellet isAttorney Docket No. ZURAP001WO resuspended in assay medium. Cell density is measured with a hemocytometer, and 20,000 HT-29 cells (in 100 mcl) are added to the 96-well plates containing the antibody / IL-17 mixture. Two hundred mcl of PBS is added to each of the unused edge wells (without cells) to reduce edge effects resulting from evaporation. The 96-well plates are placed in a tissue culture incubator (37°C, 95% relative humidity, 5%C02) for approximately 48 hours.

[0187] At the end of the assay, the plates are centrifuged (500Xg for 5 minutes at RT), and the cell culture medium is transferred to polypropylene 96-well plates, which are sealed and frozen at -80°C. On the day of measuring CXCLl by ELISA, the plates are thawed at RT. CXCLl levels in medium (either undiluted, or diluted 1 : 3) are measured with a CXCLl sandwich ELISA (R&D Systems DuoSet #DY275), as per the manufacturer's instructions, using the following buffers and modifications: IX ELISA wash buffer from BioFX Labs (from 10X, #WSHW- 1000-01); sample and standard volume of 50 mcL per well; substrate from BioFX Labs (1 component HRP substrate, #TMBW- 1000-01); a stop solution from BioFX Labs (#LSTP- 1000-01; 100 mcl per well). At the end of the ELISA reactions, plates were read at 450 nm on a microplate reader (Molecular Devices SpectraMax 190). Data are collected as % of maximum amount of CXCLl produced (with IL-17 alone being 100%). The concentration where 50% of the IL-17-induced response is inhibited (IC50) by either bispecific antibody or the positive control is calculated using a 4 parameter sigmoidal fit of the data (GraphPad Prism).

[0188] The results demonstrate that the bispecific antibody described herein inhibited IL-17- induced secretion of CXCLl by HT-29 cells in a concentration-dependent manner. The inhibition is comparable to that observed with the positive control antibody (with an IC50 for bispecific antibody of 2.00 + 0.21 nM versus 1.86 + 0.22 nM for the positive control antibody (average of 3 independent experiments + SEM)), whereas the negative control antibody did not inhibit proliferation. Moreover, a similar inhibition is observed in the presence of a saturating amount of BAFF, with an IC50 for bispecific antibody of 1.57 + 0.45 nM versus 1.41 + 0.50 nM for the positive control antibody(average of 3 independent experiments + SEM). The bispecific antibody described herein effectively neutralizes IL-17 and that this neutralization is not affected by the presence of saturating amounts of BAFF.

[0189] Tl 165.17 is a murine plasmacytoma cell line that is dependent on external factors (IL-l beta or BAFF) for survival and growth. These cells naturally express the receptor for BAFF and their response to human BAFF is measured by monitoring proliferation.

[0190] A dose range of the bispecific antibody from 1 nM to 4.1 pM (final concentration based on monomeric MW of bispecific antibody (=100 kDa)) is evaluated for the ability toAttorney Docket No. ZURAP001WO neutralize soluble BAFF (final soluble BAFF concentration in assay is 150 pM based on monomeric MW of BAFF (=20 kDa)). Various concentrations of bispecific antibody are incubated with soluble BAFF for 30-60 minutes at 37°C in the inner wells of a flat bottom 96 well tissue culture plate in a total volume of 50 mcl. A BAFF neutralizing antibody (4A5- 3.1.1-B4 of US7, 317,089) is used as positive control in the assay. Each condition is tested in triplicate. In a variation of this assay, the ability of bispecific antibody to neutralize membrane BAFF is tested. Various concentrations of bispecific antibody are incubated with the membrane fraction of HEK293 cells expressing a non- cleavable form of BAFF (achieved by mutating the furin cleavage site in BAFF, resulting in permanent expression of BAFF on the cell membrane). In another variation of this assay, a saturating concentration of human IL-17 is added (15.6 nM final concentration, based on monomeric MW of IL-17 (=16 kDa)), with the goal to determine if bispecific antibody would still be able to neutralize either soluble or membrane BAFF when simultaneously bound to IL-17.

