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, or a variant thereof, 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. ZURAP003WO METHODS OF TREATMENT

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 636,380, filed April 19, 2024; and U.S. Provisional Application No. 63 / 659,464, filed June 13, 2024, each of 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 April 3, 2025 is named ZURAP003WO.xml, and is 9,084 bytes in size.

[0003] Sjögren's syndrome is a chronic autoimmune disease characterized by progressive inflammation of the glands (e.g., the lacrimal and salivary glands), largely due to increased levels of activated lymphocytes (T and B cells) and autoantibodies. The hallmark symptoms of the disorder are dry mouth and dry eyes. Sjögren's syndrome may also cause skin, nose and vaginal dryness, and can affect other organs of the body including the kidneys, blood vessels, lungs, liver, pancreas and brain. Sjögren's syndrome affects 1-4 million people in the United States, where it is currently the second most common autoimmune rheumatic disease. The majority of Sjögren's sufferers are at least 40 years old at the time of diagnosis, and women are nine times more likely to develop the disease. Sjögren's syndrome can occur as a primary rheumatic condition or as a secondary disorder in association with other rheumatic diseases, such as systemic lupus erythematosus (“lupus”), scleroderma, biliary cirrhosis or rheumatoid arthritis.

[0004] The uvea is the middle layer inside an outermost layer of an eye ball composed of an iris, a ciliary body and a choroid membrane. Inflammation in the uvea is defined as uveitis. The uvea is susceptible to inflammation because it has abundant blood vessels and many connective tissues. Symptom of uveitis include a loss of vision, myodesopsia, pain, bleeding, and lacrimation. Uveitis may be classified into anterior uveitis, intermediate uveitis, posterior uveitis or pan-uveitis depending on location of inflammation. Also, uveitis is divided into infectious uveitis caused by viruses or germs, and non- infectious uveitis resulting from an abnormality of the autoimmune system, where a majority of such uveitis is caused by immunological factors. However, an accurate pathogenesis of uveitis has not yet been disclosed.

[0005] Behçet's disease is an inflammatory disease of unknown cause of multi-organ invasive and has four main symptoms: (1) relapsed aphthous ulcers of the oral mucosa, (2) skinAttorney Docket No. ZURAP003WO symptoms such as nodular erythema and follicular rash, (3) uveitis of the eye, and (4) vulvar ulcers. Among the symptoms of Behçet's disease, ocular lesions due to uveitis (particularly retinal uveitis) affect visual acuity and in some cases lead to serious dysfunction leading to blindness. Uveitis inflammation is characterized by repeated acute inflammation (ocular seizures). Uveitis mainly composed of inflammation in the front is referred to as iridescitis (or iritis), and the uveitis mainly composed of lesions in the funds is referred to as retinal uveitis (or choroid).

[0006] Lichen planus (LP) is a chronic, inflammatory disorder that can involve the skin, oral or genital mucosa, conjunctiva, and nails (sometimes concomitantly), while maintaining a consistent histologic phenotype. On the skin, (cutaneous lichen planus (CLP)) the disease presents as multiple papules, which can be localized or generalized, that are often extremely itchy and painful. Mucosal disease (mucosal lichen planus (MLP)) can consist of either asymptomatic plaques or extremely painful erosive lesions and ulcers. Lichen planopilaris (LPP), a follicular form of lichen planus, is a rare inflammatory lymphocyte-mediated disorder that selectively involves hair follicles. LPP leads to follicular destruction and, consequently, cicatricial alopecia. There is broad clinical overlap between the between CLP and MLP subtypes, with many patients presenting overlapping symptoms and lesions. At the same time, each subtype presents at different anatomical regions and with distinct clinical features, e.g., ulceration can be present in the mucosal subtype, but not in the cutaneous subtype, and hair follicle inflammation is a unique feature of lichen planopilaris.

[0007] LP affects up to 5% of the worldwide population. Oral or genital involvement occurs in 60-70% of patients, and it may be the sole manifestation of disease in 20-30% of patients. The disease course is unpredictable and typically lasts 1-2 years, but can follow a chronic, relapsing course. Although LP is rather frequently encountered in clinical practice and portends a negative impact on health-related quality-of-life, scarce efforts have been devoted to characterize the management and the proper treatment of LP.

