CD40L-specific TN3-derived scaffolds for the treatment and prevention of Sjogren's syndrome

Abstract

Compositions and methods are provided that include a CD40L-specific Tn3 scaffold, as well as methods of utilizing the same for the prevention and treatment of Sjogren's syndrome.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 375,282, filed September 12, 2022, and U.S. Provisional Application No. 63 / 249,553, filed September 28, 2021, the disclosures of which are incorporated herein by reference in their entireties for all purposes.

[0002] Reference to Electronic Sequence Listing The contents of the electronic sequence listing (HOPA_038_01WO_SeqList_ST26.xml, size: 24,514 bytes; and creation date: September 6, 2022) are incorporated herein by reference in their entirety.

[0003] (Technical field) The present disclosure relates to compositions comprising a Tn3 scaffold and methods of using same in the treatment and prevention of Sjogren's syndrome. [Background technology]

[0004] Sjögren's syndrome (SS) is a systemic autoimmune disease characterized by chronic lymphocytic inflammation of the exocrine glands, primarily the salivary and lacrimal glands, leading to loss of function manifested as excessive dryness. In addition, extraglandular manifestations have been described as multiorgan disorders affecting the musculoskeletal, pulmonary, renal, nervous, cutaneous, gastrointestinal, hematologic, hepatobiliary, or vascular systems, with fatigue being one of the most prominent comorbidities. Although joints, lungs, skin, and peripheral nerves are the most frequently involved organ systems, cytopenias, hypocomplementemia, and cryoglobulinemia at the time of diagnosis are strongly associated with increased systemic activity.

[0005] The subjective aspects of SS, including patient perception of dryness, musculoskeletal pain, and fatigue, can be debilitating and have been shown to have a substantial negative impact on quality of life (QoL). Dryness and fatigue are the main causes of reduced QoL. QoL is also affected by psychological and emotional problems, as well as dependency on relatives in daily life and difficulties at work, as well as impaired social life with other challenges. SS patients with exocrine insufficiency and severe subjective symptoms, defined as a European League Against Rheumatism (EULAR) Sjögren's Syndrome Patient-Reported Index (ESSPRI) score ≥ 5, considered the cut-off point for an "inadequate symptom status," but with less systemic disease activity (using the EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) score < 5), represent a large subset of SS patients who have been excluded from recent clinical trials, despite their substantial disease burden and overall unacceptable health status.

[0006] Approximately 15-20% of patients with SS have systemic symptoms beyond the commonly affected exocrine glands (salivary glands and eyes). Moderate to high systemic activity in patients with SS can be defined by an ESSDAI ≥ 5. The most common of these symptoms include arthritis, pulmonary disease, renal disease, vasculitis, neuropathy, and autonomic nervous system dysfunction with glandular involvement. Moderate to high disease activity can be debilitating and can lead to failure of affected organs or hematologic lesions such as thrombocytopenia and lymphoma, which are associated with an increased risk of mortality. Biologics or disease-modifying antirheumatic drugs (DMARDs) have not been shown to be effective in significantly reducing systemic disease activity in SS. Currently, there are no approved immunomodulators or evidence-based treatment guidelines available for the treatment of extraglandular manifestations of SS. Thus, the standard of care for extraglandular manifestations varies widely and is based on local practice, expert opinion, and the treating physician's personal experience.

[0007] New therapies aimed at reducing the substantial disease burden and overall unacceptable health status are needed. Summary of the Invention

[0008] Provided herein is a method for treating Sjogren's syndrome (SS) in a subject in need thereof, comprising administering to the subject a Tn3 scaffold comprising a CD40L-specific monomeric subunit. In some embodiments, the Tn3 scaffold specifically binds to CD40L. In some embodiments, the monomeric subunit comprises seven beta strands designated A, B, C, D, E, F, and G, and six loop regions designated AB, BC, CD, DE, EF, and FG, where the AB loop comprises SEQ ID NO: 11, the BC loop comprises SEQ ID NO: 12, the CD loop comprises SEQ ID NO: 13, the DE loop comprises SEQ ID NO: 14, the EF loop comprises SEQ ID NO: 15, and the FG loop comprises SEQ ID NO: 16. In some embodiments, the Tn3 scaffold comprising a CD40L-specific monomeric subunit is administered at a dose of about 1500 mg, about 2500 mg, or about 3000 mg.

[0009] Provided herein is a method of treating Sjogren's syndrome (SS) in a subject in need thereof, comprising administering to the subject a Tn3 scaffold at a dose of about 1500 mg, about 2500 mg, or about 3000 mg, wherein the Tn3 scaffold comprises SEQ ID NO:1.

[0010] Methods are provided for treating Sjogren's syndrome (SS) in a subject in need of treatment for Sjogren's syndrome (SS), the method comprising administering to the subject a Tn3 scaffold comprising a CD40L-specific monomeric subunit; wherein the Tn3 scaffold specifically binds to CD40L; and wherein the monomeric subunit comprises seven beta strands designated A, B, C, D, E, F, and G, and six loop regions designated AB, BC, CD, DE, EF, and FG, wherein the AB loop comprises SEQ ID NO:11, the BC loop comprises SEQ ID NO:12, the CD loop comprises SEQ ID NO:13, the DE loop comprises SEQ ID NO:14, the EF loop comprises SEQ ID NO:15, and the FG loop comprises SEQ ID NO:16, wherein the Tn3 scaffold comprising a CD40L-specific monomeric subunit is administered at a dose of about 1500 mg, about 2500 mg, or about 3000 mg. In some embodiments, the at least one CD40L-specific monomeric subunit comprises seven beta chains designated A, B, C, D, E, F, and G, where beta chain A comprises SEQ ID NO:5, beta chain B comprises SEQ ID NO:6, beta chain C comprises SEQ ID NO:17, beta chain D comprises SEQ ID NO:18, beta chain E comprises SEQ ID NO:19, beta chain F comprises SEQ ID NO:20, and beta chain G comprises SEQ ID NO:21. In some embodiments, the subject has a European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index (ESSDAI) score of ≧5. In some embodiments, the ESSDAI score is assessed based on the ESSDAI domains consisting of skin, kidney, joint, muscle, hematology, glandular, constitutional, nodal, and biological domains. In some embodiments, the subject has (a) an ESSDAI score of <5, (b) an EULAR Sjogren's Syndrome Patient-Reported Index (ESSPRI) score of ≧5, and (c) a total stimulated salivary flow rate of >0.1 ml / min.

[0011] In some embodiments, the Tn3 scaffold is administered as an induction dose and then as a maintenance dose. In some embodiments, the induction dose comprises administering the Tn3 scaffold once about every two weeks for at least three administrations. In some embodiments, the maintenance dose comprises administering the Tn3 scaffold once about every four weeks for at least four administrations. In some embodiments, the time between the induction dose and the maintenance dose is about four weeks. In some embodiments, the Tn3 scaffold is administered once about every four weeks, once about every two months, once about every three months, once about every four months, or once about every six months. In some embodiments, the Tn3 scaffold is administered at least four times. In some embodiments, the Tn3 scaffold is administered at least five times. In some embodiments, the Tn3 scaffold is administered intravenously, subcutaneously, orally, intramuscularly, intrathecally, sublingually, rectally, vaginally, dermally, systemically, topically, transdermally, or by inhalation. In some embodiments, the Tn3 scaffold is administered intravenously. In some embodiments, the Tn3 scaffold comprises two CD40L-specific monomer subunits connected in series. In some embodiments, each of the two CD40L-specific monomer subunits comprises SEQ ID NO:3. In some embodiments, the CD40L-specific monomer subunits are connected by a linker. In some embodiments, at least one CD40L-specific monomer subunit is directly fused or conjugated to polyethylene glycol (PEG). In some embodiments, at least one CD40L-specific monomer subunit is fused or conjugated to polyethylene glycol (PEG) via a linker. In some embodiments, the linker comprises a peptide linker. In some embodiments, the linker comprises SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, or SEQ ID NO:10. In some embodiments, at least one CD40L-specific monomer subunit is fused or conjugated to albumin. In some embodiments, the albumin is human serum albumin (HSA). In some embodiments, the HSA is a variant HSA comprising SEQ ID NO:4.

[0012] Methods of treating Sjogren's syndrome (SS) in a subject in need thereof are provided. In some embodiments, the methods may include administering a Tn3 scaffold at a dose of about 1500 mg, about 2500 mg, or about 3000 mg to a subject in need thereof. In some embodiments, the methods may include administering a Tn3 scaffold consisting of SEQ ID NO:1. In some embodiments, the Tn3 scaffold is administered as an induction dose and then as one or more maintenance doses. In some embodiments, the induction dose and the maintenance dose are the same amount. In some embodiments, the induction dose and the at least one maintenance dose are different amounts. In some embodiments, at least one dose is 3000 mg. In some embodiments, the induction dose and at least one maintenance dose are administered about one month apart, about two months apart, about three months apart, about four months apart, or about six months apart. In some embodiments, the induction dose includes at least three administrations of the Tn3 scaffold about every two weeks, and the maintenance dose includes at least four administrations of the Tn3 scaffold, once about every four weeks. In some embodiments, the Tn3 scaffold comprises SEQ ID NO: 1. In some embodiments, the method is effective to reduce ESSDAI score compared to other equivalent methods in which the subject receives equivalent administration. In some embodiments, the reduction is at least about 1 point, 2 points, 3 points, 4 points, or 5 points. In some embodiments, the reduction is at least about 6 points. [Brief description of the drawings]

[0013] [Figure 1]An exemplary study flow diagram is shown, including adults with moderate to severe (moderate to high) systemic disease activity as defined by ESSDAI ≥ 5, with anti-Ro autoantibodies and / or rheumatoid factor (RF) present. Seventy-four subjects were randomized (1:1) to receive either 1500 mg of VIB4920 or placebo intravenously once every 2 weeks for 3 doses, followed by 4 additional doses once every 4 weeks (Q4W) (Stage I). Starting on day 169, subjects randomized to VIB4920 received 5 doses of placebo Q4W, and subjects randomized to placebo received 5 doses of VIB4920 Q4W (Stage II). Randomization was stratified by EULAR Sjogren's Syndrome Disease Activity Index (ESSDAI) score at screening (< 10 points vs ≥ 10 points). Δ=delta; D=days; EoS=end of study; EP=endpoint; ESSDAI=European League Against Rheumatism Sjögren's Syndrome Disease Activity Index; ESSPRI=EULAR Sjögren's Syndrome Patient-Reported Index; IA=interim analysis; mos=months; PE=primary endpoint. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] Provided herein is a cluster of differentiation (CD) 40 ligand (CD40L)-third fibronectin type III (Fn3) protein domain of human tenascin-C (Tn3) protein fusion protein, Tn3 scaffold, and methods of using it in SS. In some embodiments, the provided compositions and methods are utilized to treat glandular and extraglandular symptoms in SS patients with moderate to high systemic disease activity, and subjective complaints of dryness, fatigue, and pain in SS patients with exocrine dysfunction. Cluster of differentiation (CD40) activation has been shown to be important in germinal center formation, immunoglobulin (Ig) class switching, and expression of cytokines such as interferon-alpha, tumor necrosis factor-alpha, and interleukin-6, all of which have previously been linked to the pathophysiology of SS. Dysregulation of CD40 / CD40L has been observed in both circulating cells and epithelial salivary cells in SS patients. These observations suggest that inhibition of the CD40L / CD40 pathway may be beneficial in SS.

[0015] The following description includes information that may be useful in understanding the present disclosure. No admission is made that any information provided herein is prior art or relevant to the presently claimed disclosure, or that any publication specifically or implicitly referenced is prior art.

[0016] definition Although the following terms are believed to be well understood to those of skill in the art, the following definitions are provided to facilitate description of the presently disclosed subject matter.

[0017] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. References to technology used herein are intended to refer to technology as commonly understood in the art, and include variations of these technologies and / or equivalent technology alternatives that are apparent to those of ordinary skill in the art.

[0018] As used herein, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise.

[0019] The term "about" or "approximately" when immediately preceding a numerical value means a range (e.g., ±10% of the value). For example, unless otherwise indicated in the context of the disclosure or inconsistent with such an interpretation, "about 50" can mean 45 to 55, "about 25,000" can mean 22,500 to 27,500, etc. For example, in a list of numerical values, e.g., "about 49, about 50, about 55, ...", "about 50" means a range that spans less than half the interval(s) of the values ​​before and after it, e.g., a range of more than 49.5 and less than 52.5. Furthermore, the expressions "about" "less than" a value or "about" "greater than" a value should be understood in light of the definition of the term "about" provided herein. Similarly, when preceding a series of numerical values ​​or a range of values ​​(e.g., "about 10, 20, 30" or "about 10 to 30"), the term "about" refers to all values ​​in the series, or to the end points of the range, respectively.

[0020] The term "subject" as used herein refers to any individual, e.g., a human or non-human mammal, for whom diagnosis, prognosis, or treatment is desired. The term "subject" may refer to a human or non-human mammal that is suffering from, likely to be suffering from, or suspected of suffering from a disease. The terms "subject" and "patient" are used interchangeably herein. In some embodiments, the subject is a mammal. Mammals include primates, e.g., humans, monkeys, chimpanzees, and apes, as well as non-primates, e.g., livestock, including laboratory animals (e.g., rabbits and rodents, e.g., guinea pigs, rats, or mice) and household pets and livestock (e.g., cats, dogs, pigs, cows, sheep, goats, horses, rabbits), and non-domestic animals, e.g., wild animals, birds, reptiles, and the like; fish, and the like. Typically, the subject is a human subject.

[0021] As used herein, the term "subject in need thereof" includes subjects who can benefit or will benefit from the methods described herein. Subjects in need of treatment include, but are not limited to, subjects who already have a condition or disorder, subjects prone to have a condition or disorder, subjects suspected of having a condition or disorder, and subjects with a condition or disorder in which the condition or disorder is to be prevented, alleviated, or reversed.