[0191] Tl 165 cells are routinely cultured in assay medium (RPMI1640 containing 10% FBS, HEPES, L-Glutamine, l mM Sodium Pyruvate, 5 x 10"5M 2-mercaptoethanol, IX Antibiotic-Antimycotic) supplemented with 2 ng / mL recombinant human IL-l beta. On the day of the assay cells are washed 3 times with assay medium and resuspended to lxlO5cells / mL in assay medium. Fifty mcl of the cell suspension is added to the 96 well plate, containing the mixture of antibody and BAFF. One hundred mcl of assay medium is added to each of the unused edge wells (without cells) to reduce edge effects resulting from evaporation. Plates are placed in a tissue culture incubator (37°C, 95% relative humidity, 5%C02) for approximately 44 hours. At the end of the assay 20 mcl of Promega Cell Titer 96 Aqueous One Solution is added to each well and incubated for 1 to 4 hours at 37°C. Plates are read at 490 nm on a microplate reader (Molecular Devices SpectraMax 190). Data are collected as % inhibition, using wells without BAFF as the minimum and wells with 150 pM BAFF as the maximum responses. The concentration where 50% of the BAFF-induced response is inhibited (IC50) by either bispecific antibody or the positive control is calculated using a 4 parameter sigmoidal fit of the data (SigmaPlot).

[0192] The results demonstrate that the bispecific antibody inhibits soluble BAFF- induced proliferation of Tl 165 cells in a concentration-dependent manner. This inhibition is comparable to that observed with the positive control antibody (with an IC50 for bispecific antibody of 0.064 + 0.021 pM versus 0.071 + 0.002 pM for the positive control antibody (average of 2 independent experiments + SEM)), whereas the negative control antibody did not inhibit proliferation. Moreover, a similar inhibition is observed in the presence of aAttorney Docket No. ZURAP001WO saturating amount of IL-17, with an IC50 for bispecific antibody of 0.060 + 0.014 pM versus 0.073 + 0.012 pM for the positive control antibody (average of 2 independent experiments + SEM). The bispecific antibody effectively neutralizes BAFF and this neutralization is not affected by the presence of saturating amounts of IL- 17.

[0193] The ability of bispecific antibody to inhibit proliferation of Tl 165 cells induced by membrane-bound BAFF is also demonstrated. The bispecific antibody described herein effectively inhibits proliferation induced by membrane-bound BAFF similarly to the positive control BAFF antibody (4A5-3.1.1-B4 of US7,317,089). Moreover, similar inhibition is observed in the presence of a saturating amount of IL-17.

[0194] [Injection of human IL-17 leads to a rapid and transient increase in mouse CXCL1 in the circulation. Regular female C57B16 mice (n=8 per group) are injected SC with either bispecific antibody (66 meg / mouse), or a positive control anti-IL-17 antibody (Fab 126 of US7, 838,638, 50 meg / mouse) or negative control antibody (huIgG4, 50 meg / mouse). Two days later, mice receive a single IP injection of human IL-17 (3 meg / mouse) and 2 hours later serum is collected and stored at -80°C until analysis. The concentration of CXCL1 is determined by ELISA. Microtiter plates are coated with an antibody capturing human Fc (Jackson ImmunoResearch 109-005-098, 1 mcg / mL) and incubated overnight at 4°C. Plates are washed, blocked with casein, and 100 mcl of serum (1 : 1000 dilution) is added. Plates are incubated for 2h at RT, washed and an HRP-labeled detection antibody (anti-human IgG, Jackson ImmunoResearch 709-035-149) is added. Plates are incubated for l hour at RT, washed and developed using TMB substrate and read using a plate reader. The concentration is calculated based on appropriate standard curves. IL-17-induced levels of CXCL1 after exposure to bispecific antibody.