[0008] Psoriasis is a chronic relapsing disease of the skin characterized by variable clinical features. The lesions are classified as erythrosquamous, which indicates that both the vasculature (erythema) and the epidermis (increased scale formation) are involved. Pustular psoriasis is a variant of psoriasis with sterile pustules presenting locally or broadly on the skin either acutely, subacutely, or chronically. Pustular psoriasis is frequently categorized as either generalized pustular psoriasis (GPP) or localized pustular psoriasis. In generalized pustular psoriasis, sterile pustules can cover almost the entire body, and in the localized form, pustules are confined to isolated locations. GPP includes von ZumbuschAttorney Docket No. ZURAP003WO (acute GPP), generalized form of acrodermatitis continua (Hallopeau), acute exanthematic, GPP of pregnancy (impetigo herpetiformis), infantile and juvenile GPP, and circinate and annular GPP, whilst localized pustular psoriasis includes chronic and acute palmoplantar pustulosis.

[0009] GPP is a rare form of psoriasis that usually presents as numerous aseptic pustules occurring on reddened skin over the whole body and is a potentially life-threatening systemic inflammatory disease. It is frequently associated with fever, and involves the formation of subcorneal pustules histopathologically characterized by Kogoj's spongiform pustules. It is characterized by recurrence in periodic episodes. In the course of the disease, GPP patients may have laboratory abnormalities associated with systemic inflammation response, frequently complicated with mucosal symptoms and arthritis, and less frequently with respiratory failure, eye disease, or secondary amyloidosis. GPP can be preceded by psoriasis vulgaris (PV). However, this is not always the case, and recent research shows that GPP that is not preceded by PV is a distinct subtype of GPP, distinguishable from GPP with PV by a deficiency in the Interleukin 36 Receptor Antagonist (DITRA) due to mutations in IL36RN.

[0010] Impetigo herpetiformis (IH) is among rare dermatosis of pregnancy, which is currently considered as a form of generalized pustular psoriasis. It is diagnosed by characteristic lesions of erythematous patches and grouped pustules mostly in the third trimester of pregnancy and may have systemic associations.

[0011] Pityriasis rubra pilaris (PRP) is a rare inflammatory skin disease phenotypically presenting features within the spectrum of psoriasis and atopic eczema. It is characterized by reddish orange scaly plaques, palmoplantar keratoderma, and keratotic follicular papules. The disease may progress to erythroderma with distinct areas of uninvolved skin, the so-called islands of sparing.

[0012] There are significant unmet needs for safe, effective, and tolerable treatment for certain diseases or disorders characterized by IL-17 and / or BAFF-mediated inflammation . The present disclosure satisfies these needs and provides related advantages as well. SUMMARY

[0013] The bispecific antibodies described herein have been engineered to target T-cell and B-cell pathways, but have not been evaluated in patients with certain diseases or disorders characterized by IL-17 and / or BAFF-mediated inflammation. Described herein are studies to determine and evaluate doses and dosing regimens that generate sufficient target engagement in the heterogeneous tissues impacted by certain diseases or disorders characterized by IL-17 and / or BAFF-mediated inflammation.Attorney Docket No. ZURAP003WO

[0014] 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.

[0015] Also provided are methods of 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 against interleukin 17 (IL-17) and human B cell activating factor (BAFF).

[0016] Also provided are methods of treating certain diseases or disorders characterized by IL-17 and / or BAFF-mediated inflammation 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.

[0017] 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.

[0018] In some embodiments, the bispecific antibody is tibulizumab, or a variant thereof. In some embodiments, the bispecific antibody is tibulizumab.

[0019] In some embodiments, the disease or disorder characterized by IL-17 and / or BAFF- mediated inflammation is chosen from Sjögren's syndrome, rheumatoid arthritis, uveitis, Behçet's Disease, lichen planus, pustular psoriasis, impetigo herpetiformis, pityriasis rubra pilaris, pyoderma gangrenosum, and dermatomyositis.

[0020] 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

[0021] 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.

[0022] Figure 2 shows the design of a phase 1 randomized multiple ascending dose study that investigated the safety, tolerability, pharmacokinetics and pharmacodynamics of subcutaneously administered tibulizumab in patients with Sjogren’s syndrome.Attorney Docket No. ZURAP003WO

[0023] Figure 3 shows observed and model-predicted total BAFF (upper panel) and total IL- 17 (lower panel) concentrations versus time following multiple tibulizumab administrations.

[0024] Figure 4 shows that serological levels of total BAFF and IL-17A increased following tibulizumab administration, reflecting target engagement.

[0025] Figure 5 shows that total B cell counts were dose-dependently reduced in Sjogren’s syndrome patients throughout the clinical trial.