[0022] As used herein, "treating" or "treating" refers to the management and care of a subject for the purpose of combating a disease, condition, or disorder, and includes administration of a Tn3 scaffold used in the methods described herein to alleviate symptoms or complications of the disease, condition, or disorder, or to eliminate the disease, condition, or disorder. Thus, the term "treating" or "treating" refers to both therapeutic and prophylactic or preventative measures, the purpose of which is to prevent, slow (alleviate), or ameliorate the progression of a disease (e.g., SS). Beneficial or desired clinical outcomes include, but are not limited to, alleviation of symptoms, reduction in the extent of the disease, stabilization of disease pathology (i.e., not worsening), delay or slowing of disease progression, remission or alleviation of disease pathology, and reversal of disease (whether partial or complete). The term "treating" may also include treatment of in vitro cells or animal models.

[0023] As used herein, "fused" refers to at least two recombinantly linked polypeptides. As used herein, "conjugated" refers to the formation of a bond between two components by a chemical reaction. The bond may be covalent or non-covalent. Usually, the two components that are conjugated to each other are chemically connected via a covalent bond.

[0024] When referring to nucleic acid or protein sequences, the term "identity" is used to indicate the similarity between two sequences. Unless otherwise specified, the percent identity described herein is determined using the BLAST algorithm, available on the world wide web at the following address: blast.ncbi.nlm.nih.gov / Blast.cgi, using default parameters.

[0025] Described herein are methods for treating SS using a Tn3 scaffold that contains CD40L-specific monomeric subunits.

[0026] In some embodiments, the Tn3 scaffold is used in a method of treating SS. SS is a systemic autoimmune disease characterized by chronic lymphocytic inflammation of exocrine glands, primarily salivary and lacrimal glands, leading to loss of function manifested as excessive dryness. Extraglandular symptoms are described as multiorgan disorders affecting the musculoskeletal, pulmonary, renal, nervous, cutaneous, gastrointestinal, hematological, hepatobiliary, or vascular systems, with fatigue being one of the most prominent comorbidities. SS may also occur in association with other autoimmune diseases. In some embodiments, the method includes treating SS patients with moderate to high systemic disease activity by administering the Tn3 scaffold. In some embodiments, moderate to high systemic disease activity is defined by a European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index (ESSDAI) of ≧5. In some embodiments, the methods include treating a patient with SS having moderate to severe (and potentially severe) subjective symptoms by administering a Tn3 scaffold, in some embodiments, moderate to severe subjective symptoms are defined by a EULAR Sjogren's Syndrome Patient-Reported Index (ESSPRI) score of ≧5 and residual stimulated salivary flow rate, but with mild systemic disease activity as defined by an ESSDAI score of <5.

[0027] In some embodiments, the method includes treating SS in a subject in need thereof by administering a Tn3 scaffold comprising a CD40L-specific monomeric subunit. In some embodiments, the Tn3 scaffold specifically binds to CD40L. In some embodiments, the monomeric subunit of the Tn3 scaffold comprises seven beta strands designated A, B, C, D, E, F, and G, and six loop regions designated AB, BC, CD, DE, EF, and FG, where the AB loop comprises SEQ ID NO: 11, the BC loop comprises SEQ ID NO: 12, the CD loop comprises SEQ ID NO: 13, the DE loop comprises SEQ ID NO: 14, the EF loop comprises SEQ ID NO: 15, and the FG loop comprises SEQ ID NO: 16. In some embodiments, the Tn3 scaffold is VIB4920. The CD40 receptor is a member of the TNF family of receptors expressed on the plasma membrane of antigen-stimulated B cells, macrophages, and dendritic cells. The CD40 receptor functions to provide a costimulatory signal to antigen-bound B cells. The cognate ligand for CD40 is CD40L (also known as CD154), which is expressed on the plasma membrane of T cells and other cell types, including platelets.

[0028] Tn3 scaffold Provided herein is a composition that binds to CD40L. In some embodiments, the compositions provided include a CD40L antagonist. In some embodiments, provided herein is a composition that includes a Tn3 scaffold (e.g., a "Tn3 scaffold") that includes a CD40L-specific monomeric subunit. In some embodiments, provided herein is a composition that includes a Tn3 scaffold that includes two CD40L-specific monomeric subunits.

[0029] In some embodiments, the compositions provided may comprise an amino acid sequence as set forth in International Application Nos. PCT / US2012 / 059477 and PCT / US2019 / 052997, which are incorporated herein by reference in their entireties. In some embodiments, the compositions provided may comprise an amino acid sequence as set forth in SEQ ID NO:1 (referred to herein as VIB4920). VIB4920 comprises a bivalent CD40L-specific Tn3 protein fused to a protein.

[0030] In some embodiments, the CD40L monomer subunit of the Tn3 scaffold comprises seven beta strands designated A, B, C, D, E, F, and G, and six loop regions designated AB, BC, CD, DE, EF, and FG. In some embodiments, the Tn3 scaffold comprises a single CD40L-specific monomer subunit. In some embodiments, the Tn3 scaffold comprises two CD40L-specific monomer subunits. In some embodiments, the two CD40L-specific monomer subunits are connected in series. In some embodiments, the two CD40L-specific monomer subunits are connected by a linker. In some embodiments, the linker comprises a peptide linker, which may be a flexible peptide linker. In some embodiments, the peptide linker may be a peptide linker such as (G m X) n wherein X is serine (S), alanine (A), glycine (G), Leu (L), isoleucine (I), or valine (V); m and n are integer values; m is 1, 2, 3, or 4; and n is 1, 2, 3, 4, 5, 6, or 7.

[0031] In some embodiments, the Tn3 scaffold comprises a linker that comprises a functional moiety. In some embodiments, the functional moiety is an immunoglobulin or a fragment thereof. In some embodiments, the immunoglobulin or fragment thereof comprises an Fc domain. In some embodiments, the Fc domain is incapable of inducing at least one FcγR-mediated effector function (e.g., Fc-deficient). In some embodiments, the at least one FcγR-mediated effector function is antibody-dependent cellular cytotoxicity (ADCC).

[0032] In some embodiments, the Tn3 scaffold comprises seven beta strands designated A, B, C, D, E, F, and G, and six loop regions designated AB, BC, CD, DE, EF, and FG, where the AB loop comprises or consists of SEQ ID NO:11, the BC loop comprises or consists of SEQ ID NO:12, the CD loop comprises or consists of SEQ ID NO:13, the DE loop comprises or consists of SEQ ID NO:14, the EF loop comprises or consists of SEQ ID NO:15, and the FG loop comprises or consists of SEQ ID NO:16. In some embodiments, the Tn3 scaffold comprises or consists of SEQ ID NO:1 (also known as VIB4920). In some embodiments, beta chain A comprises or consists of SEQ ID NO:5, beta chain B comprises or consists of SEQ ID NO:6, beta chain C comprises or consists of SEQ ID NO:17, beta chain D comprises or consists of SEQ ID NO:18, beta chain E comprises or consists of SEQ ID NO:19, beta chain F comprises or consists of SEQ ID NO:20, and beta chain G comprises or consists of SEQ ID NO:21.

[0033] In some embodiments, one or more CD40L-specific Tn3 monomers have a beta chain A that comprises or consists of IEV (SEQ ID NO:5), RLDAPSQIEV (SEQ ID NO:23), or SQIEV (SEQ ID NO:24). In some embodiments, a Tn3 scaffold can comprise one or more CD40L-specific Tn3 monomers with the same or different beta chain A sequences. For example, a first CD40L-specific Tn3 monomer beta chain A can comprise or consist of IEV (SEQ ID NO:5), and a second CD40L-specific Tn3 monomer beta chain A can comprise or consist of RLDAPSQIEV (SEQ ID NO:23) or SQIEV (SEQ ID NO:24).

[0034] The Tn3 scaffold may have the amino acid sequence shown in SEQ ID NO:1 and described above, or may have one or more amino acid residue changes relative to the amino acid sequence shown in SEQ ID NO:1. For example, where the scaffold has an amino acid sequence change compared to that shown in SEQ ID NO:1, the change may be to one of the linkers. The Tn3 scaffold may include a Gly15 linker separating the two CD40L-specific monomers, and a Gly10 linker separating the CD40L-specific monomer from the HSA sequence. Both or either of these linkers may be altered, and may include, for example, a Gly2 linker, Gly10 linker, ... m X) n where X is serine (S), alanine (A), glycine (G), Leu (L), isoleucine (I), or valine (V); m and n are integer values; m is 1, 2, 3, or 4; and n is 1, 2, 3, 4, 5, 6, or 7. For example, one or both linkers may be modified to have an amino acid sequence comprising one of GGGGSGGGGS (SEQ ID NO: 7), GGGGSGGGGSGGGGS (SEQ ID NO: 8), GGGGGGGGGG (SEQ ID NO: 9), or GGGGGGGGGGGGGG (SEQ ID NO: 10). If the Tn3 scaffold has an amino acid sequence compared to the amino acid sequence shown in SEQ ID NO: 1, it may be due to a change(s) in the HSA amino acid sequence fused to the two CD40L-specific monomers. The HSA fused to two CD40L-specific monomers may be modified compared to the HSA fused to two CD40L-specific Tn3 monomers, except for at least one amino acid substitution; at positions selected from the group consisting of 407, 415, 463, 500, 506, 508, 509, 511, 512, 515, 516, 521, 523, 524, 526, 535, 550, 557, 573, 574, and 580, numbered relative to positions in full-length mature HSA; where the at least one amino acid substitution does not include a lysine (K) for glutamic acid (E) at position 573.

[0035] Exemplary sequences of Tn3 scaffolds are shown in Table 1. In some embodiments, the Tn3 scaffold comprises at least or up to about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or up to about 100% identity to any one of SEQ ID NOs: 1-25 shown in Table 1. In some embodiments, any one of the sequences in Table 1 may be modified. In some embodiments, the modifications include one or more truncations, deletions, insertions, and combinations thereof. Modifications may occur at any of the residues shown in Table 1, and at any number of residues in Table 1. In some embodiments, modifications may include 1-3, 1-5, 1-10, 5-20, 1-3, 1-5, 1-10, 1-20, 3-8, 3-10, 3-15, 5-8, 5-10, or 5-20 residues. In some embodiments, modifications may occur at up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, or 450 residues.

[0036] [Table 1-1]

[0037] [Table 1-2]

[0038] [Table 1-3]

[0039] [Table 1-4]

[0040] If the Tn3 scaffold has an amino acid sequence change compared to that shown in SEQ ID NO:1, the change may be to the amino acid sequence of one or both of the CD40L-specific Tn3 monomers, so long as it does not adversely affect the in vivo efficacy of the scaffold, e.g., the amino acid sequence change such that one or both of the CD40L-specific Tn3 monomers have the amino acid sequences shown in SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:22, and SEQ ID NO:25. In some embodiments, the first one or two N-terminal amino acid residues (SQ) may be absent and / or replaced with alternative amino acid residues. In some embodiments, the Tn3 scaffold comprises a monomer subunit comprising SEQ ID NO:22, SEQ ID NO:25, or both SEQ ID NO:22 and SEQ ID NO:25.

[0041] In some embodiments, the Tn3 scaffold comprises at least one CD40L-specific monomeric subunit linked to a heterologous moiety. In some embodiments, the heterologous moiety is selected from the group consisting of a protein, a peptide, a protein domain, a linker, a drug, a toxin, a cytotoxic agent, an imaging agent, a radionuclide, a radioactive compound, an organic polymer, an inorganic polymer, polyethylene glycol (PEG), biotin, albumin, an HSA FcRn binding moiety, an antibody or fragment thereof, a single chain antibody, a domain antibody, an albumin binding domain, an enzyme, a ligand, a receptor, a binding peptide, a non-FnIII scaffold, an epitope tag, a recombinant polypeptide polymer, a cytokine, and a combination of two or more of the foregoing moieties. In some embodiments, the heterologous moiety is albumin, and the albumin comprises human serum albumin. In some embodiments, the heterologous moiety is an antibody. In some embodiments, the antibody is selected from the group consisting of an Fc domain of an antibody, an antibody fragment, and a single chain antibody.

[0042] In some embodiments, the heterologous moiety is an antibody. In some embodiments, the antibody is selected from the group consisting of an Fc domain of an antibody, an antibody fragment, and a single chain antibody.

[0043] In some embodiments, the heterologous moiety is an imaging agent, such as a radionuclide or biotin. In some embodiments, the heterologous moiety is a drug, such as a cytotoxic agent or a radioactive compound.

[0044] In some embodiments, the heterologous moiety comprises PEG. In some embodiments, the Tn3 scaffold comprises at least one CD40L-specific monomer subunit fused or conjugated to PEG, either directly or via a linker. In some embodiments, both CD40L-specific monomer subunits are fused, conjugated, or connected to PEG via a linker. In some embodiments, the Tn3 scaffold comprises at least one (e.g., two) CD40L-specific monomer subunits fused or conjugated to PEG, either directly or via a linker.

[0045] In some embodiments, the heterologous moiety comprises albumin. In some embodiments, the Tn3 scaffold comprises at least one CD40L-specific monomer subunit fused or conjugated to albumin directly or via a linker. In some embodiments, the albumin is HSA. In some embodiments, the HSA is a variant HSA. In some embodiments, the amino acid sequence of the variant HSA is SEQ ID NO: 4. In some embodiments, the variant HSA has at least one improved property compared to native HSA or a native HSA fragment. In some embodiments, the amino acid sequence of the variant HSA is SEQ ID NO: 4, or a sequence having at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or up to 100% identity with SEQ ID NO: 4. In some embodiments, the improved property is an altered plasma half-life compared to the plasma half-life of native HSA or a native HSA fragment. In some embodiments, the altered plasma half-life is a longer plasma half-life compared to the plasma half-life of native HSA or a fragment of native HSA. In some embodiments, the altered plasma half-life is a shorter plasma half-life compared to the plasma half-life of native HSA or a fragment of native HSA.

[0046] Dosage In some embodiments, any composition comprising the Tn3 scaffold of the present disclosure can be administered in any form.In some embodiments, the Tn3 scaffold is administered intravenously, subcutaneously, orally, intramuscularly, intrathecally, sublingually, rectally, vaginally, cutaneously, systemically, topically, transdermally, or by inhalation.In some embodiments, the Tn3 scaffold is administered intravenously.In some embodiments, the Tn3 scaffold is administered by intravenous infusion.