[0195] These data confirms that human IL-17 results in an increase in serum CXCL1 levels. However, in the presence of the bispecific antibody these results demonstrate that the IL-17- induced increase of CXCL1 is reduced (P<0.01, ANOVA) relative to animals that receive the negative control antibody. The reduction in CXCL1 with bispecific antibody is comparable to that observed with the positive control anti-IL-17 antibody. Equivalent exposure to eitherAttorney Docket No. ZURAP001WO bispecific antibody, the positive and negative control antibodies within each group is confirmed by quantitative ELISA. Thus, bispecific antibody described herein effectively neutralizes biological effects induced by human IL-17 in the mouse. P value determination is compared to negative control / IL-17 group.

[0196] Mice that carry a transgene encoding soluble human BAFF have an abnormally high number of B lymphocytes in the spleen.

[0197] Mice transgenic for human BAFF (n=5 per group) are injected IP with either a single dose of bispecific antibody (660 meg / mouse), or a positive control anti-BAFF antibody (4A5- 3.1.1-B4 US7,317,089, 500 meg / mouse) or negative control antibody (huIgG4, 500 meg / mouse). Eight days later, serum and spleens are collected. A single cell suspension of spleen cells is prepared and the total number of leukocytes is determined after lysing the red blood cells. The relative percentage of B lymphocytes is determined using the cell surface marker B220 by flow cytometry. The total number of B cells per spleen is calculated by multiplying the percentage of B220 positive cells by the total number of lymphocytes in the spleen. Microtiter plates are coated with an antibody capturing human Fc (Jackson ImmunoResearch 109-005-098, 1 mcg / mL) and incubated overnight at 4°C. Plates are washed, blocked with casein, and 100 mcl of serum (1 :5000 dilution) is added. Plates are incubated for 2h at RT, washed and an HRP-labeled detection antibody (anti-human IgG, Jackson ImmunoResearch 709-035-149) is added. Plates are incubated for l hour at RT, washed and developed using TMB substrate and read using a plate reader. The concentration is calculated based on appropriate standard curves. B cell numbers in the spleen of mice transgenic for human BAFF after exposure of bispecific antibody.

[0198] These results demonstrate that the number of B cells in the spleens of mice transgenic for human BAFF is reduced (p<0.0001, ANOVA) by a single administration of bispecific antibody. This normalization of B cell numbers is equivalent to that observed with the positive control BAFF antibody. Equivalent exposure to either bispecific antibody, the positive and negative control antibodies within each group is confirmed by quantitativeAttorney Docket No. ZURAP001WO ELISA. Thus, bispecific antibody described herein effectively neutralizes biological effects induced by human BAFF in the mouse. P value determination is compared to negative control group.

[0199] The bispecific antibody is formulated in PBS at pH 7.4. The bispecific antibody is concentrated from 1-2 mg / mL to a concentration ranging from 52 mg / mL to 58 mg / mL using Amicon concentrators. Concentrated samples are stored at 25°C over a period of 4 weeks. Samples are analyzed for percent high molecular weight (%HMW) with size exclusion chromatography (SEC) at initial concentration, 1 day, 1 week, and 4 weeks incubations. SEC is performed on an Agilent 1100 system using a TSK G3000SW-XL (Tosoh Bioscience) column. PBS + 0.35M NaCl, pH 7.4 is used as the mobile phase running at 0.5 mL / min for 35 minutes. A volume of l uL of the concentrated antibody is injected into the column and the detection is measured at 280nm. Chromatograms are analyzed using ChemStation and % high molecular weight (HMW) is calculated using the ratio of AUC of the peaks eluted before the monomer peak to total AUC. Samples stored at 25°C at different time points are analyzed for %HMW and the results are summarized in Table 5. Summary of % high molecular weight species measured by SE-HPLC.