[0026] Figure 6 shows the model-predicted blood tibulizumab pharmacokinetics for total and free BAFF and IL-17 following 24-week subcutaneous administration of 150 mg Q4W with an additional dose at Week 2.

[0027] Figure 7 shows the model-predicted skin / lung tibulizumab pharmacokinetics for total and free BAFF and IL-17 following 24-week subcutaneous administration of 150 mg Q4W with an additional Dose at Week 2.

[0028] Figure 8 shows the model-predicted blood tibulizumab pharmacokinetics for total and free BAFF and IL-17 following 24-week subcutaneous administration of 300 mg Q4W with an additional dose at Week 2.

[0029] Figure 9 shows the model-predicted skin / lung tibulizumab pharmacokinetics for total and free BAFF and IL-17 following 24-week subcutaneous administration of 300 mg Q4W with an additional dose at Week 2. DETAILED DESCRIPTION

[0030] Provided are methods of treating a disease or disorder chosen from Sjögren's syndrome, rheumatoid arthritis, uveitis, Behçet's Disease, lichen planus, pustular psoriasis, impetigo herpetiformis, pityriasis rubra pilaris, pyoderma gangrenosum, and dermatomyositis 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.

[0031] In some embodiments, the bispecific antibody is administered subcutaneously.

[0032] 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. InAttorney Docket No. ZURAP003WO 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).

[0033] 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.

[0034] In some embodiments, the bispecific antibody is administered by subcutaneous injections totaling about 120 mg every 2 weeks. 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.

[0035] 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).

[0036] In some embodiments, the bispecific antibody is administered by subcutaneous injections of about 300mg every 2 weeks.

[0037] In some embodiments, the bispecific antibody is administered by subcutaneous injections of about 300mg every 4 weeks. In some embodiments, the bispecific antibody is administered by subcutaneous injections of about 300mg every month.

[0038] In some embodiments, the bispecific antibody is administered by subcutaneous injections of about 150mg every 2 weeks.

[0039] In some embodiments, the bispecific antibody is administered by subcutaneous injections of about 150mg every 4 weeks. In some embodiments, the bispecific antibody is administered by subcutaneous injections of about 150mg every month.Attorney Docket No. ZURAP003WO

[0040] 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.

[0041] In some embodiments, the bispecific antibody is administered in an amount of about 150 mg.

[0042] In some embodiments, the bispecific antibody is administered in an amount of about 240 mg.

[0043] In some embodiments, the bispecific antibody is administered in an amount of about 300 mg.

[0044] 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.

[0045] In some embodiments, the bispecific antibody is administered in an amount of about 150 mg once every four weeks.

[0046] In some embodiments, the bispecific antibody is administered as tibulizumab 150 mg every four weeks.

[0047] In some embodiments, the method further comprises administering an additional 150 mg tibulizumab between the first and second administration of 150 mg every four weeks.

[0048] In some embodiments, the bispecific antibody is administered in an amount of about 240 mg once every four weeks.

[0049] In some embodiments, the bispecific antibody is administered as tibulizumab 240 mg every four weeks.

[0050] In some embodiments, the method further comprises administering an additional 240 mg tibulizumab between the first and second administration of 240 mg every four weeks.

[0051] In some embodiments,the bispecific antibody is administered in an amount of about 300 mg once every four weeks.Attorney Docket No. ZURAP003WO

[0052] In some embodiments,the bispecific antibody is administered as tibulizumab 300 mg every four weeks.

[0053] In some embodiments, the method further comprises administering an additional 300 mg tibulizumab between the first and second administration of 300 mg every four weeks.

[0054] In some embodiments, the bispecific antibody is administered according to a multiple variable dose regimen.

[0055] 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.

[0056] 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.

[0057] 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.

[0058] 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 isAttorney Docket No. ZURAP003WO 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.

[0059] 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.

[0060] In some embodiments, the disease or disorder is Sjögren's syndrome. In some embodiments, the Sjögren's syndrome occurs alone. In some embodiments, the disease or disorder is primary Sjögren's syndrome. In some embodiments, the Sjögren's syndrome occurs in the presence of another autoimmune connective tissue disease such as rheumatoid arthritis, lupus, or scleroderma. In some embodiments, the disease or disorder is secondary Sjögren's syndrome.

[0061] In some embodiments, the disease or disorder is rheumatoid arthritis.

[0062] In some embodiments, the disease or disorder is uveitis. In some embodiments, the uveitis is anterior uveitis, intermediate uveitis, posterior uveitis or pan-uveitis. In some embodiments, the uveitis is infectious uveitis or non-infectious uveitis.