[0047] The Tn3 scaffold of the present disclosure may be administered in any dose. In some embodiments, the Tn3 scaffold may be administered in a dose of about 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, 650 mg, 660 mg, 670 mg, 680 mg, 690 mg, 700 mg, 710 mg, 720 mg, 730 mg, 7 0mg, 1850mg, 1900mg, 1950mg, 2000mg, 2050mg, 2100mg, 2150mg, 2200mg, 2250mg, 2300mg, 235 0mg, 2400mg, 2450mg, 2500mg, 2550mg, 2600mg, 2650mg, 2700mg, 2750mg, 2800mg, 2850mg, 2900 mg, 2950mg, 3000mg, 3050mg, 3100mg, 3150mg, 3200mg, 3250mg, 3300mg, 3350mg, 3400mg, 3450 mg, 3500mg, 3550mg, 3600mg, 3650mg, 3700mg, 3750mg, 3800mg, 3850mg, 3900mg, 3950mg, 4000m g, 4050 mg, 4100 mg, 4150 mg, 4200 mg, 4250 mg, 4300 mg, 4350 mg, 4400 mg, 4450 mg, 4500 mg, 4550 mg, 4600 mg, 4650 mg, 4700 mg, 4750 mg, 4800 mg, 4850 mg, 4900 mg, 4950 mg, or about 5000 mg. Any of the foregoing doses can be effective doses for methods involving treatment, mitigation, or elimination.

[0048] In some embodiments, the Tn3 scaffold is administered at a dose of between about 800-5000 mg, 900-4900 mg, 1000-4800 mg, 1100-4700 mg, 1200-4600 mg, or 1300-4500 mg. In some embodiments, the Tn3 scaffold may be present in an amount of 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg, 2050 mg, 2100 mg, 2150 mg, 2200 mg, 2250 mg, 2300 mg, 2350 mg, 2400 mg, 2450 mg, 2500 mg, 2550 mg, 2600 mg, 2650 mg, 2700 mg, 2750 mg, 2800 mg, 2850 mg, 2900 mg, In some embodiments, the Tn3 scaffold is administered at a dose selected from the group consisting of 2950mg, 3000mg, 3050mg, 3100mg, 3150mg, 3200mg, 3250mg, 3300mg, 3350mg, 3400mg, 3450mg, 3500mg, 3550mg, 3600mg, 3650mg, 3700mg, 3750mg, 3800mg, 3850mg, 3900mg, 3950mg, 4000mg, 4050mg, 4100mg, 4150mg, 4200mg, 4250mg, 4300mg, 4350mg, 4400mg, 4450mg, and 4500mg. In some embodiments, the Tn3 scaffold is administered at a dose selected from the group consisting of 1500mg and 3000mg. In some embodiments, the Tn3 scaffold is administered at a dose of about 1500 mg. In some embodiments, the Tn3 scaffold is administered at a dose of about 3000 mg.

[0049] Dosing frequency In some embodiments, the Tn3 scaffold of the present disclosure is administered according to a schedule that produces optimal results.In some embodiments, the Tn3 scaffold is administered to the subject in need thereof about once a week, about twice a week, about every two weeks, about once a month, about every four weeks, about every two months, about every three months, about every 12 weeks, about every 15 weeks, about every 16 weeks, about every four months, about every five months, about every six months, or every six months.Any number of administrations may be provided to the subject in need.

[0050] The Tn3 scaffold of the present disclosure may be administered in a total dose of about 1-10, 10-50, 50-75, 75-100, 100-200, 200-300, or up to the lifetime of the subject. In some embodiments, the Tn3 scaffold is administered about 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to about 10 doses. In some embodiments, the Tn3 scaffold is administered in a total dose of at least about or up to about 2, 3, 4, or 5 doses.

[0051] In some embodiments, the subject is administered an effective dose about every 1, 2, 3, 4, 5, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, 3 years, 4 years, or 5 years after the start of treatment, or up to the subject's lifetime. In some embodiments, the subject is administered an effective dose on the 1st, 15th, 29th, and 57th days after the start of treatment. In some embodiments, the subject is administered 1500 mg to 3000 mg of Tn3 scaffold on the 1st, 15th, 29th, and 57th days after the start of treatment. In some embodiments, the subject is administered about 1500 mg to 3000 mg of the Tn3 scaffold about three times every two weeks, then every four weeks thereafter. In some embodiments, the subject is administered about 1500 mg of the Tn3 scaffold about three times every two weeks, then every four weeks thereafter. In some embodiments, the subject is administered about 3000 mg of the Tn3 scaffold at weeks 1, 4, and 12, then every twelve weeks thereafter. In some embodiments, the subject in need thereof is administered 1500 mg of the Tn3 scaffold on days 1, 15, 29, and 57 after the start of treatment. In some embodiments, the subject in need thereof is administered 1500 mg of the Tn3 scaffold on days 1 and 57 after the start of treatment. In some embodiments, the subject in need thereof is administered 3000 mg of the Tn3 scaffold on days 1, 15, 29, and 57 after the start of treatment. In some embodiments, a subject in need thereof is administered 3000 mg of a Tn3 scaffold on day 1 and day 57 after the start of treatment, and then every 6 months as needed. In some embodiments, a subject is administered an initial dose of about 1500-3000 mg of a Tn3 scaffold of the present disclosure at least twice, at least three times, or more every 2 weeks, and then every 4 weeks. In some embodiments, a subject is administered an initial dose of about 1500 mg of a Tn3 scaffold of the present disclosure at least twice, at least three times, or more every 2 weeks, and then every 4 weeks. In some embodiments, a subject is administered an initial dose of about 3000 mg of a Tn3 scaffold of the present disclosure at least twice, at least three times, or more every 2 weeks, and then every 12 weeks.In some embodiments, a subject is administered 1500 mg of a Tn3 scaffold of the present disclosure every 4 weeks, with a loading dose of 1500 mg of the Tn3 scaffold administered in week 2. In some embodiments, a subject is administered 3000 mg of a Tn3 scaffold of the present disclosure every 12 weeks, with a loading dose of 3000 mg of the Tn3 scaffold administered in week 4. In some embodiments, a subject is administered 1500 mg of a Tn3 scaffold of the present disclosure every 4 weeks, with a loading dose of 1500 mg of the Tn3 scaffold administered in week 2. In some embodiments, a subject is administered 3000 mg of a Tn3 scaffold comprising SEQ ID NO:1 every 12 weeks, with a loading dose of 3000 mg of the Tn3 scaffold administered in week 4. In some embodiments, a subject is administered 3000 mg of a Tn3 scaffold comprising SEQ ID NO:22 and / or SEQ ID NO:25 every 12 weeks, followed by a loading dose of 3000 mg of Tn3 scaffold at week 4. In some embodiments, a subject is administered 3000 mg of a Tn3 scaffold comprising SEQ ID NO:1 every 12 weeks, followed by a loading dose of 3000 mg of Tn3 scaffold at week 4. In some embodiments, a subject is administered 1500 mg of a Tn3 scaffold comprising SEQ ID NO:22 or SEQ ID NO:25 every 4 weeks, followed by a loading dose of 1500 mg of Tn3 scaffold at week 2. In some embodiments, a subject is administered 3000 mg of a Tn3 scaffold comprising SEQ ID NO:22 or SEQ ID NO:25 every 12 weeks, followed by a loading dose of 3000 mg of Tn3 scaffold at week 4.

[0052] The therapeutic or prophylactic methods of the present disclosure include administering a Tn3 scaffold of the present disclosure to a subject in need thereof. In some embodiments, the therapeutic methods include administering an effective amount of a Tn3 scaffold to a subject in need thereof about three doses (± 2 doses) every 2 weeks, followed by administration of the Tn3 scaffold every 4 weeks. In some embodiments, the therapeutic methods include administering an effective amount of a Tn3 scaffold to a subject in need thereof at weeks 1, 4, and 12, followed by administration of the Tn3 scaffold every 12 weeks. In some embodiments, the therapeutic methods include administering about 1400 mg to 1600 mg of a Tn3 scaffold to a subject in need thereof about three doses (± 2 doses) every 2 weeks, followed by administration of the Tn3 scaffold every 4 weeks. In some embodiments, the therapeutic methods include administering about 2000 mg to 4000 mg of a Tn3 scaffold to a subject in need thereof at weeks 1, 4, and 12, followed by administration of the Tn3 scaffold every 12 weeks. In some embodiments, the method of treatment includes administering to a subject in need about 3 doses (± 2 doses) of about 1500 mg of Tn3 scaffold every 2 weeks, followed by administration of Tn3 scaffold every 4 weeks thereafter. In some embodiments, the method of treatment includes administering to a subject in need about 3000 mg of Tn3 scaffold at weeks 1, 4, and 12, followed by administration of Tn3 scaffold every 12 weeks thereafter. In some embodiments, administration continues every 4 weeks thereafter for up to about 1, 2, 3, 4, or 5 years. In some embodiments, administration of Tn3 scaffold continues until the subject dies. Any of the foregoing doses can be offset by about 0-5 days, 0-4 days, 0-3 days, 0-2 days, or about 1 day.

[0053] In some embodiments, the subject is administered an effective dose of the Tn3 scaffold on day 1, day 15 (±1 day), day 29 (±3 days), and day 57 (±3 days) after the start of treatment. In some embodiments, the subject in need thereof is administered 1500 mg of the Tn3 scaffold on day 1, day 15 (±1 day), day 29 (±3 days), and day 57 (±3 days) after the start of treatment, and then every six months thereafter as needed. In some embodiments, the subject in need thereof is administered 1500 mg of the Tn3 scaffold on day 1, day 15 (±1 day), and day 29 (±3 days) after the start of treatment. In some embodiments, the subject in need thereof is administered 1500 mg of the Tn3 scaffold on day 1 and day 57 (±3 days) after the start of treatment. In some embodiments, a subject in need thereof is administered 3000 mg of the Tn3 scaffold on days 1, 15 (± 1 day), 29 (± 3 days), and 57 (± 3 days) after treatment begins, and then every 6 months thereafter as needed. In some embodiments, a subject in need thereof is administered 3000 mg of the Tn3 scaffold on days 1, 15 (± 1 day), and 29 (± 3 days) after treatment begins. In some embodiments, a subject in need thereof is administered 3000 mg of the Tn3 scaffold on days 1 and 57 (± 3 days) after treatment begins, and then every 6 months thereafter as needed.

[0054] In some embodiments, a subject in need thereof is administered a dose of a Tn3 scaffold on days 1, 15 (± 1 day), 29 (± 3 days), 57 (± 3 days), 85 (± 3 days), 113 (± 3 days), and 141 (± 3 days). In some embodiments, a subject in need thereof is administered an effective dose of a Tn3 scaffold on days 169 (± 3 days), 197 (± 3 days), 225 (± 3 days), 253 (± 3 days), and 281 (± 3 days).

[0055] In some embodiments, a subject in need thereof is administered an effective dose of the Tn3 scaffold once every 2-4 weeks. In some embodiments, a subject in need thereof is administered an effective dose of the Tn3 scaffold once every 2 weeks, 4 weeks, or 12 weeks. In some embodiments, a subject in need thereof is administered 1500 mg of the Tn3 scaffold once every 2 weeks at least 3 times, once every 4 weeks at least 4 times, once every 4 weeks at least 5 times, or a combination thereof. In some embodiments, a subject in need thereof is administered 3000 mg of the Tn3 scaffold once every 2 weeks at least 3 times, once every 4 weeks at least 4 times, once every 4 weeks at least 5 times, or a combination thereof. In some embodiments, a subject in need thereof is administered an effective dose of the Tn3 scaffold as an induction dose and thereafter as a maintenance dose. In some embodiments, 3000 mg of the Tn3 scaffold is administered every 3 months. In some embodiments, 3000 mg of the Tn3 scaffold is administered every 12 weeks.

[0056] In some embodiments, the Tn3 scaffold is administered at a dose of about 1500 mg once about every two weeks at least twice, and then once about once every month. In some embodiments, the Tn3 scaffold is administered at a dose of about 1500 mg once about every two weeks at least three times, and then once about once every month. In some embodiments, the Tn3 scaffold is administered at a dose of about 1500 mg once about every two weeks at least three times, and then once every four weeks. In some embodiments, the Tn3 scaffold is administered at a dose of about 1500 once about every month, once about every two months, or once about every three months. In some embodiments, the Tn3 scaffold is administered at a dose of about 3000 mg once about every month, once about every two months, or once about every three months. In some embodiments, the Tn3 scaffold is administered more than once. In some embodiments, a subject is administered 1500 mg of a Tn3 scaffold of the present disclosure every 4 weeks, with a loading dose of 1500 mg of the Tn3 scaffold administered in week 2. In some embodiments, a subject is administered 3000 mg of a Tn3 scaffold of the present disclosure every 12 weeks, with a loading dose of 3000 mg of the Tn3 scaffold administered in week 4. In some embodiments, a subject is administered 1500 mg of a Tn3 scaffold comprising SEQ ID NO: 1 every 4 weeks, with a loading dose of 1500 mg of the Tn3 scaffold administered in week 2. In some embodiments, a subject is administered 3000 mg of a Tn3 scaffold comprising SEQ ID NO: 1 every 12 weeks, with a loading dose of 3000 mg of the Tn3 scaffold administered in week 4. In some embodiments, a subject is administered 1500 mg of a Tn3 scaffold comprising SEQ ID NO:22 or SEQ ID NO:25 every 4 weeks, followed by a loading dose of 1500 mg of Tn3 scaffold on week 2. In some embodiments, a subject is administered 3000 mg of a Tn3 scaffold comprising SEQ ID NO:22 or SEQ ID NO:25 every 12 weeks, followed by a loading dose of 3000 mg of Tn3 scaffold on week 4.