[0200] Preliminary studies with a starting bispecific antibody comprising a BAFF antibody of WO2003016468 and an IL-17 antibody of WO2007070750 demonstrated that after concentration to only 6 mg / mL, a 25% increase in % HMW species was detected by SE- HPLC after 3 weeks storage at 4°C in PBS, and at 30 mg / mL the increase in % HMW species was 15% after just 2 days storage at 4°C in PBS. These results demonstrate that the bispecific antibody described herein has much improved properties, including decreased aggregation and increased physical stability, over the starting bispecific antibody. Example 2: Dose Selection for Tibulizumab

[0201] A combined PK dataset from individuals administered tibulizumab or placebo (including 24 patients with Sjögren's syndrome, 33 patients with rheumatoid arthritis, and 8Attorney Docket No. ZURAP001WO healthy participants) was evaluated to predict BAFF and IL-17 response through population PK modeling. Free BAFF concentration and free IL-17 concentration relative to baseline were predicted using a pharmacokinetic / pharmacodynamic PK / PD model based on assayed free drug, total soluble BAFF, and total soluble IL-17. Results are shown in Table 1 and Figure 1. Table 1. Model-predicted maximum change from baseline of free unbound BAFF and IL-17 concentration following the last dose of tibulizumab administrationCI = confidence interval; Q2W = once every two weeks; Q4W = once every four weeks

[0202] The pharmacokinetics of tibulizumab have not been measured clinically in skin or lungs. A PK / PD model with a theoretical skin / lung compartment was developed to provide comparative predictions for diseases involving those tissues. Total and free target BAFF and IL-17 were simulated for 150 mg and 300 mg Q4W dosing regimens administered subcutaneously for 24 weeks (with an additional dose of 150 mg and 300 mg at Week 2, respectively).

[0203] Predicted median trough changes from baseline (5th / 95thpercentile) were calculated for free BAFF and IL-17 for peripheral blood and skin / lung at weeks 16 and 24. Results are shown in Table 2, Figure 2 (predicted blood PK for the 150 mg regimen), Figure 3 (predicted skin / lung PK for the 150 mg regimen), Figure 4 (predicted blood PK for the 300 mg regimen), and Figure 5 (predicted skin / lung PK for the 300 mg regimen).

[0204] Steady state was reached by week 12 for both dosing regimens. For the 150 mg regimen, the lower predicted concentration of tibulizumab in skin and lung tissue relative to peripheral blood resulted in lower target engagement (Table 2), with median steady state trough target engagement ~ 75% for BAFF and ~79% for IL-17. In addition, variability for skin and lung was higher than in peripheral blood.Attorney Docket No. ZURAP001WO

[0205] For the 300 mg regimen, the lower predicted concentration of tibulizumab in skin and lung tissue relative to peripheral blood again resulted in lower target engagement (Table 2), with median steady state trough target engagement between 83 and 87% for both BAFF and IL-17. Variability for skin and lung was also higher than in blood, but was reduced relative to the 150 mg regimen. Table 2. Model-predicted change from baseline of free BAFF and IL-17 trough concentration in peripheral blood and skin / lung following the last dose of tibulizumab administrationCFB = change from baseline; Q4W = once every 4 weeks

[0206] The efficacy and safety of tibulizumab in hidradenitis suppurativa patients will be investigated for two doses in a phase 2 study. 150 mg Q4W and 300 mg Q4W (with additional 150 mg and 300 mg doses at Week 2, respectively) were selected for the study based on factors including predicted target engagement in skin (particularly with respect to trough concentrations), predicted safety risk and margin, and feasibility for administration. The additional dose of each at Week^2 will be included with the aim of facilitating more rapid achievement of steady state.Attorney Docket No. ZURAP001WO Example 3: Safety and Efficacy in Patients with Moderate to Severe Hidradenitis Suppurativa (HS)

[0207] In a phase 2 clinical trial study, hidradenitis suppurativa patients will be randomized into three treatment groups in a 1: 1: 1 ratio: (1) administration of tibulizumab at dose level 1 (150 mg once every 4 weeks (Q4W) with an additional 150 mg dose at week 2); (2) administration of tibulizumab at dose level 2 (300 mg Q4W with an additional 300 mg dose at week 2); and (3) matching placebo, each of which is administered via subcutaneous (SC) injection.