[0063] In some embodiments, the disease or disorder is Behçet's Disease.

[0064] In some embodiments, the disease or disorder is lichen planus. In some embodiments, the subject has cutaneous lichen planus (CLP), mucosal lichen planus (MLP) or lichen planopilaris (LPP).

[0065] In some embodiments, the disease or disorder is Pustular Psoriasis. In some embodiments, the subject has generalized pustular psoriasis (GPP). In some embodiments, the subject has GPP without psoriasis vulgaris. In some embodiments, the subject has GPP with psoriasis vulgaris. In some embodiments, the subject has with palmoplantar pustular psoriasis (PPP).

[0066] In some embodiments, the disease or disorder is impetigo herpetiformis.

[0067] In some embodiments, the disease or disorder is pityriasis rubra pilaris.

[0068] In some embodiments, the disease or disorder is pyoderma gangrenosum.

[0069] In some embodiments, the disease or disorder is dermatomyositis.Attorney Docket No. ZURAP003WO

[0070] 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.

[0071] 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.

[0072] 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

[0073] 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.

[0074] 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. ZURAP003WO

[0075] 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).

[0076] 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. ZURAP003WO

[0077] 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.

[0078] 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.

[0079] 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 polypeptides 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.

[0080] 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. ZURAP003WO 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.

[0081] 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).

[0082] In some embodiments, the relationship of the various regions and linkers is as follows:

[0083] 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. ZURAP003WO 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.

[0084] 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.

[0085] 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. ZURAP003WO

[0086] 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.

[0087] 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.

[0088] In some embodiments, the bispecific antibody is tibulizumab. In some embodiments, the bispecific antibody comprises components of tabalumab combined with components of ixekizumab.

[0089] 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.

[0090] 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.

[0091] 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. ZURAP003WO

[0092] 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.

[0093] A particular DNA polynucleotide sequence encoding the first polypeptide having an amino acid sequence of SEQ ID NO: 1 is: CAGGTGCAACTACAGCAGTGGGGCGCAGGACTGTTGAAGCCTTCGGAGACCCTG TCCCTC ACCTGCGCTGTCTATGGTGGGTCCTTCAGTGGTTACTACTGGAGCTGGATTCGCC AGCCC CCAGGGAAGGGGCTGGAGTGGATTGGGGAAATCAATCATAGTGGAAGCACCAAC TACAAC CCGTCCCTCAAGAGTCGAGTCACCATATCAGTAGACACGTCCAAGAACCAGTTCT CCCTG AAACTGAGCTCTGTGACCGCCGCGGACACGGCTGTGTATTACTGTGCGAGAGGG TATTAC GATATTTTGACTGGTTATTATTACTACTTTGACTACTGGGGCCAGGGAACCCTGG TCACC GTCTCCTCAGCCTCCACCAAGGGCCCATCGGTCTTCCCGCTAGCGCCCTGCTCCA GGAGC ACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAAC CGGTG ACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTG TCCTA CAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCT TGGGC ACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGAC AAGAGA GTTGAGTCCAAATATGGTCCCCCATGCCCACCCTGCCCAGCACCTGAGTTCCTGG GGGGA CCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCTCCCGGA CCCCT GAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAttorney Docket No. ZURAP003WO AACTGG TACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCA GTTCAAC AGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACG GCAAG GAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACC ATCTCC AAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAG GAGGAG ATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGC GACATC GCCGTGGAGTGGGAAAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCC TCCCGTG CTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCA GGTGG CAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACT ACACA CAGAAGAGCCTCTCCCTGTCTCCTGGAGGCGGAGGATCCGGGGGAGGGGGTACC GGAGGA GGGGGCTCGCAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGG TCCTCAGTGAAGGTTTCCTGCAAGGCATCTGGTTACAAGTTCACTGACTACCATA TTCATTGGGTG CGACAGGCCCCTGGACAATGCCTTGAGTGGATGGGAGTAATTAATCCTACTTATG GTACT ACTGACTACAATCAGCGGTTCAAAGGCCGTGTCACCATTACCGCGGACGAATCC ACGAGC ACAGCCTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATTAC TGTGCG AGATATGATTACTTTACTGGGACGGGTGTGTACTGGGGCCAAGGAACCCTGGTCA CCGTC TCCTCAGGTGGCGGAGGATCTGGTGGAGGTGGCTCAGGAGGTGGCGGAAGCGGC GGAGGT GGAAGTGATATTGTGATGACTCAGACTCCACTCTCCCTGTCCGTCACCCCTGGAC AGCCGAttorney Docket No. ZURAP003WO GCCTCCATCTCCTGCAGATCTAGTAGGAGCCTTGTACACAGTCGTGGAGAAACCT ATTTA CATTGGTATCTGCAGAAGCCAGGCCAATCTCCACAGCTCCTAATTTATAAAGTTT CCAAC CGGTTTATTGGGGTCCCAGACAGATTCAGCGGCAGTGGGTCAGGCACAGATTTCA CACTG AAAATCAGCAGGGTGGAGGCCGAAGATGTTGGGGTTTATTACTGCTCTCAAAGT ACACAT CTTCCATTCACGTTTGGCTGCGGGACCAAGCTGGAGATCAAA SEQ ID NO:3.