[0057] In some embodiments, a subject is administered 1500 mg of a Tn3 scaffold of the present disclosure every 4 weeks, followed by a loading dose of 1500 mg of Tn3 scaffold in week 2. In some embodiments, a subject is administered 3000 mg of a Tn3 scaffold comprising SEQ ID NO:1 every 12 weeks, followed by a loading dose of 3000 mg of Tn3 scaffold in week 4. In some embodiments, a subject is administered 3000 mg of a Tn3 scaffold comprising SEQ ID NO:22 and / or SEQ ID NO:25 every 12 weeks, followed by a loading dose of 3000 mg of Tn3 scaffold in week 4. In some embodiments, a subject is administered 3000 mg of a Tn3 scaffold comprising SEQ ID NO:1 every 12 weeks, followed by a loading dose of 3000 mg of Tn3 scaffold in week 4. In some embodiments, a subject is administered 1500 mg of a Tn3 scaffold comprising SEQ ID NO:22 or SEQ ID NO:25 every 4 weeks, followed by a loading dose of 1500 mg of Tn3 scaffold on week 2. In some embodiments, a subject is administered 3000 mg of a Tn3 scaffold comprising SEQ ID NO:22 or SEQ ID NO:25 every 12 weeks, followed by a loading dose of 3000 mg of Tn3 scaffold on week 4.

[0058] Treatment method In some embodiments herein, the method is for treating SS. In some embodiments, the method includes administering a Tn3 scaffold of the present disclosure. In some embodiments, the Tn3 scaffold is used to treat SS. In some embodiments, the Tn3 scaffold is administered to a subject in need of treating SS using any of the dosing schedules disclosed herein. In some embodiments, the Tn3 scaffold is administered at a dose of about 1500 mg once about every two weeks at least twice, and then once about once every month. In some embodiments, the Tn3 scaffold is administered at a dose of about 1500 mg once about every two weeks at least three times, and then once about once every month. In some embodiments, the Tn3 scaffold is administered at a dose of about 1500 once about every month, once about every two months, or once about every three months. In some embodiments, the Tn3 scaffold is administered at a dose of about 3000 mg about once every month, about once every two months, or about once every three months. In some embodiments, the Tn3 scaffold is administered two or more times.

[0059] In some embodiments, the methods include treating a patient with SS. In some embodiments, the methods include treating a patient with SS with a European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index (ESSDAI) score of about 1, about 2, about 3, about 5, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 25, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100 or more. In some embodiments, the methods include treating a patient with SS with a EULAR Sjogren's Syndrome Patient-Reported Index (ESSPRI) score of about 1, about 2, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20 or more.

[0060] In some embodiments, the method includes treating a patient in need of treatment. In some embodiments, the method includes treating a patient with SS. In some embodiments, the method includes treating a patient with SS with moderate systemic disease activity. In some embodiments, the method includes treating a patient with SS with high systemic disease activity. In some embodiments, the method includes treating a patient with SS with moderate to high systemic disease activity. In some embodiments, the method includes treating a patient with SS with moderate to high systemic disease activity by administering a Tn3 scaffold at any dose on any schedule disclosed herein. In some embodiments, moderate to high systemic disease activity may be defined by an ESSDAI≧5. In some embodiments, the method includes treating a patient with SS with moderate to high (or severe) subjective symptoms by administering a Tn3 scaffold. In some embodiments, moderate to high (or severe) subjective symptoms may be defined by an EULAR Sjogren's Syndrome Patient-Reported Index (ESSPRI) score > 5 and residual stimulated salivary flow rate, while mild systemic disease activity is defined by an ESSDAI score < 5. In some embodiments, the Tn3 scaffold is administered at a dose of 1500 mg. In some embodiments, the Tn3 scaffold is administered at a dose of 3000 mg.

[0061] evaluation In some embodiments, the subject is evaluated. In some embodiments, the evaluation can be performed at any time before, during, or after administration of the Tn3 scaffold. The evaluation can be performed at any time before, during, or after administration of the Tn3 scaffold. In some embodiments, the evaluation is performed before administration. In some embodiments, the evaluation is performed during administration. In some embodiments, the evaluation is performed after administration.

[0062] Any assessments referenced below can be performed at any time. In some embodiments, subjects are assessed every minute, hour, day, week, month, or year. In some embodiments, assessments are completed twice daily, every other week, every other month, or every six months. In some embodiments, the assessments are performed at the following intervals after treatment: -10, -9, -8, -7, -6, -5, -4, -3, -2, -1, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 6 0, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 125, 130, 135, 140, 141, 145, 150, 155, 160, 165, 169, 170, 180, 190, 197, 200, 205, 210, 215, 220, 225, 230, 235, 240, 250, 252, 253, 255, 260, 265, 270, 280, 281, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 31 5, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, or up to about 365 ± 7 days.

[0063] In some embodiments, treatment of SS may be characterized by at least about 5%, about 10%, about 15%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, or up to about 100% reduction in clinical symptoms of the disease or disorder, or reduced inflammation, or a biomarker of the disease or disorder compared to levels prior to treatment with the Tn3 scaffold. The reduction in any of these symptoms, inflammation, or biomarkers may be at least about 10%, 15%, 20%, 25%, about 30%, about 40%, about 50%, about 60%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, or up to about 100% reduction in symptoms, or inflammation or biomarkers compared to levels prior to the start of treatment with the Tn3 scaffold. The reduction may be such that the SS is characterized as being in remission.

[0064] In some embodiments, the efficacy of treatment can be assessed using the European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index (ESSDAI), EULAR Sjogren's Syndrome Patient-Reported Index (ESSPRI), 36-Item Short Form Survey version 2 (SF-36v2), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue), Visual Analog Scale (VAS) Oral / Ocular, Patient-Reported Outcomes Measurement Information System® (PROMIS-29 Profile v2.1), Ocular Surface Disease Index (OSDI), Patient's Global Impression of Change (PGIC), Patient's Global Impression of Severity (GPS ... Patient-reported outcome (PRO) measures may be used to determine efficacy of treatment. Patient-reported outcome measures (PGIS), stimulated salivary flow measurements, Schirmer test, 28-joint assessment, physician's global impression of severity, Clinical EULAR Sjogren's Syndrome Disease Activity Index (ClinESSDAI), and combinations thereof. In some embodiments, efficacy of treatment may be measured using assessments that are patient-reported outcomes (PRO) measures.

[0065] Systemic disease activity and patient-reported outcomes ESSDAI In some embodiments, the assessment includes the ESSDAI. The ESSDAI is a systemic disease activity index that includes definitions of disease activity by organ (see Seror R, Ravaud P, Bowman SJ, Baron G, Tzioufas A, Theander E, et al; EULAR Sjogren's Task Force. EULAR Sjogren's syndrome disease activity index: development of a consensus systemic disease activity index for primary Sjogren's syndrome. Ann Rheum Dis. 2010; 69(6): 1103-9, which is incorporated herein by reference). The ESSDAI grades disease activity in 12 domains (skin, respiratory (lung), kidney, joint, muscle, peripheral nervous system, central nervous system, blood, glandular, constitutional, nodal, biological). Weights for each domain were obtained by multiple regression modeling, using the Physician's Global Assessment of Activity as the gold standard.

[0066] Each domain is weighted from 1 (biological domain) to 6 (muscular domain), with three or four levels of activity per domain spanning from 0 (no activity) to 3 (high activity).

[0067] In some embodiments, the following domains are scored: peripheral nervous system, central nervous system, and pulmonary, but they may not contribute to the minimum ESSDAI score of 5 required for inclusion in the studies of the present disclosure.

[0068] The theoretical range of values ​​for the ESSDAI is 0-123, and the final score is calculated as follows: Final score = sum of all 12 domain scores Domain score = activity level x domain weight Low disease activity is defined as ESSDAI<5, moderate disease activity as 5≦ESSDAI≦13, and high disease activity as ESSDAI≧14.

[0069] In embodiments, the change from baseline in ESSDAI is determined. In some embodiments, the baseline ESSDAI score is reduced by at least about 1, 2, 3, 4, or 5 points after treatment with the compositions provided herein. In some embodiments, the baseline ESSDAI score is reduced by 3 points after treatment with the compositions provided herein. In some embodiments, the baseline ESSDAI score is reduced by 4 points after treatment with the compositions provided herein. In some embodiments, the ESSDAI score after treatment is ≦2, ≦5, or ≦13. Administration of the Tn3 scaffold of the present disclosure can be effective to reduce ESSDAI score by at least about or up to about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 18, or 20 points compared to the ESSDAI baseline score before administration. Administration of a Tn3 scaffold of the present disclosure can be effective to reduce the ESSDAI score by at least about or up to about 1-5, 3-5, 5-8, 5-10, or 10-15 points compared to the ESSDAI baseline score prior to administration. In some embodiments, administration of a Tn3 scaffold of the present disclosure is effective to reduce the ESSDAI score by at least about 6 points. In some embodiments, administration of a Tn3 scaffold of the present disclosure is effective to reduce the ESSDAI score by at least about 6.3 points.

[0070] ESSDAI score can refer to absolute or relative value. For example, relative value can include the difference between subjects treated with Tn3 scaffold of the present disclosure and subjects treated with placebo control. In some embodiments, ESSDAI score refers to absolute value, for example, the decrease of ESSDAI compared to baseline level or level determined before treatment. In some embodiments, ESSDAI score refers to relative value. Relative value can refer to the difference between ESSDAI score between subjects treated with Tn3 scaffold and subjects treated with control. In some embodiments, relative value is the least square mean difference between subjects treated with Tn3 scaffold and subjects treated with control.

[0071] In some embodiments, subjects administered a Tn3 scaffold of the present disclosure achieve a 3, 4, 5, 6, 7, 8, 9, or 10 point reduction in their ESSDAI compared to the ESSDAI before administration (e.g., baseline level). In some embodiments, subjects administered a Tn3 scaffold of the present disclosure achieve a 6.4 point reduction in their ESSDAI compared to the ESSDAI before administration (e.g., baseline level).

[0072] In some embodiments, ESSDAI assessments for the Tn3 scaffold are performed at about 0 days, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, or 24 weeks after initiation of treatment. , 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, or at least about 53 weeks. In some embodiments, ESSDAI assessments for Tn3 scaffolds may be assessed at about 1 day, 29±3 days, 57±3 days, 85±3 days, 113±3 days, 141±3 days, 169±3 days, 197±3 days, 225±3 days, 253±3 days, 281±3 days, 309±7 days, and 365±7 days after initiation of treatment.

[0073] ClinESSDAI In some embodiments, the assessment includes the Clinical EULAR Sjogren's Syndrome Disease Activity Index (ClinESSDAI). The ClinESSDAI is a validated SS disease activity index based on the ESSDAI that excludes the biological domain and assigns different weights to each domain. The ClinESSDAI was developed in an effort to mitigate possible associations between B-cell biomarkers and clinical activity measures measured by the ESSDAI biological domains. The theoretical value range of the ClinESSDAI is 0-135, with low activity defined as <5, moderate activity defined as 5≦ClinESSDAI≦13, and high activity defined as ≧14, similar to the ESSDAI. The ClinESSDAI has been validated and shown to correlate well with the ESSDAI, and is considered a useful tool to detect changes independent of the biological effects of the drug. In some embodiments, a change from baseline in the ClinESSDAI is determined. In some embodiments, the baseline ClinESSDAI score is reduced by at least about 1, 2, 3, 4, or 5 points after treatment with a composition provided herein. In some embodiments, the ClinESSDAI score after treatment is ≦2, ≦5, or ≦13.

[0074] In some embodiments, ClinESSDAI assessments for the Tn3 scaffold are performed at about 0 days, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, 53 weeks, 54 weeks, 55 weeks, 56 weeks, 57 weeks, 58 weeks, 59 weeks, 60 weeks, 61 weeks, 62 weeks, 63 weeks, 64 weeks, 65 weeks, 66 weeks, 67 weeks, 68 weeks, 69 weeks, 70 weeks, 71 weeks, 72 weeks, 73 weeks, 74 weeks, 75 weeks, 76 weeks, 77 weeks, 78 weeks, 79 weeks, 80 weeks, 81 weeks, 82 weeks, 83 weeks, 84 weeks, 85 weeks, 86 weeks, 87 weeks, 88 weeks, 89 weeks, 90 weeks, 91 weeks, 92 weeks, 93 weeks, 94 weeks The ClinESSDAI assessments may be evaluated at 3 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, or at least about week 53. In some embodiments, ClinESSDAI assessments for the Tn3 scaffold may be evaluated at about 85±3 days, 169±3 days, and 309±7 days after initiation of treatment.

[0075] ESSPRI In some embodiments, the assessment includes the ESSPRI (see Seror R, Ravaud P, Mariette X, Bootsma H, Theander E, Hansen A, et al. EULAR Sjogren's Task Force. EUULAR Sjogren's Syndrome Patient-Reported Index (ESSPRI): Development of a Consensus Patient Index for Primary Sjogren's Syndrome. Ann Rheum Dis. 2011;70(6):968-72, which is incorporated herein by reference). The ESSPRI is a self-assessment tool developed in a multicenter international cohort of 230 patients. The ESSPRI uses a 0-10 numeric analog scale (0 [no symptoms] to 10 [maximum possible severity]), one to rate each of three domains: dryness, fatigue, and pain (joints and / or muscles). The weights of the domains are identical, and the average of the scores of the three domains represents the final score. The recall period is noted in each question as "past 2 weeks." In some embodiments, subjects in group #2 achieve an ESSPRI response, defined as a reduction in ESSPRI score from baseline of 1 point or 15% without early discontinuation of Tn3 scaffold or rescue therapy. In some embodiments, the baseline ESSPRI score is reduced by about 3%, 5%, 8%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or up to about 100%. In some embodiments, the post-treatment ESSPRI score is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9. In some embodiments, the post-treatment ESSPRI score is reduced by at least about 1, 2, 3, 4, 5, 6, 7, 8, or 9 points compared to the pre-treatment ESSPRI score.

[0076] In some embodiments, ESSPRI assessments for the Tn3 scaffold are performed at about 0 days, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, or 24 weeks after initiation of treatment. , 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, or at least about 53 weeks. In some embodiments, ESSPRI assessments for the Tn3 scaffold may be assessed at about 1 day, 29±3 days, 57±3 days, 85±3 days, 113±3 days, 141±3 days, 169±3 days, 197±3 days, 225±3 days, 253±3 days, 281±3 days, 309±7 days, and 365±7 days after initiation of treatment.