[0208] Randomization will be stratified by Hurley staging for HS and prior use of anti-TNF alpha therapies. This period of the study (Period 1) will be conducted over 16 weeks, as a double-blind, placebo-controlled treatment period to evaluate efficacy and safety. All patients who complete study treatment in Period 1, attend their Week 16 visit, and are deemed by the Investigator to have a favorable benefit:risk for continuation in the study, will be eligible to continue into an open label extension (OLE) period (Period 2), during which all patients will receive tibulizumab (150 mg) administered via SC injection Q4W for a treatment period of 16 weeks.

[0209] In the event that a patient has an acutely painful lesion, investigators will have the option to intervene with either an injection of intralesional triamcinolone acetonide suspension or performance of incision and drainage. Two protocol-allowed interventions are permitted during Period 1. Patients requiring more than two interventions during Period 1 are to be discontinued from the study.

[0210] Qualified patients are males and females > 18 years old, having lesions in at least two distinct anatomical areas, at least one of which is Hurley Stage II or III, and a total abscess and inflammatory count (AN) ≥ 5.

[0211] Study objectives and endpoints of Period 1 include the assessment of safety, efficacy, effect on HS lesions, and effect on HS-related quality of life. For example, endpoints at Week 16 will include percentage change from baseline in AN count; achievement of HiSCR50 and HiSCR75 (defined as at least a 50% and 75% reduction from baseline in abscess and inflammatory nodule (AN) count with no increase from baseline in abscess or draining fistula count, respectively); change from baseline in dermatology life quality index (DLQI) score; change from baseline in HS-PtGA score; change from baseline in skin pain NRS; incidence and severity of treatment-emergent adverse events (TEAEs) and change from baseline in vital signs, ECG parameters, and clinical laboratory results.Attorney Docket No. ZURAP001WO

[0212] Additional endpoints may include evaluation of pharmacokinetics, immunogenicity, potential biomarkers (including to predict or reflect patient response), and potential genetic variations (including to predict or reflect patient response). For example, endpoints at specified weeks may include: percentage change from baseline in AN count; achievement of HiSCR50, HiSCR75, and HiSCR 90 (defined as at least a 50%, 75%, and 90% reduction from baseline in abscess and inflammatory nodule (AN) count with no increase from baseline in abscess or draining fistula count, respectively); change from baseline in draining tunnel count; change from baseline in international hidradenitis suppurative severity score system (IHS4) score; occurrence of a flare (where a flare is defined as ≥25% increase from baseline in AN count with an increase in AN count of ≥2 relative to baseline); change from baseline in DLQI score; change from baseline in HS-PtGA score; achievement of ≥4-point reduction from baseline in DLQI score; change from baseline in skin pain NRS; change in suicide risk as assessed using the C-SSRS; serum tibulizumab concentration; anti-drug antibodies against tibulizumab; change from baseline in peripheral blood markers; and assessment of DNA samples for gene polymorphisms that may affect clinical response to tibulizumab.

[0213] Safety, tolerability, and the effect on HS lesions will be evaluated in Period 2, and may include the following: incidence and severity of TEAEs, change from baseline in vital signs, ECG parameters, and clinical laboratory results; change in suicide risk; percentage change from baseline in AN count; achievement of HiSCR50, HiSCR75, and HiSCR90; change from baseline in draining tunnel count; change from baseline in international hidradenitis suppurative severity score system (IHS4) score baseline; occurrence of flare; change from baseline in DLQI score; change from baseline in HS-PtGA score; change from baseline in NRS; serum tibulizumab concentrations; anti-drug antibodies against tibulizumab at baseline; and change from baseline in peripheral blood biomarkers.