[0094] A particular DNA polynucleotide sequence encoding the second polypeptide having an amino acid sequence of SEQ ID NO:2 is: GAAATTGTGTTGACGCAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGGAAAGAG CCACC CTCTCCTGCAGGGCCAGTCAGAGTGTTAGCCGCTACTTAGCCTGGTACCAGCAGA AACCT GGCCAGGCTCCCAGGCTCCTCATCTATGATGCATCCAACAGGGCCACTGGCATCC CAGCC AGGTTCAGTGGCAGTGGGTCTGGGACAGACTCCACTCTCACCATCAGCAGCCTAG AGCCT GAAGATTTTGCAGTTTATTACTGTCAGCAGCGTAGCAACTGGCCTCGGACGTTCG GCCAA GGGACCAAGGTGGAAATCAAACGAACTGTGGCGGCGCCATCTGTCTTCATCTTCC CGCCA TCTGATGAGCAGTTGAAATCCGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACT TCTAT CCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAAC TCCCAG GAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAACACC CTGACG CTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCAT CAGGGC CTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGC SEQ ID NO:4.Attorney Docket No. ZURAP003WO

[0095] 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.

[0096] 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.

[0097] 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.

[0098] 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 ofAttorney Docket No. ZURAP003WO 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, between 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

[0099] 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 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%, orAttorney Docket No. ZURAP003WO 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 antibody 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.

[0100] 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.

[0101] 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 alsoAttorney Docket No. ZURAP003WO 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.

[0102] 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 acid 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.

[0103] 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.

[0104] 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).

[0105] 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-Attorney Docket No. ZURAP003WO 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- aceylgalactosamine, galactose, or xylose to a hydroxyamino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine may also be used.

[0106] 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).

[0107] 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

[0108] 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.Attorney Docket No. ZURAP003WO

[0109] 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.

[0110] 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 to 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.

[0111] In some embodiments, the pharmaceutical composition comprises tibulizumab.

[0112] In some embodiments, the pharmaceutical composition is formulated for injection.

[0113] In some embodiments, the pharmaceutical composition is formulated for subcutaneous injection.

[0114] In some embodiments, the pharmaceutical composition is formulated for intravenous injection.

[0115] In some embodiments, the pharmaceutical composition is in a liquid formulation.

[0116] 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.

[0117] 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 reducedAttorney Docket No. ZURAP003WO compared to the administration of ixekizumab with citrate. In some embodiments, the buffer does not comprise citrate.

[0118] In some embodiments, the pharmaceutical composition comprises histidine. In some embodiments, the buffer is histidine.

[0119] In some embodiments, the pharmaceutical composition is lyophilized. In some embodiments, the pharmaceutical composition has not been lyophilized.

[0120] In some embodiments, the pharmaceutical composition comprises sucrose. In some embodiments, the stabilizer is sucrose. In some embodiments, the tonicity agent is sucrose.

[0121] 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.

[0122] 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.

[0123] 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 has a pH close to that of human skin. In some embodiments, the pharmaceutical composition has a pH close to that of human skin impacted by disease.

[0124] 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.

[0125] 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 ofAttorney Docket No. ZURAP003WO 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.

[0126] In some embodiments, the pharmaceutical composition comprises tibulizumab, a buffer, a stabilizer or tonicity agent, and a solubilizer.

[0127] In some embodiments, the pharmaceutical composition is a subcutaneous injection in a liquid formulation comprising tibulizumab, histidine, sucrose, and polysorbate.

[0128] In some embodiments, the pharmaceutical composition comprises tibulizumab and has a pH of about 5.5.