[0077] Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue In some embodiments, the assessment includes the FACIT-Fatigue Scale. The FACIT-Fatigue Scale is a 13-item questionnaire completed by the subject used to assess the impact of fatigue. The FACIT-Fatigue Scale has a recall period of approximately 7 days. Responses to the FACIT-Fatigue Scale range from 0 (not at all) to 4 (very high). To calculate a total score, negatively written items are inverted by subtracting the response from "4". The final score is the sum of the responses and ranges from 0 to 52. Higher scores indicate better quality of life (QoL). In some embodiments, the change from baseline in the FACIT-Fatigue can be determined. In some embodiments, a method of administering a Tn3 scaffold to a subject has a higher FACIT-Fatigue Scale compared to a comparable method of not administering a Tn3 scaffold to a subject.

[0078] In some embodiments, the FACIT-Fatigue scale for the Tn3 scaffold is The PTSD Scale assessments may be assessed at about 0 days, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, or at least about 53 weeks after initiation of treatment. In some embodiments, FACIT-Fatigue Scale assessments for the Tn3 scaffold may be assessed at about 1 day, 29±3 days, 57±3 days, 85±3 days, 113±3 days, 141±3 days, 169±3 days, 197±3 days, 225±3 days, 253±3 days, 281±3 days, 309±7 days, and 365±7 days after initiation of treatment.

[0079] Ocular Surface Disease Index (OSDI) (c) ) In some embodiments, the assessment may include the OSDI. The OSDI is a valid and reliable instrument for assessing the impact on vision-related function and severity of dry eye disease (normal, mild, moderate, and severe). The OSDI recall period is one week. The OSDI assessment may consist of 12 questions asked by a physician to the subject, with circling the number that best describes each question. Answers to each question range from 0 (never) to 4 (always). The OSDI score is calculated as (sum of scores of questions answered) / (number of questions answered)×25, with a range of 0 to 100, with higher scores indicating more severe impairment. In some embodiments, the change from baseline in the OSDI is determined.

[0080] In some embodiments, OSDI assessments for the Tn3 scaffold are performed at about 0 days, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, The OSDI assessment may be assessed at 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, or at least about week 53. In some embodiments, OSDI assessments for the Tn3 scaffold may be assessed at about 1 day, 29±3 days, 57±3 days, 85±3 days, 113±3 days, 141±3 days, 169±3 days, 197±3 days, 225±3 days, 253±3 days, 281±3 days, 309±7 days, and 365±7 days after initiation of treatment.

[0081] Patient Global Impression of Severity (PGIS) In some embodiments, the assessment comprises completing the PGIS.The PGIS is a single item designed to capture the subject's perception of the overall severity of symptoms over the past week on a 5-point categorical response scale (none, mild, moderate, severe, or very severe).In some embodiments, the PGIS score is reduced after administration of the Tn3 scaffold of the present disclosure.The reduction can be about 1, 2, 3, 4, or up to about 5 points.

[0082] In some embodiments, PGIS assessments for the Tn3 scaffold are performed at about 0 days, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, The PGIS evaluation may be evaluated at about 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, or at least about week 53. In some embodiments, the PGIS evaluation for the Tn3 scaffold may be evaluated at about 1 day, 29±3 days, 57±3 days, 85±3 days, 113±3 days, 141±3 days, 169±3 days, 197±3 days, 225±3 days, 253±3 days, 281±3 days, 309±7 days, and 365±7 days after the start of treatment.

[0083] Physician's Global Impression of Severity In some embodiments, the assessment may include a physician's global impression of severity. The physician's global impression of severity may include an overall assessment of the severity of SS disease. The PGIS may be scored on a five-point categorical response scale (none, mild, moderate, severe, or very severe). In some embodiments, the change from baseline in the physician's global impression of severity is determined. In some embodiments, the Physician's Global Impression of Severity score is reduced after administration of the Tn3 scaffold of the present disclosure. The reduction may be about 1, 2, 3, 4, or up to about 5 points.

[0084] In some embodiments, the Physician's Global Impression of Severity ratings for the Tn3 scaffold are measured at about 0 days, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, 53 weeks, 54 weeks, 55 weeks, 56 weeks, 57 weeks, 58 weeks, 59 weeks, 60 weeks, 61 weeks, 62 weeks, 63 weeks, 64 weeks, 65 weeks, 66 weeks, 67 weeks, 68 weeks, 69 weeks, 70 weeks, 71 weeks, 72 weeks, 73 weeks, 74 weeks, 75 weeks, 76 weeks, 77 weeks, 78 weeks, 79 weeks, 80 weeks, 81 weeks, 82 weeks, 83 weeks, 84 weeks, 85 weeks, 86 weeks, 87 weeks, 88 weeks, 89 weeks, 90 weeks, 91 weeks, 92 weeks In some embodiments, the present invention may be evaluated at about 53 weeks, 54 weeks, 55 weeks, 56 weeks, 57 weeks, 58 weeks, 59 weeks, 60 weeks, 61 weeks, 62 weeks, 63 weeks, 64 weeks, 65 weeks, 66 weeks, 67 weeks, 68 weeks, 69 weeks, 70 weeks, 71 weeks, 72 weeks, 73 weeks, 74 weeks, 75 weeks, 76 weeks, 77 weeks, 78 weeks, 79 weeks, 80 weeks, 81 weeks, 82 weeks, 83 weeks, 84 weeks, 85 weeks, 86 weeks, 87 weeks, 88 weeks, 89 weeks, 90 weeks, 91 weeks, 92 weeks, or at least about 93 weeks. In some embodiments, the Physician's Global Impression of Severity assessment for the Tn3 scaffold may be assessed at about 1 day, 15±1 day, 29±3 days, 57±3 days, 85±3 days, 113±3 days, 141±3 days, 169±3 days, 197±3 days, 225±3 days, 253±3 days, 281±3 days, 309±7 days, and 365±7 days after initiation of treatment.

[0085] composite index In some embodiments, the evaluation includes determining a composite index, which may be defined as either an improvement in ESSDAI-3 (i.e., a 3 point reduction) or an improvement in ESSPRI-1 (i.e., a 1 point or greater or 15% reduction from baseline in the ESSPRI score) with no worsening of Physician Global Impression of Severity from baseline.

[0086] In some embodiments, composite index assessments for the Tn3 scaffold are performed at about 0 days, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, The composite index assessments for the Tn3 scaffold may be evaluated at about 85±3 days, 169±3 days, and 309±7 days after initiation of treatment.

[0087] 28-Joint Assessment In some embodiments, the assessment may include a 28-Joint Count. In the 28-Joint Count, the following joints may be assessed for tenderness and swelling: left and right shoulders, elbows, wrists, metacarpophalangeal joints (MCP)1, MCP2, MCP3, MCP4, MCP5, proximal interphalangeal (PIP)1, PIP2, PIP3, PIP4, PIP5 joints of the upper limbs, and left and right knees of the lower limbs. Each of the 28 joints may be assessed for the presence of synovitis. At the start of the 28-Joint Count (before the assessment of tenderness and swelling), the subject may be asked whether they have experienced or are experiencing pain in any of the 28 joints.

[0088] In some embodiments, 28-joint counts for the Tn3 scaffold are The Count) assessment may be assessed at about 0 days, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, or at least about 53 weeks after initiation of treatment. In some embodiments, 28-Joint Count assessments for the Tn3 scaffold may be assessed at about days 1, 29±3, 57±3, 85±3, 113±3, 141±3, 169±3, 197±3, 225±3, 253±3, 281±3, 309±7, and 365±7 after initiation of treatment.

[0089] Functions of saliva and tears Total stimulated saliva flow In some embodiments, the evaluation includes determining the total stimulated saliva flow rate. The total stimulated saliva flow rate can be measured to objectively evaluate the functional changes of the salivary glands. Subjects who are receiving standard treatment for xerostomia at screening must discontinue the use of pilocarpine or cevimeline for at least 12 hours and artificial saliva for at least 3 hours before saliva collection. Subjects should refrain from eating and drinking for at least 90 minutes before saliva collection. Every attempt should be made to collect saliva at the same time of day for all subsequent evaluations to minimize diurnal variation.

[0090] In an exemplary total stimulated saliva flow measurement, a square of parafilm approximately 5 x 5 cm is rolled up and given to the subject to chew at a rate of approximately 60 strokes per minute, like gum. The subject must sit upright with eyes open and tilt their head slightly forward to begin chewing the parafilm for 60 seconds, at which point all collected saliva must be spat into an extra (not pre-weighed) Falcon tube, with the parafilm still in their mouth. This first collection familiarizes the subject with the procedure. Three rounds of saliva are collected, each after 20 seconds of chewing, in a pre-weighed Falcon tube. These rounds are consecutive, but timing is stopped during the collection of saliva and resumed immediately after the saliva is deposited in the pre-weighed Falcon tube, for a total stimulation time of 60 seconds. If 60 seconds of collection is not possible due to subject incompetence, the total collection time should be recorded. Total stimulated saliva collected is assessed by subtracting the final weight of the tube from the weight before collection. In some embodiments, the change from baseline in total stimulated saliva flow rate is determined. In some embodiments, the post-treatment unstimulated total saliva flow rate is >0.1 ml / min in subjects in Population #1.

[0091] In some embodiments, stimulated saliva flow assessments for the Tn3 scaffold are performed at about 0 days, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, or 24 weeks after the start of treatment. , 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, or at least about 53 weeks. In some embodiments, evaluation of stimulated saliva flow to the Tn3 scaffold may be evaluated at about 1 day, 85±3 days, 169±3 days, 253±3 days, 309±7 days, and 365±7 days after initiation of treatment.

[0092] Oral / Ocular Visual Analog Scale (VAS) In some embodiments, the assessment includes determining an oral / ocular (VAS). These two instruments assess changes in the severity of oral and ocular dryness using a continuous 100mm VAS from 0mm (best) to 100mm (worst). Respondents are asked to draw a line perpendicular to the VAS line to a point that represents the intensity of the symptom. The oral VAS may assess the question, "How dry do you feel your mouth most of the time?" (0mm for not dry at all, 100mm for very dry). The ocular VAS may assess the question, "How dry do you feel your eyes most of the time?" (0mm for not dry at all, 100mm for very dry). In some embodiments, baseline (VAS) oral / ocular scores are reduced by about 3%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or up to about 100% compared to the subject's VAS score prior to administration of the Tn3 scaffold.

[0093] In some embodiments, the VAS ratings for the Tn3 scaffold are measured at about 0 days, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, The VAS ratings may be assessed at about 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, or at least about week 53. In some embodiments, the VAS ratings for the Tn3 scaffold may be assessed at about 1 day, 29±3 days, 57±3 days, 85±3 days, 113±3 days, 141±3 days, 169±3 days, 197±3 days, 225±3 days, 253±3 days, 281±3 days, 309±7 days, and 365±7 days after initiation of treatment.

[0094] Schirmer test In some embodiments, the Schirmer test may be performed without topical anesthesia. The Schirmer test measures the function of the lacrimal gland. The Schirmer test may use a graduated strip of non-toxic filter paper to measure tear flow. One end of the strip is placed in the lower eyelid. Both eyes should be measured simultaneously. After placement, the subject is asked to keep their eyes gently closed for 5 minutes, at which point the strip is removed from the eyelid and the degree of wetting of each strip is recorded. In some embodiments, the change from baseline in the Schirmer test may be determined. In some embodiments, the post-treatment score is >5mm / 5 minutes in at least one eye.

[0095] In some embodiments, Schirmer test assessments for the Tn3 scaffold are performed at about 0 days, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks Weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, or at least about 53 weeks. In some embodiments, Schirmer test assessments on the Tn3 scaffold may be assessed at about 1 day, 85±3 days, 169±3 days, 253±3 days, 309±7 days, and 365±7 days after initiation of treatment.

[0096] Subjective complaints Patient Global Impression of Change (PGIC) In some embodiments, the assessment comprises PGIC.PGIC is a single item designed to capture subject's perception of the change in overall symptom severity due to the start of investigational drug treatment.The change in severity is captured using a 5-point scale (much better, a little better, no change, a little worse, or much worse).In some embodiments, the change from baseline in PGIC is determined.

[0097] In some embodiments, PGIC assessments for the Tn3 scaffold are performed at about 0 days, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, 53 weeks, 54 weeks, 55 weeks, 56 weeks, 57 weeks, 58 weeks, 59 weeks, 60 weeks, 61 weeks, 62 weeks, 63 weeks, 64 weeks, 65 weeks, 66 weeks, 67 weeks, 68 weeks, 69 weeks, 70 weeks, 71 weeks, 72 weeks, 73 weeks, 74 weeks, 75 weeks, 76 weeks, 77 weeks, 78 weeks, 79 weeks, 80 weeks, 81 weeks, 82 weeks, 83 weeks, 84 weeks, 85 weeks, 86 weeks, 87 weeks, 88 weeks, 89 weeks, 90 weeks, 91 weeks, 92 weeks, 93 weeks, 94 weeks, The PGIS evaluation may be evaluated at 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, or at least about week 53. In some embodiments, the PGIS evaluation for the Tn3 scaffold may be evaluated at about 15±1 days, 29±3 days, 57±3 days, 85±3 days, 113±3 days, 141±3 days, 169±3 days, 197±3 days, 225±3 days, 253±3 days, 281±3 days, 309±7 days, and 365±7 days after the start of treatment.

[0098] 36-Item Short Form Survey Version 2 (SF36v2) Physical Component Score and Mental Component Score In some embodiments, the assessment includes an SF-36v2 profile. The SF-36v2 (acute recall) is a 36-item general health status assessment that collects information on eight health domains: physical functioning, role physical, bodily pain, general health status, vitality, social functioning, role emotional, and mental health. The SF-36v2 provides a score for each domain and two psychometric summary scores: a physical dimension score and a mental dimension score. The recall period for the acute version is one week (i.e., "last week"). In some embodiments, the change from baseline in the SF36v2 physical dimension score and mental dimension score is determined.