[0214] Although the disclosure has been described with reference to the above examples, it will be understood that modifications and variations are encompassed within the spirit and scope of the disclosure. The various embodiments described above can be combined to provide further embodiments. All of the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and / or listed in the Application Data Sheet are incorporated herein by reference, in their entirety. Aspects of the embodiments can be modified, if necessary to employ concepts of the various patents, applications and publications to provide yet further embodiments.Attorney Docket No. ZURAP001WO

[0215] These and other changes can be made to the embodiments in light of the above- detailed description. In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and the claims but should be construed to include all possible embodiments along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the disclosure.

Claims

Attorney Docket No. ZURAP001WO What is claimed in:

1. A method of treating hidradenitis suppurativa in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of a bispecific antibody against interleukin 17 (IL-17) and human B cell activating factor (BAFF).

2. The method of claim 1, wherein the bispecific antibody comprises two first polypeptides and two second polypeptides.

3. The method of claim 2, wherein the first polypeptide comprises a first heavy chain variable region (HCVR1), a heavy chain constant region (CH), a second heavy chain variable region (HCVR2) and a second light chain variable region (LCVR2).

4. The method of claim 3, wherein HCVR1 comprises CDRHl-1, CDRHl-2, and CDRHl- 3; HCVR2 comprises CDRH2-1, CDRH2-2, and CDRH2-3; and / or LCVR2 comprises CDRL2-1, CDRL2-2 and CDRL2-3.

5. The method of claim 2, wherein the second polypeptide comprises a first light chain variable region (LCVRl) and a light chain constant region (CL).

6. The method of claim 5, wherein LCVRl comprises CDRLl-1, CDRLl-2 and CDRLl-3.

7. A method of treating hidradenitis suppurativa in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of a bispecific antibody, or a variant thereof, wherein the bispecific antibody comprises two first polypeptides and two second polypeptides wherein the amino acid sequence of the first polypeptide is SEQ ID NO: 1, or a variant thereof, and the amino acid sequence of the second polypeptide is SEQ ID NO:2, or a variant thereof.

8. The method of any one of the preceding claims, wherein the hidradenitis suppurativa is moderate to severe hidradenitis suppurativa.

9. The method of any one of the preceding claims, wherein the subject has lesions in at least two distinct anatomic areas prior to treatment.

10. The method of any one of the preceding claims, wherein the median size of the subject’s lesions is reduced after administration of the bispecific antibody.

11. The method of any one of the preceding claims, wherein the number of the subject’s lesions is reduced after administration of the bispecific antibody.

12. The method of claim 11, wherein the number of the subject’s lesions is reduced by at least a 50% reduction in the subject relative to baseline lesion count.Attorney Docket No. ZURAP001WO 13. The method of any one of the preceding claims, wherein the subject’s pain associated with the subject’s lesions is reduced after administration of the bispecific antibody.

14. The method any one of the preceding claims, wherein the subject’s time to new lesions is increased after administration of the bispecific antibody.

15. The method of any one of the preceding claims, wherein the subject has no increase in an abscess count and / or no increase in a draining fistula count following administration with the bispecific antibody.

16. The method of any one of the preceding claims, wherein the hidradenitis suppurativa in the human subject failed to resolve after treatment with a tumor necrosis factor alpha inhibitor.

17. The method of any one of the preceding claims, wherein the subject had an inadequate response to, contraindication to, or was intolerant to oral antibiotics for treatment of hidradenitis suppurativa.

18. The method of any one of the preceding claims, wherein the subject has previously been administered an anti-TNF alpha therapy.

19. The method of any one of the preceding claims, wherein the subject is selected from a subject having an abscess and inflammatory nodule (AN) count of greater than or equal to 3 at baseline, a subject who is a female, a subject who is over 40 years old, a subject who is a smoker, or any combination thereof.

20. The method of any one of claims 9 to 19, wherein the subject is selected from a subject having moderate to severe HS, a Hurley staging system category of Hurley Stage II or III, and / or a total abscess and inflammatory count (AN) ≥ 5.