[0129] In some embodiments, the pharmaceutical composition comprises about 75 mg / mL tibulizumab and has a pH of about 5.5.

[0130] In some embodiments, the pharmaceutical composition comprises about 75 mg / mL tibulizumab and histidine.

[0131] In some embodiments, the pharmaceutical composition comprises about 75 mg / mL tibulizumab and does not comprise citrate.

[0132] In some embodiments, the pharmaceutical composition has a pH of about 5.5 and comprises histidine.

[0133] In some embodiments, the pharmaceutical composition has a pH of about 5.5 and does not comprise citrate.

[0134] In some embodiments, the pharmaceutical composition comprises about 75 mg / mL tibulizumab; about 20 mM histidine; about 270 mM sucrose; and polysorbate.

[0135] In some embodiments, the pharmaceutical composition comprises about 75 mg / mL tibulizumab; about 20 mM histidine; about 270 mM sucrose; and polysorbate 80; and has a pH of about 5.5.

[0136] In some embodiments, the polysorbate is polysorbate 80.

[0137] 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.Attorney Docket No. ZURAP003WO In some embodiments, the pharmaceutical composition has a viscosity of less than about 30, 25, or 20 centiPoise.

[0138] 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 about 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. 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.

[0139] 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.

[0140] 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.

[0141] 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,Attorney Docket No. ZURAP003WO 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.

[0142] In some embodiments, the pharmaceutical composition is in an autoinjector. In some embodiments, the pharmaceutical composition is administered by autoinjector.

[0143] As used in the present specification, the following words and phrases are generally intended to have the meanings as set forth herein.

[0144] 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.

[0145] 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.

[0146] 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 unacceptableAttorney Docket No. ZURAP003WO 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 not 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.

[0147] 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.”

[0148] ADVERSE EVENT: As used herein, an “adverse event” is an untoward medical occurrence that is associated with treatment with the active agent.

[0149] 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.

[0150] 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.

[0151] 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.

[0152] 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 andAttorney Docket No. ZURAP003WO 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 within the judgment of the clinician. In some embodiments, the therapeutically effective amount is the standard dose.

[0153] CLINICAL RESPONSE: As used herein, a "clinical response" refers to an indicator of therapeutic effectiveness of an agent.

[0154] 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.

[0155] When an integer is used in a method disclosed herein, the term “about” can be inserted before the integer.

[0156] 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.

[0157] 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.

[0158] Each embodiment described herein is to be applied mutatis mutandis to each and every other embodiment unless specifically stated otherwise.

[0159] 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.

[0160] 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. FunctionallyAttorney Docket No. ZURAP003WO equivalent products, compositions, and methods are clearly within the scope of the invention(s), as described herein.

[0161] 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 a 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.

[0162] Further embodiments include the embodiments disclosed in the following Examples, which is not to be construed as limiting in any way.Attorney Docket No. ZURAP003WO EXAMPLES Example 1: Bispecific Antibodies

[0163] 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

[0164] 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. AntibodyAttorney Docket No. ZURAP003WO samples are prepared at 10 mcg / mL by dilution into running buffer. Human IL-17 or human 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. Table 1: Binding affinity to human IL-17 and human BAFF by the bispecific antibody.

[0165] These results demonstrate that the bispecific antibody described herein binds human IL-17 and human BAFF.

[0166] 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 lOmM 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. ZURAP003WO typically at ~ 1.0 based on a kinetic binding experiment. Control BAFF Ab is 4A5-3.1.1-B4 of US7,317,089.

[0167] 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.

[0168] 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.

[0169] 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.

[0170] 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. ZURAP003WO 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.

[0171] 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).

[0172] 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.

[0173] 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.

[0174] 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. ZURAP003WO 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.

[0175] 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-lbeta. 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).

[0176] 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. ZURAP003WO 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.

[0177] 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.

[0178] [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 1 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.

[0179] 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. ZURAP003WO 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.

[0180] Mice that carry a transgene encoding soluble human BAFF have an abnormally high number of B lymphocytes in the spleen.

[0181] 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 1 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.

[0182] 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. ZURAP003WO 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.

[0183] 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.

[0184] 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

[0185] 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. ZURAP003WO 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 model based on assayed free drug, total soluble BAFF, and total soluble IL-17. Results are shown in the table below and Figure 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

[0186] 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).

[0187] 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 5, Figure 6 (predicted blood PK for the 150 mg regimen), Figure 7 (predicted skin / lung PK for the 150 mg regimen), Figure 8 (predicted blood PK for the 300 mg regimen), and Figure 9 (predicted skin / lung PK for the 300 mg regimen).