[0099] In some embodiments, 36v2 profile assessments on the Tn3 scaffold are performed at about 0 days, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 4 The 3, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, or at least about week 53. In some embodiments, the 36v2 profile assessment on the Tn3 scaffold may be assessed at about day 1, day 29±3, day 57±3, day 85±3, day 113±3, day 141±3, day 169±3, day 197±3, day 225±3, day 253±3, day 281±3, day 309±7, and day 365±7 after initiation of treatment.

[0100] Patient-Reported Outcomes Measurement Information System (PROMIS-29 Profile) In some embodiments, the assessment includes a PROMIS-29 profile. PROMIS-29 assesses seven domains (depression, anxiety, physical function, pain interference, fatigue, sleep disturbance, and ability to participate in social roles and activities) with four questions for each domain. The assessment of the domains is for the past seven days, except for physical function, which is not time-specified. In some embodiments, treated subjects have improved scores on PROMIS-29 compared to otherwise equivalent methods, where otherwise equivalent subjects of the method do not receive the Tn3 scaffold.

[0101] In some embodiments, PROMIS-29 profile assessments for the Tn3 scaffold are performed at about 0 days, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, 53 weeks, 54 weeks, 55 weeks, 56 weeks, 57 weeks, 58 weeks, 59 weeks, 60 weeks, 61 weeks, 62 weeks, 63 weeks, 64 weeks, 65 weeks, 66 weeks, 67 weeks, 68 weeks, 69 weeks, 70 weeks, 71 weeks, 72 weeks, 73 weeks, 74 weeks, 75 weeks, 76 weeks, 77 weeks, 78 weeks, 79 weeks, 80 weeks, 81 weeks, 82 weeks, 83 weeks, 84 weeks, 85 weeks, 86 weeks, 87 weeks, 88 weeks, 89 weeks, 90 weeks, 91 weeks, 92 weeks, 93 weeks, 9 In some embodiments, the present invention may be evaluated at about 53 weeks, 54 weeks, 55 weeks, 56 weeks, 57 weeks, 58 weeks, 59 weeks, 60 weeks, 61 weeks, 62 weeks, 63 weeks, 64 weeks, 65 weeks, 66 weeks, 67 weeks, 68 weeks, 69 weeks, 70 weeks, 71 weeks, 72 weeks, 73 weeks, 74 weeks, 75 weeks, 76 weeks, 77 weeks, 78 weeks, 79 weeks, 80 weeks, 81 weeks, 82 weeks, 83 weeks, 84 weeks, 85 weeks, 86 weeks, 87 weeks, 88 weeks, 89 weeks, 90 weeks, 91 weeks, 92 weeks, or at least about 93 weeks. In some embodiments, PROMIS-29 profile assessments for the Tn3 scaffold may be assessed at about day 1, day 29±3, day 57±3, day 85±3, day 113±3, day 141±3, day 169±3, day 197±3, day 225±3, day 253±3, day 281±3, day 309±7, and day 365±7 after initiation of treatment.

[0102] Pharmacokinetic (PK) analysis In some embodiments, the methods provided herein may include determining the concentration of Tn3 scaffold in a subject in need thereof after administration. In some embodiments, the methods include a pharmacokinetic assessment. In some embodiments, the sample is a blood sample or a plasma sample, or a combination of both. In some embodiments, suitable assays for measuring pharmacokinetics may include electrochemiluminescence (ECL) assays, bead-based assays, cell-based assays, and combinations thereof. In some embodiments, the sample may include plasma, which may be assayed for a maximum observed concentration (C max ), area under the concentration-time curve (AUC), CL, and terminal elimination half-life (t 1 / 2 ) to assess Tn3 scaffold concentration.

[0103] In some embodiments, PK assessments for the Tn3 scaffold are performed at about 0 days, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, 53 weeks, 54 weeks, 55 weeks, 56 weeks, 57 weeks, 58 weeks, 59 weeks, 60 weeks, 61 weeks, 62 weeks, 63 weeks, 64 weeks, 65 weeks, 66 weeks, 67 weeks, 68 weeks, 69 weeks, 70 weeks, 71 weeks, 72 weeks, 73 weeks, 74 weeks, 75 weeks, 76 weeks, 77 weeks, 78 weeks, 79 weeks, 80 weeks, 81 weeks, 82 weeks, 83 weeks, 84 weeks, 85 weeks, 86 weeks, 87 weeks, 88 weeks, 89 weeks, 90 weeks, 91 weeks, 92 weeks, 93 weeks, 94 weeks, 9 The PK assessments may be evaluated at 4 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, or at least about week 53. In some embodiments, PK assessments for the Tn3 scaffold may be evaluated at about day 1, day 15±1, day 29±3, day 57±3, day 85±3, day 113±3, day 141±3, day 169±3, day 197±3, day 225±3, day 253±3, day 281±3, day 309±7, and day 365±7 after initiation of treatment.

[0104] immunogenicity In some embodiments, the evaluation includes determining the level of immunogenicity (if any) of the Tn3 scaffold. Immunogenicity includes determining the presence of anti-drug antibodies (ADA) against the Tn3 scaffold. The presence of ADA can be evaluated using a plasma sample from a subject administered the Tn3 scaffold. In some embodiments, ADA is not detected after administration of the Tn3 scaffold. In some embodiments, ADA levels are reduced compared to an otherwise equivalent method in which the subject of the method is not administered a Tn3 scaffold; for example, the reduction can be about 10%, 15%, 20%, 25%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or up to 100% compared to ADA levels in an otherwise equivalent method in which the subject of the method is not administered a Tn3 scaffold.

[0105] In some embodiments, immunogenicity assessments for the Tn3 scaffold are performed at about 0 days, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, The immunogenicity assessment may be evaluated at about 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, or at least about week 53. In some embodiments, immunogenicity assessment to the Tn3 scaffold may be evaluated at about 1 day, 29±3 days, 85±3 days, 169±3 days, 197±3 days, 253±3 days, 309±7 days, and 365±7 days after initiation of treatment.

[0106] Pharmacodynamic and biomarker analysis In some embodiments, the method includes pharmacodynamic evaluation. In some embodiments, the evaluation includes determining the following biomarker results and their changes from baseline: SS-A, SS-B, and IgG and IgM RF autoantibodies and / or inflammatory markers (immunoglobulin, beta-2 microglobulin, CRP, C3, C4, and serum-free light chains). In some embodiments, serum and plasma can be collected to measure changes in exploratory biomarkers of disease activity, such as proinflammatory cytokines and CXCL13 levels. In some embodiments, biomarkers can include blood flow, cytometry for changes in T and B cell subsets, and salivary proteins, as well as changes in fecal microbiota.

[0107] In some embodiments, whole blood samples may be collected to assess changes in the numbers, activation state, and frequency of major white blood cell populations, including B and T lymphocytes, using flow cytometry.

[0108] In some embodiments, administration of a Tn3 scaffold of the present disclosure reduces the levels of certain B cell and plasmablast / plasma cell populations, hi some embodiments, administration of a Tn3 scaffold reduces the levels of T cell and / or other immune cell populations.

[0109] In some embodiments, the Tn3 scaffold may achieve at least about a 10%, 15%, 20%, 25%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or up to a 100% reduction in biomarker levels compared to an otherwise equivalent method in which the subject of the otherwise equivalent method is not administered a Tn3 scaffold.

[0110] In some embodiments, pharmacokinetic assessments for the Tn3 scaffold are performed at about 0 days, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, or 24 weeks after initiation of treatment. , 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, or at least about 53 weeks. In some embodiments, pharmacokinetic assessments for the Tn3 scaffold may be assessed at about 1 day, 15±1 day, 29±3 days, 57±3 days, 85±3 days, 113±3 days, 141±3 days, 169±3 days, 197±3 days, 225±3 days, 253±3 days, 281±3 days, 309±7 days, and 365±7 days after initiation of treatment.

[0111] Fecal microbiota samples In some embodiments, the assessment may include changes in fecal microbiota. In some embodiments, stool samples from whole stool may be collected to assist in the assessment of changes in gut microbiota composition over time by 16S microarray and / or deep sequencing methods. In some embodiments, a self-collection microbial DNA collection kit from stool is provided before or during the visit to collect and test fecal samples. In some embodiments, changes from baseline in fecal microbiota are determined.

[0112] In some embodiments, fecal microbiota assessments for the Tn3 scaffold are performed at about 0 days, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, or 24 weeks after initiation of treatment. , 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, or at least about 53 weeks. In some embodiments, fecal microbiota assessments for the Tn3 scaffold may be assessed at about 1 day, 169±3 days, and 309±7 days after initiation of treatment.

[0113] autoantibodies In some embodiments, the evaluation includes determining the level of autoantibodies in the subject. Autoantibodies include those that react with autoantigens. Exemplary autoantibodies include SS-A, SS-B, and IgG and / or IgM rheumatoid factor (RF) autoantibodies, and combinations thereof. In some embodiments, serum is collected to evaluate the presence of anti-SSA (Ro), anti-SSB (La), antinuclear antibodies, and RF. Exemplary methods for evaluating the level of autoantibodies include EliA immunoassay, microarray, ELISA, or combinations thereof. In some embodiments, autoantibodies are not detected after administration of the Tn3 scaffold. In some embodiments, the treatment comprises reducing autoantibodies in the subject by about: 20%, 30%, 40%, 45%, 50%, 60%, 75%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or up to 100% as compared to the levels of autoantibodies in an otherwise comparable method in which the subject of the method is not administered a Tn3 scaffold. In some embodiments, the change from baseline in SS-A, SS-B, and IgG and / or IgM rheumatoid factor (RF) autoantibodies is determined. In some embodiments, the autoantibodies are detected at levels up to about 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, or 50-fold as compared to an otherwise comparable method in which the subject of the method is not administered a Tn3 scaffold. In some embodiments, administration of a Tn3 scaffold of the present disclosure is effective to reduce levels of autoantibodies in a subject by at least about or up to about 3%-5%, 5%-10%, 10%-20%, or 5%-25% compared to baseline levels prior to administration. In some embodiments, administration of a Tn3 scaffold is effective to eliminate autoantibodies in a subject in need thereof.

[0114] In some embodiments, autoantibody assessments against the Tn3 scaffold are performed at about 0 days, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, 53 weeks, 54 weeks, 55 weeks, 56 weeks, 57 weeks, 58 weeks, 59 weeks, 60 weeks, 61 weeks, 62 weeks, 63 weeks, 64 weeks, 65 weeks, 66 weeks, 67 weeks, 68 weeks, 69 weeks, 70 weeks, 71 weeks, 72 weeks, 73 weeks, 74 weeks, 75 weeks, 76 weeks, 77 weeks, 78 weeks, 79 weeks, 80 weeks, 81 weeks, 82 weeks, 83 weeks, 84 weeks, 85 weeks, 86 weeks, 87 weeks, 88 weeks, 89 weeks, 90 weeks, 91 weeks, 92 weeks, 93 weeks, 94 weeks, The evaluation may be performed at 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, or at least about week 53. In some embodiments, evaluation of autoantibodies against the Tn3 scaffold may be performed at about day 1, day 85±3, day 169±3, and day 253±3 after initiation of treatment.

[0115] Markers of inflammation In some embodiments, the evaluation includes determining the level of a marker of inflammation. Exemplary markers of inflammation include, but are not limited to, immunoglobulins (IgM, IgG, IgA), beta 2 microglobulin, C-reactive protein (CRP), CXCL13, C3, C4 and serum free light chains, cryoglobulins, and serum and urine immunofixation and combinations thereof. In some embodiments, whole blood, plasma, serum, and urine are collected to evaluate the markers of inflammation. In some embodiments, a change compared to baseline is determined. In some embodiments, a change from baseline in the levels of markers of inflammation (immunoglobulins, beta 2 microglobulin, C-reactive protein [CRP], CXCL13, C3, C4 and serum free light chains) is determined. In some embodiments, suitable assays for evaluating the level of inflammation include ELISA, hs-CRP test, CRP test, Luminex, and combinations thereof. In some embodiments, administration of a Tn3 scaffold of the present disclosure is effective to reduce the level of a biomarker of inflammation in a subject by at least about or by up to about: 20%, 30%, 40%, 45%, 50%, 60%, 75%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or up to 100%, as compared to the level of autoantibodies in an otherwise comparable method in which the subject of the otherwise comparable method is not administered a Tn3 scaffold. In some embodiments, administration of a Tn3 scaffold of the present disclosure is effective to reduce the level of a biomarker of inflammation in a subject by at least about or by up to about: 3%-5%, 5%-10%, 10%-20%, or 5%-25%, as compared to baseline levels prior to administration.

[0116] In some embodiments, assessment of markers of inflammation on the Tn3 scaffold is at about 0 days, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks In some embodiments, evaluation of markers of inflammation on a Tn3 scaffold may be evaluated at about 1 day, 15±1 day, 29±3 days, 57±3 days, 85±3 days, 113±3 days, 141±3 days, 169±3 days, 197±3 days, 225±3 days, 253±3 days, 281±3 days, 309±7 days, and 365±7 days after initiation of treatment.

[0117] RNA and DNA analysis In some embodiments, the evaluation involves quantifying expression levels of genes associated with disease activity by RNA and / or DNA analysis. In some embodiments, RNA testing is performed. In some embodiments, RNA testing is performed to measure expression levels of genes associated with disease activity, specific cell types including plasma cell gene signature, T follicular helper gene signature, and signal transduction including the CD40L / CD40 pathway.

[0118] In some embodiments, blood RNA is used to measure expression levels of genes associated with disease activity, specific cell types including plasma cell gene signature, T follicular helper gene signature, and signal transduction including the CD40L / CD40 pathway. In some embodiments, blood samples are collected using the PAXgene Blood RNA System for collection, transport, and storage of blood, stabilization of intracellular RNA in sealed tubes, and subsequent isolation and purification of intracellular RNA from whole blood for microarray analysis and quantitative polymerase chain reaction.