21. The method of any one of the preceding claims, wherein the subject’s Hidradenitis Suppurativa Clinical Response (HiSCR) score is improved after administration of the bispecific antibody.

22. The method of any one of the preceding claims, wherein the subject has a HiSCR improvement following administration selected from HiSCR50, HiSCR75, and HiSCR90.

23. The method of any one of the preceding claims, wherein the subject’s Hidradenitis Suppurativa Physician's Global Assessment (HS-PGA) score is improved after administration of the bispecific antibody.

24. The method of any one of the preceding claims, wherein the subject’s International Hidradenitis Suppurativa Severity Score System (IHS4) score is improved after administration of the bispecific antibody.Attorney Docket No. ZURAP001WO 25. The method of any one of the preceding claims, wherein the subject’s Dermatology Life Quality Index (DLQI) is improved after administration of the bispecific antibody.

26. The method of any one of the preceding claims, wherein the bispecific antibody is administered in an amount of about 100, about 110, about 120, about 125, about 130, about 140, about 150, about 160, about 170, about 175, about 180, about 190, about 200, about 210, about 220, about 225, about 230, about 240, about 250, about 260, about 270, about 275, about 280, about 290, about 300, about 310, about 320, about 325, about 330, about 340, about 350, about 360, about 370, about 375, about 380, about 390, or about 400 mg.

27. The method of claim 26, wherein the bispecific antibody is administered in an amount of about 150 mg.

28. The method of claim 26, wherein the bispecific antibody is administered in an amount of about 240 mg.

29. The method of claim 26, wherein the bispecific antibody is administered in an amount of about 300 mg.

30. The method of any one of claims 19 to 29, wherein the bispecific antibody is administered once per week, once every other week, once every two weeks, once every three weeks, once every four weeks, or once every month.

31. The method of claim 26, wherein the bispecific antibody is administered in an amount of about 150 mg once every four weeks.

32. The method of claim 26, wherein the bispecific antibody is administered in an amount of about 240 mg once every four weeks.

33. The method of claim 26, wherein the bispecific antibody is administered in an amount of about 300 mg once every four weeks.

34. The method of any one of the preceding claims, wherein the bispecific antibody is administered as a subcutaneous injection.

35. The method of any one of claims 1 to 25, wherein the bispecific antibody is administered as 240 mg Q4W tibulizumab.

36. The method of claim 35, further comprising administering an additional 240 mg of tibulizumab between the first and second administration of 240 mg Q4W tibulizumab.

37. The method of any one of claims 1 to 25, wherein the bispecific antibody is administered as 150 mg Q4W tibulizumab.

38. The method of claim 37, further comprising administering an additional 150 mg of tibulizumab between the first and second administration of 150 mg Q4W tibulizumab.Attorney Docket No. ZURAP001WO 39. The method of any one of claims 1 to 25, wherein the bispecific antibody is administered as 300 mg Q4W tibulizumab.

40. The method of claim 39, further comprising administering an additional 300 mg of tibulizumab between the first and second administration of 300 mg Q4W tibulizumab.

41. The method of any one of the preceding claims, wherein the subcutaneous injection is in a liquid formulation comprising 75 mg / mL tibulizumab; 20 mM histidine; 270 mM sucrose; and polysorbate.

42. The method of any one of the preceding claims, wherein the liquid formulation has a pH of about 5.

5.

43. The method of any of the preceding claims, wherein the bispecific antibody is administered by autoinjector.

44. The method of any one of claims 1 to 33, wherein the bispecific antibody is administered as an intravenous injection.

45. The method of any one of the preceding claims, further comprising evaluating a biomarker.

46. A liquid pharmaceutical composition comprising: tibulizumab; a buffer; a stabilizer or tonicity agent; and a solubilizer.

47. A liquid pharmaceutical composition comprising: tibulizumab; histidine; sucrose; and polysorbate.

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