[0188] 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. ZURAP003WO

[0189] 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 (see table below), 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. 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

[0190] The efficacy and safety of tibulizumab will be investigated in phase 2 studies with between 150 mg Q4W and 300 mg Q4W (and potentially an additional matched dose at Week 2). This dosage regimen will be selected based on factors including disease involvement in blood, lung, and skin (with a particular focus on target engagement for trough concentrations), predicted safety risk and margin, and feasibility for administration. The additional dose at Week^2 may be included with the aim of facilitating more rapid achievement of steady state.Attorney Docket No. ZURAP003WO Example 3: Clinical Trial in Patients with Systemic Sclerosis

[0191] A phase 2 study in patients with systemic sclerosis will be conducted. There will be assessments performed at Screening (-14 days to Study Hour 0), Baseline (Study Visit 1 / Study Hour 0), Week 12 (Study Visit 2), and Week 24 (Study Visit 3). Safety will be monitored throughout the Treatment Period. The study will evaluate patients with SSc having a mRSS score of 10-29 and presenting the first symptoms of sclerosis other than Raynaud’s phenomenon within 60 months of enrollment.

[0192] The objectives of the study may include the determination of: • safety of the bispecific antibody in patients with SSc as measured by treatment emergent adverse events (TEAE) and standard laboratory assessments. • whether administration of the bispecific antibody improves the patient’s mRSS score. • whether administration of the bispecific antibody improves the patient’s scleroderma health assessment questionnaire disability index. • whether administration of the bispecific antibody improves the patient’s visual analog scale (VAS) score for Raynaud's phenomenon, pain, ulcers, and / or breathing. whether administration of the bispecific antibody improves the patient’s ratio of forced vital capacity to diffusion capacity (FVC / DLCO). Example 4: Clinical Trial in Patients with Sjögren's Syndrome

[0193] A phase 1 randomized multiple ascending dose study investigated the safety, tolerability, pharmacokinetics and pharmacodynamics of subcutaneously administered tibulizumab in patients with Sjogren’s syndrome.

[0194] Participants were males and females between the ages of 18 to 65 with confirmed diagnosis of Sjogren’s syndrome using the American-European Consensus Group criteria with active disease. Participants were seropositive for anti-nuclear antibodies (SSA or SSB) at screening or documented within 6 months prior to screening.

[0195] Serum samples were analyzed for levels of tibulizumab using IL-17A and BAFF antigen capture ELISAs.

[0196] Levels of IL-17A and BAFF were assessed in sera using electrochemiluminescent assays.

[0197] Epiontis ID®was used to phenotype cells using cell-type specific epigenetic markers.

[0198] OLINK®was used to assess circulating levels of inflammatory mediators.Attorney Docket No. ZURAP003WO

[0199] Statistical differences between treatment arms were assessed using Graph Pad Prism software.

[0200] The study design is shown in Figure 2. Participants were administered subcutaneous tibulizumab (30 mg Q4W, 100 mg Q4W, 300 mg Q4W, or 300 mg Q2W) for 12 weeks followed by another 12-week follow-up period. Serum samples were collected throughout the trial for the assessment of target engagement (circulating levels of IL-17A and BAFF), pharmacokinetics, anti-tibulizumab antibodies (ADA), and exploratory biomarkers.

[0201] Baseline characteristics of the subjects are shown below.Q2W = once every two weeks; Q4W = once every 4 weeks

[0202] Figure 3 shows observed and model-predicted total BAFF (upper panel) and total IL- 17 (lower panel) concentrations versus time following multiple tibulizumab administrations. Based on PK modeling, the T1 / 2 was calculated at 26.9 days.

[0203] Figure 4 shows that serological levels of total BAFF and IL-17A increased following tibulizumab administration, reflecting target engagement. At doses of 100 mg Q4W and higher, the total BAFF and IL-17A concentrations appeared to plateau, suggesting near maximum target engagement.

[0204] Figure 5 shows that total B cell counts were dose-dependently reduced in Sjogren’s syndrome patients throughout the clinical trial. Additionally, administration of tibulizumab was associated with lower levels of Th1 cells throughout the clinical trial.Attorney Docket No. ZURAP003WO

[0205] The levels of 40 inflammatory mediators were analyzed using proteomic methods. The table below highlights some of the modulatory activity of tibulizumab on mediators associated with immune defense (serum amyloid a), Th2 biology (interleukin-5), T regulatory cells (interleukin-10) and fibroblast repair (basic fibroblast growth factor).