[0119] In some embodiments, DNA testing may be performed. Because certain CD40 SNPs have been identified as susceptibility loci in certain disease subsets of SLE or Graves' disease, DNA may be isolated at baseline from blood for pharmacogenomic (single nucleotide polymorphism [SNP]) profiling of CD40 and other genes involved in the CD40 / CD40L axis. In some embodiments, blood DNA is collected for epigenetic analysis, such as DNA methylation in immune-related genes. In some embodiments, epigenomic profiling is assessed by methods including, but not limited to, ATACseq and DNA methylation sequencing.

[0120] In some embodiments, expression levels of genes associated with disease activity by RNA and / or DNA analysis may be reduced by at least about 10%, 15%, 20%, 25%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or up to 100% as compared to an otherwise equivalent method in which the subject of the otherwise equivalent method is not administered a Tn3 scaffold.

[0121] In some embodiments, RNA and / or DNA analysis for the Tn3 scaffold is performed at about 0 days, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, 53 weeks, 54 weeks, 55 weeks, 56 weeks, 57 weeks, 58 weeks, 59 weeks, 60 weeks, 61 weeks, 62 weeks, 63 weeks, 64 weeks, 65 weeks, 66 weeks, 67 weeks, 68 weeks, 69 weeks, 70 weeks, 71 weeks, 72 weeks, 73 weeks, 74 weeks, 75 weeks, 76 weeks, 77 weeks, 78 weeks, 79 weeks, 80 weeks, 81 weeks, 82 weeks, 83 weeks, 84 weeks, 85 weeks, 86 weeks, 87 weeks, 88 weeks, 89 weeks, 90 weeks, 91 weeks, 92 weeks, 93 weeks, 94 weeks, The assay may be evaluated at 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, or at least about week 53. In some embodiments, RNA and / or DNA analysis on the Tn3 scaffold may be evaluated at about 1 day, 15±1 day, 29±3 days, 57±3 days, 85±3 days, 141±3 days, 169±3 days, 197±3 days, 225±3 days, 253±3 days, 281±3 days, 309±7 days, and 365±7 days after initiation of treatment.

[0122] Actigraphy In some embodiments, the assessment may include measurements of overall activity and / or sleep patterns. In some embodiments, the assessment may include actigraphy. In some embodiments, actigraphy is collected throughout the study to measure overall activity and sleep patterns, including but not limited to sleep duration and / or fragmentation. In some embodiments, the activity monitor device is an ActiGraph, a wearable watch device. In some embodiments, changes in overall activity and sleep patterns during the study may be determined.

[0123] In some embodiments, actigraphy analysis for the Tn3 scaffold is performed at about 0 days, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, The actigraphy analysis may be evaluated at 3 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, 52 weeks, or at least about week 53. In some embodiments, actigraphy analysis for the Tn3 scaffold may be evaluated at about 365±7 days after initiation of treatment.

[0124] Duration of response (duration of clinical response) In some embodiments, the evaluation includes determining the duration of response to the Tn3 scaffold. In some embodiments, the evaluation includes determining the duration of response to the Tn3 scaffold by quantifying the time to initiation of rescue therapy. In some embodiments, administration of the Tn3 scaffold is effective to reduce or eliminate the initiation of rescue therapy in treated subjects compared to subjects who did not receive the Tn3 scaffold. In some embodiments, administration of the Tn3 scaffold is effective to extend the time to initiation of rescue therapy by at least about: 1 day, 6 days, 11 days, 16 days, 21 days, 26 days, 30 days, 2 months, 3 months, 4 months, 5 months, 6 months, 9 months, 11 months, 1 year, 2 years, or up to about 5 years after administration.

[0125] Pharmaceutical Compositions In some embodiments, pharmaceutical compositions are provided. The pharmaceutical compositions may comprise the Tn3 scaffold of the present disclosure. In some embodiments, the pharmaceutical compositions are part of a treatment regimen that includes the Tn3 scaffold of the present disclosure and one or more additional therapeutic agents provided herein.

[0126] Many drugs can be administered orally as liquids, capsules, tablets, or chewable tablets. The oral route is the most convenient and usually the safest and least expensive, so it is the most frequently used. However, it has limitations due to the general way drugs move through the digestive tract. For orally administered drugs, absorption may begin in the mouth and stomach. However, most drugs are usually absorbed from the small intestine. The drug passes through the intestinal wall to the liver and is then transported via the bloodstream to its target site. The intestinal wall and liver chemically change (metabolize) many drugs, reducing the amount of drug that reaches the bloodstream. As a result, these drugs are often administered in smaller doses when injected intravenously to achieve the same effect.

[0127] For the subcutaneous route, the needle is inserted into the fatty tissue just under the skin. After the drug is injected, it travels to small blood vessels (capillaries) and is carried by the bloodstream. Alternatively, the drug reaches the bloodstream through lymphatic vessels. If a larger amount of medication is needed, the intramuscular route is preferred over the subcutaneous route. A longer needle is used because the muscle is under the skin and fatty tissue. The drug is usually injected into the muscle of the upper arm, thigh, or buttocks. How quickly the drug is absorbed into the bloodstream depends in part on the blood supply to the muscle. The sparser the blood supply, the longer it takes for the drug to be absorbed. For the intravenous route, the needle is inserted directly into a vein. A solution containing the drug may be administered by a single dose or by continuous infusion. For infusion, the solution moves by gravity (from a collapsible plastic bag) or, more commonly, by an infusion pump through a thin flexible tube into a tube (catheter) inserted into a vein (usually the forearm).

[0128] In some embodiments, the pharmaceutical compositions provided herein are administered by infusion. The infusion may be administered over a period of time. For example, the infusion may be administration of the drug over a period of about 5 minutes to about 10 hours. The infusion may be administered over a period of about 5 minutes, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, or up to about 10 hours. In some embodiments, intravenous administration is used to deliver precise doses to the whole body in a rapid and well-controlled manner. It is also used for irritating solutions that cause pain and damage tissues when administered subcutaneously or intramuscularly. When administered intravenously, the drug is delivered quickly to the bloodstream and tends to take effect sooner than when administered by other routes. Therefore, medical professionals closely monitor people who receive intravenous injections for signs that the drug is working or causing undesirable side effects. Also, the effects of drugs administered by this route tend to be short-lived. Therefore, some drugs must be administered by continuous infusion to maintain their effectiveness. In some embodiments, infusion reactions may occur, including headache, nausea, somnolence, dyspnea, fever, muscle pain, rash, or other symptoms. Potential risks associated with administration of Tn3 scaffolds include infection, redness, swelling, pain, and induration at the administration site. Before each IV infusion, subjects may receive prophylaxis with IV methylprednisolone, oral diphenhydramine, and oral acetaminophen, or equivalent(s), to reduce the risk or severity of potential reactions.

[0129] In some embodiments, the medicine is administered intrathecally. In the intrathecal route, a needle is inserted between two vertebrae in the lower spine and into the space around the spinal cord. The drug is then injected into the spinal canal. A small amount of local anesthetic is often used to numb the injection site. This route is used when a drug is needed to have a rapid or local effect on the brain, spinal cord, or the tissue layers that cover them (meninges), for example, to treat infections of these structures.

[0130] Drugs administered by inhalation through the mouth can be atomized into smaller droplets than those administered through the nasal route, so that the drug can pass through the windpipe (trachea) and enter the lungs. How deep into the lungs they reach depends on the size of the droplets. Smaller droplets reach deeper and increase the amount of drug absorbed. Inside the lungs, they are absorbed into the bloodstream. Drugs applied to the skin are usually used to achieve a local effect, so they are most commonly used to treat superficial skin disorders such as psoriasis, eczema, skin infections (viral, bacterial, and fungal), itching, and dry skin. The drug is mixed with an inactive substance. Depending on the consistency of the inactive substance, the formulation may be an ointment, cream, lotion, solution, powder, or gel.

[0131] In some embodiments, the treatment regimen including the pharmaceutical composition may be dosed according to the subject's weight. In subjects who are determined to be obese (BMI>35), actual weight may need to be used. BMI is calculated as BMI=weight(kg) / [height(m)]2. Ideal weight is calculated as 50kg+2.3*(inches over 60 inches) for men or 45.5kg+2.3(inches over 60 inches) for women. Adjusted weight may be calculated for subjects who are over 20% of their ideal weight. Adjusted weight may be the sum of ideal weight+(0.4×(actual weight-ideal weight)). In some embodiments, body surface area may be used to calculate the dosage. Body surface area (BSA) may be calculated by BSA(m2)=Vheight(cm)*weight(kg) / 3600.

[0132] In some embodiments, the pharmaceutical composition may be administered by any route, alone or together with a pharma- ceutically acceptable carrier or excipient, and such administration may be in both single and multiple doses. More specifically, the pharmaceutical composition may be combined with various pharma- ceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hand candies, powders, sprays, aqueous suspensions, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media, and various non-toxic organic solvents. Furthermore, the pharmaceutical preparations may be suitably sweetened and / or flavored with various agents of the type commonly used for such purposes. Exemplary carriers and excipients include dextrose, sodium chloride (NaCl), sucrose, lactose, cellulose, xylitol, sorbitol, maltitol, gelatin, PEG, PVP, histidine / histidine hydrochloride, trehalose dihydrate, polysorbate 80, and any combination thereof. In some embodiments, the excipients include histidine / histidine hydrochloride, NaCl, trehalose dihydrate, and polysorbate 80.

[0133] Numbered embodiments Notwithstanding the appended claims, the following numbered embodiments also form part of this disclosure.

[0134] Embodiment 1. A method for treating Sjogren's syndrome (SS) in a subject in need thereof comprising: administering to the subject a Tn3 scaffold comprising a CD40L-specific monomeric subunit; wherein the Tn3 scaffold specifically binds to CD40L; wherein the monomeric subunit comprises seven beta strands designated A, B, C, D, E, F, and G, and six loop regions designated AB, BC, CD, DE, EF, and FG, wherein the AB loop comprises SEQ ID NO:11, the BC loop comprises SEQ ID NO:12, the CD loop comprises SEQ ID NO:13, the DE loop comprises SEQ ID NO:14, the EF loop comprises SEQ ID NO:15, and the FG loop comprises SEQ ID NO:16, wherein the Tn3 scaffold comprising a CD40L-specific monomeric subunit is administered at a dose of about 1500 mg, about 2500 mg, or about 3000 mg, about 75-1500 mg, or about 300-3000 mg.

[0135] Embodiment 2. The method of embodiment 1, wherein at least one CD40L-specific monomeric subunit comprises seven beta chains designated A, B, C, D, E, F, and G, where beta chain A comprises SEQ ID NO:5, beta chain B comprises SEQ ID NO:6, beta chain C comprises SEQ ID NO:17, beta chain D comprises SEQ ID NO:18, beta chain E comprises SEQ ID NO:19, beta chain F comprises SEQ ID NO:20, and beta chain G comprises SEQ ID NO:21.

[0136] Embodiment 3. The method of any one of embodiments 1-2, wherein the subject has a European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index (ESSDAI) score ≧5.

[0137] Embodiment 4. The method of embodiment 3, wherein the ESSDAI score is assessed based on the ESSDAI domains consisting of skin, kidney, joint, muscle, blood, glandular, constitutional, nodal, and biological domains.

[0138] Embodiment 5. The method of any one of embodiments 1-2, wherein the subject has (a) an ESSDAI score <5, (b) a EULAR Sjogren's Syndrome Patient-Reported Index (ESSPRI) score ≧5, and (c) a total stimulated salivary flow rate >0.1 mL / min.

[0139] Embodiment 6. The method of any one of embodiments 1 to 5, wherein the Tn3 scaffold is administered as an induction dose and then as a maintenance dose.

[0140] Embodiment 7. The method of embodiment 6, wherein said induction dose comprises at least three administrations of a Tn3 scaffold, once about every two weeks.

[0141] Embodiment 8. The method of embodiment 6, wherein said maintenance dose comprises administering said Tn3 scaffold about once every two weeks for at least four times.

[0142] Embodiment 9. The method of embodiment 8, wherein the time between the last induction dose and the first maintenance dose is about 4 weeks.

[0143] Embodiment 10. The method of any one of embodiments 1-5, wherein the Tn3 scaffold is administered about once every 4 weeks, about once every 2 months, about once every 3 months, about once every 4 months, or about once every 6 months.

[0144] Embodiment 11. The method of embodiment 10, wherein the Tn3 scaffold is administered at least four times.

[0145] Embodiment 12 The method of embodiment 11, wherein the Tn3 scaffold is administered at least five times.

[0146] Embodiment 13. The method of any one of embodiments 1-12, wherein the Tn3 scaffold is administered intravenously, subcutaneously, orally, intramuscularly, intrathecally, sublingually, rectally, vaginally, cutaneously, systemically, topically, transdermally, or by inhalation.

[0147] Embodiment 14. The method of claim 13, wherein the Tn3 scaffold is administered intravenously.

[0148] Embodiment 15. The method of any one of embodiments 1 to 13, wherein the Tn3 scaffold comprises two CD40L-specific monomeric subunits connected in series.

[0149] Embodiment 16. The method of embodiment 15, wherein the two CD40L-specific monomeric subunits each comprise SEQ ID NO:3.

[0150] Embodiment 17. The method of any one of embodiments 1 to 16, wherein the CD40L-specific monomeric subunits are connected by a linker.

[0151] Embodiment 18. The method of any one of embodiments 1 to 17, wherein at least one CD40L-specific monomeric subunit is directly fused or conjugated to polyethylene glycol (PEG).

[0152] Embodiment 19. The method of any one of embodiments 1 to 17, wherein at least one CD40L-specific monomeric subunit is conjugated to polyethylene glycol (PEG) either directly fused or via a linker.

[0153] Embodiment 20 The method of embodiment 17, wherein the linker comprises a peptide linker.

[0154] Embodiment 21 The method of embodiment 20, wherein the linker comprises SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, or SEQ ID NO:10.

[0155] Embodiment 22 The method of embodiment 21, wherein at least one CD40L-specific monomeric subunit is fused or conjugated to albumin.

[0156] Embodiment 23 The method of embodiment 22, wherein the albumin is human serum albumin (HSA).

[0157] Embodiment 24. The method of embodiment 23, wherein the HSA is a variant HSA comprising SEQ ID NO:4.