[0206] Treatment with tibulizumab was generally well tolerated in patients with Sjogren’s syndrome.

[0207] Mechanistic reductions in total B cells and modulation of inflammatory mediators suggest the potential for tibulizumab in additional autoimmune conditions.

[0208] 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.

[0209] 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. ZURAP003WO What is claimed in:

1. A method of treating a disease or disorder chosen from Sjögren's syndrome, rheumatoid arthritis, uveitis, Behçet's Disease, lichen planus, pustular psoriasis, impetigo herpetiformis, pityriasis rubra pilaris, pyoderma gangrenosum, and dermatomyosis 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 a disease or disorder chosen from Sjögren's syndrome, rheumatoid arthritis, uveitis, Behçet's Disease, lichen planus, pustular psoriasis, impetigo herpetiformis, pityriasis rubra pilaris, pyoderma gangrenosum, and dermatomyositis 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 disease or disorder is uveitis.

9. The method of claim 8, wherein the uveitis is anterior uveitis, intermediate uveitis, posterior uveitis or pan-uveitis.

10. The method of any one of claims 1 to 8, wherein the uveitis is infectious uveitis or non- infectious uveitis.Attorney Docket No. ZURAP003WO 11. The method of any one of claims 1 to 7, wherein the disease or disorder is Behçet's Disease.

12. The method of any one of claims 1 to 7, wherein the disease or disorder is lichen planus.

13. The method of claim 12, wherein the subject has cutaneous lichen planus (CLP), mucosal lichen planus (MLP) or lichen planopilaris (LPP).

14. The method of any one of claims 1 to 7, wherein the disease or disorder is pustular psoriasis.

15. The method of claim 14, wherein the subject has generalized pustular psoriasis (GPP) without psoriasis vulgaris.

16. The method of claim 14, wherein the subject has GPP with psoriasis vulgaris.

17. The method of any one of claims 1 to 7, wherein the subject has palmoplantar pustular psoriasis (PPP).

18. The method of any one of claims 1 to 7, wherein the disease or disorder is impetigo herpetiformis.

19. The method of any one of claims 1 to 7, wherein the disease or disorder is pityriasis rubra pilaris.

20. The method of any one of claims 1 to 7, wherein the disease or disorder is pyoderma gangrenosum.

21. The method of any one of claims 1 to 7, wherein the disease or disorder is dermatomyositis.

22. The method of any one of claims 1 to 7, wherein the disease or disorder is Sjögren's syndrome.

23. The method of any one of claims 1 to 7, wherein the disease or disorder is rheumatoid arthritis.

24. The method of any of claims 1 to 23, 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.

25. The method of claim 24, wherein the bispecific antibody is administered in an amount of about 150 mg.Attorney Docket No. ZURAP003WO 26. The method of claim 24, wherein the bispecific antibody is administered in an amount of about 240 mg.

27. The method of claim 24, wherein the bispecific antibody is administered in an amount of about 300 mg.

28. The method of any one of claims 24 to 27, 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.

29. The method of claim 25, wherein the bispecific antibody is administered in an amount of about 150 mg once every four weeks.

30. The method of claim 29, wherein the bispecific antibody is administered as tibulizumab 150 mg once every four weeks.

31. The method of claim 30, further comprising administering an additional 150 mg tibulizumab between the first and second administration of 150 mg 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 32, wherein the bispecific antibody is administered as tibulizumab 240 mg once every four weeks.

34. The method of claim 33, further comprising administering an additional 240 mg tibulizumab between the first and second administration of 240 mg every four weeks.

35. The method of claim 27, wherein the bispecific antibody is administered in an amount of about 300 mg once every four weeks.

36. The method of claim 35, wherein the bispecific antibody is administered as tibulizumab 300 mg once every four weeks.

37. The method of claim 36, further comprising administering an additional 300 mg tibulizumab between the first and second administration of 300 mg every four weeks.

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

39. The method of any one of claims 1 to 37, wherein the bispecific antibody is administered as an intravenous injection.

40. The method of claim 38, wherein the subcutaneous injection is in a liquid formulation comprising 75 mg / mL tibulizumab; 20 mM histidine; 270 mM sucrose; and polysorbate.

41. The method of claim 40, wherein the liquid formulation has a pH of about 5.5.Attorney Docket No. ZURAP003WO 42. The method of any of the preceding claims, wherein the bispecific antibody is administered by autoinjector.

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

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

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