[0158] Embodiment 25. A method of treating Sjogren's Syndrome (SS) in a subject in need of such treatment, comprising administering to the subject a Tn3 scaffold at a dose of about 1500 mg, about 2500 mg, or about 3000 mg, wherein the Tn3 scaffold comprises SEQ ID NO:1.

[0159] Embodiment 26 The method of embodiment 25, wherein the Tn3 scaffold is administered as an induction dose, followed by one or more maintenance doses.

[0160] Embodiment 27. The method of embodiment 26, wherein the induction dose and the maintenance dose are the same amount.

[0161] Embodiment 28. The method of embodiment 27, wherein the induction dose and the maintenance dose are different amounts.

[0162] Embodiment 29. The method of any one of embodiments 25 to 28, wherein at least one dose is 3000 mg.

[0163] Embodiment 30. The method of any one of embodiments 25-29, wherein the induction dose and at least one maintenance dose are administered about one month apart, about two months apart, about three months apart, about four months apart, or about six months apart.

[0164] Embodiment 31. The method of any one of embodiments 25-30, wherein the induction dose comprises at least three administrations of a Tn3 scaffold about every two weeks, and the maintenance dose comprises at least four administrations of a Tn3 scaffold, once about every four weeks.

[0165] Embodiment 32. The method of any one of embodiments 1 to 31, wherein the Tn3 scaffold comprises SEQ ID NO:1.

[0166] Embodiment 33. The method of any one of embodiments 1 to 32, wherein said administration is effective to reduce ESSDAI score compared to an otherwise similar subject receiving a placebo control.

[0167] Embodiment 34. The method of embodiment 33, wherein the decrease is at least about 1 point, 2 points, 3 points, 4 points, or 5 points.

[0168] Embodiment 35 The method of embodiment 33, wherein the decrease is at least about 6 points. EXAMPLES

[0169] Example 1 - A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Proof-of-Concept Study to Evaluate the Efficacy and Safety of VIB4920 in Subjects with Sjogren's Syndrome (SS) research design This study was a randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy, safety, and tolerability of VIB4920, an anti-CD40L-Tn3 fusion protein, in adult subjects diagnosed with SS according to the 2016 American College of Rheumatology (ACR) / European League Against Rheumatism (EULAR) criteria. Two SS populations were enrolled in the study. Population #1 consisted of subjects with moderate to severe (moderate to high) systemic disease activity defined by an ESSDAI score <5. Population #2 consisted of subjects with mild systemic disease activity defined by an ESSDAI score <5, but with moderate to high (or severe) subjective symptoms defined by an ESSPRI score ≥5 and residual stimulated salivary flow rate.

[0170] Within each cohort, eligible subjects were randomized to receive VIB4920 1500 mg IV or placebo once every 2 weeks (Q2W) for 3 doses, followed by 4 more doses once every 4 weeks (Q4W) (Stage I). Starting on day 169, subjects randomized to VIB4920 received placebo Q4W for 5 doses, and subjects randomized to placebo received VIB4920 Q4W for 5 doses (Stage II). Subjects who discontinued VIB4920 were ineligible for treatment during Stage II. All subjects were followed for at least 12 weeks after their last IP dose.

[0171] An exemplary study schematic is shown in FIG. population

[0172] The two SS populations distinguish between patients with primarily glandular dysfunction and those with both glandular dysfunction and systemic symptoms. The two SS populations represent subsets with significant unmet need that require different endpoints to assess efficacy. The ESSDAI is a validated instrument to assess systemic disease activity. The ESSPRI uses a 0-10 numeric analog scale to assess each of the three domains of SS symptoms: dryness, fatigue, and pain (joints and / or muscles).

[0173] Population #1 consisted of SS patients with moderate to high systemic activity defined by an ESSDAI ≥ 5. The following domains were scored but did not contribute to the minimum ESSDAI score of 5 required for inclusion: peripheral nervous system, central nervous system, and pulmonary. Population #2 consisted of SS patients with exocrine insufficiency and subjective symptoms defined by an ESSPRI score ≥ 5, considered as the cut-off point for an "inadequate symptom state," but with low systemic disease activity (ESSDAI score < 5).

[0174] A complete physical examination was performed, including weight, height, and a 28-joint evaluation. The 2016 ACR / EULAR criteria were used to classify SS in both Population #1 and Population #2, as confirmed by a medically qualified individual. The classification of SS was based on the following criteria: 1 , and do not have any of the conditions listed as exclusion criteria 2 and has a score of 4 or more when the weights of the following items in Table 2 are summed:

[0175] [Table 2]

[0176] 1. Inclusion Criteria: These criteria apply to any subject with at least one symptom of dry eyes or dry mouth (defined as a positive response to at least one of the following questions: 1) Have you experienced persistent and bothersome dry eyes every day for >3 months? 2) Do you have a recurrent sensation of sand or gravel in your eyes? 3) Do you use tear substitutes 3 or more times a day? 4) Have you had dry mouth every day for >3 months? 5) Do you drink liquids frequently to make it easier to swallow dry food?); or suspected SS by the ESSDAI questionnaire (at least one domain with a positive item) 2. Exclusion Criteria: A previous diagnosis of any of the following conditions precludes a diagnosis of SS and participation in an SS study or treatment trial due to overlapping clinical features or interference with baseline testing. History of head and neck radiation therapy ●Active hepatitis C infection (PCR positive) ●Acquired immunodeficiency syndrome Sarcoidosis Amyloidosis Graft-versus-host disease IgG4-related diseases NOTE: Patients taking anticholinergic drugs should usually be evaluated for objective signs of salivary hypofunction and dry eyes after adequate spacing between doses of these medications, as these components are valid measures of oral and ocular dryness. 3. Histopathological examination should be performed to determine the diagnosis of focal lymphocytic sialadenitis and the focal score number (4 mm 2 The protocol should be performed by a pathologist with expertise in the following areas: 4. Ocular staining score as described by Whitcher et al., Am J Ophthalmol. 2009;149(3):405-15; van Bijsterfeld score (as described by van Bijsterfeld Arch Ophthalmol. 1969 Jul;82(1):10-4) 5. Unstimulated whole saliva as described by Navazesh and Kumar (J Am Dent Assoc. 2008 May;139 Suppl:35S-40S).

[0177] Eligibility related to ESSDAI scores for Population #1 was also confirmed by a medically qualified individual. To determine study eligibility, a total stimulated salivary flow rate, ESSDAI, and ESSPRI were performed at screening. Blood testing required for the ESSDAI was also completed. In addition, an autoantibody panel including RF was collected.

[0178] Inclusion criteria for Population #1 To be included in Population #1 of this study, individuals must meet all of the following criteria: 1. Adults aged 18 years or older at the time of informed consent (in countries with different regulations, the minimum age for adult participants may be greater than 18 years). 2. SS was diagnosed based on fulfilling the 2016 ACR / EULAR classification criteria. 3. ESSDAI score ≥ 5 at screening; the following domains were scored but did not contribute to the minimum ESSDAI score of 5 required for inclusion in the peripheral nervous system, central nervous system, and pulmonary domains: 4. Positive anti-Ro autoantibodies and / or RF at screening as defined by standard central clinical testing. 5. Written informed consent and any locally required authorizations (e.g., Health Insurance Portability and Accountability Act in the United States and European Union Data Privacy Directive in the EU) obtained from subject / legal representative prior to performing any protocol-related procedures, including screening assessments. 6. Women of childbearing potential who are sexually active with an unsterilized male partner must use highly effective contraception from the time of signing the Informed Consent Form (ICF) and agree to continue such precautions until the end of study follow-up. Discontinuation of contraception after this point should be discussed with the investigator. Highly effective contraception methods include: Combined (estrogen and progestogen-containing) hormonal contraceptive methods associated with the inhibition of ovulation: -Oral -In the vagina -Transdermal Progestogen-only hormonal contraception associated with inhibition of ovulation: -Oral -Injectable -Portable ●Intrauterine device (IUD) Intrauterine hormone releasing system (IUS) Bilateral fallopian tube obstruction Partner who has had a vasectomy ●Sexual abstinence Sexual abstinence will be considered a highly effective method only if it is the subject's preference and usual lifestyle and the subject agrees to abstain from heterosexual intercourse from ICF signing until the end of study follow-up. Periodic abstinence, rhythm methods, and withdrawal methods are not acceptable contraceptive methods. Female partners (of childbearing potential) of male study participants are encouraged to use a highly effective method of contraception other than a barrier method. - A woman of childbearing potential is defined as a woman who is not surgically infertile (sterilization includes bilateral tubal ligation, bilateral oophorectomy, or hysterectomy) or who is not postmenopausal (defined as 12 months of absence of menstruation without another medical cause). -The vasectomized partner is a highly effective method of contraception only if he or she is the only sexual partner of the female study participant of childbearing potential and if the vasectomized partner has been medically evaluated for surgical success. 7. Non-infertile male subjects who are sexually active with a female partner of childbearing potential must use spermicide-containing condoms from day 1 through the end of the study. 8. Meet all of the following tuberculosis (TB) criteria: a. No history of latent or active TB prior to screening, except for latent TB with documented completion of appropriate treatment. b. There are no signs or symptoms suggestive of active tuberculosis from medical history or physical examination. c. No recent (within 12 weeks of screening) close contact with a person with active TB (close contact is defined as more than 4 hours per week or living in the same household or living in a home frequently visited by a person with active TB). Negative interferon-gamma release assay (IGRA) test results for tuberculosis obtained within 12 weeks prior to randomization. Subjects with indeterminate test results may have repeat testing, but will be excluded if repeat testing is also indeterminate. e. Chest radiograph (taken during the screening period or any time within 12 weeks prior to signing of the ICF) showing no evidence of current active TB or other infection, or old active TB, malignancy, or clinically significant abnormalities suggestive of an active process (other than attributable to SS).

[0179] If an individual in Population #1 meets any of the following criteria, he or she is ineligible: 1. Patients with a history of confirmed deep vein thrombosis or arterial thromboembolism within 2 years after signing of the ICF. 2. Patients with risk factors for venous thromboembolism or arterial thrombosis (e.g., fixation or major surgery within 12 weeks prior to screening), prothrombotic conditions (including but not limited to congenital or inherited deficiencies of antithrombin III, protein C, protein S, or a confirmed diagnosis of fulminant antiphospholipid syndrome). 3. Patients who require treatment with anticoagulants (e.g., clopidogrel, prasugrel, warfarin, low molecular weight heparin). Low-dose aspirin therapy (up to 325 mg per day) is permitted. 4. Concomitant polymyositis, dermatomyositis, or systemic sclerosis. 5. Active malignancy or history of malignancy within the past 5 years, except for the following: Cervical intraepithelial neoplasia with demonstrable success with curative therapy >12 months prior to screening; or b. Basal cell carcinoma of the skin after apparently curative treatment. 6. Subjects who are pregnant, lactating, or planning pregnancy during the study period. 7. Subjects who have tested positive for or are receiving treatment for Hepatitis B, Hepatitis C, or HIV infection. For hepatitis B, a positive test for chronic hepatitis B infection at the time of screening was defined as either (1) hepatitis B surface antigen (HBsAg) positivity or (2) hepatitis B core antibody (anti-HBc) positivity. 8. Subjects with the following: a.- History of multiple episodes of herpes zoster and / or opportunistic infections during the past 12 months, excluding oral candidiasis, vaginal candidiasis, and fungal skin infections. b.- Active viral, bacterial, or other infection requiring systemic treatment at screening or throughout randomization, or history of more than two infections requiring IV antibiotics within 12 months prior to ICF signing. c. The epidemiological risk of COVID-19 (recent exposure, high-risk residence), and health-related risk of severity of COVID-19, based on current understanding of risk factors for severe disease, in making decisions regarding the risk of participation for each individual subject. Subjects with active COVID-19 infection or disease, or other significant infectious diseases, or who, in the investigator's judgment, may be at unacceptable risk of COVID-19 or its complications, should not be randomized. d. Documented positive SARS-CoV-2 test within 2 weeks prior to randomization. Subjects who test positive for SARS-CoV-2 may be rescreened at least 2 weeks after the positive test if asymptomatic and at least 3 weeks after the onset of symptomatic COVID-19 infection. 9. Subject with a known history of severe allergy or reaction to any component of the VIB4920 formulation or any other biologic therapy. 10.- Subject with severe cardiovascular, respiratory, endocrine, gastrointestinal, hematological, neurological, psychiatric, or systemic disease, or any other condition that, in the Investigator's opinion, places the subject at unacceptable risk of complications that would interfere with the evaluation of VIB4920 or confound the subject's safety or interpretation of the study results. 11. Subjects unable or unwilling to comply with protocol requirements (e.g., drug or alcohol abuse). 12.Subject has received a live (attenuated) vaccine within 4 weeks prior to signing of the ICF. 13. The last dose of an experimental biological agent (except those listed in point 14) or oral medication was received less than 3 months or 5 half-lives prior to randomization. 14.- Subject has prior treatment with biologic B-cell depleting therapy (e.g., rituximab, ocrelizumab, or ofatumumab) within 12 months prior to randomization, or other B-cell targeted therapy (e.g., belimumab) within 3 months. 15.- Corticosteroid injections (including intra-articular) or oral prednisone or equivalent at doses >10 mg / day within 6 weeks prior to randomization. Concomitant treatment with oral corticosteroids ≤ 10 mg / day prednisone or equivalent is permitted only if the dose has been stable through randomization (Day 1) for at least 2 weeks prior to screening and is expected to remain stable during treatment. Inhaled or topical corticosteroids administered for asthma, chronic obstructive pulmonary disease, or dermatological conditions are permitted if the dose is expected to remain stable during the study. 16.Subject has been treated with systemic corticosteroids for a total of >2 weeks within the 24 weeks prior to the Screening Visit for an indication other than SS, RA, or SLE. 17. Use of the following medications: If antimalarial medication (e.g., chloroquine, hydroxychloroquine, quinacrine) was initiated or the dose was changed within 8 weeks prior to signing the ICF or during the screening period. b. MTX, if the dose is >20 mg / week; or if there is a new dose change or initiation within 4 weeks prior to ICF signing through randomization (Day 1), or if there is any change in route of administration. c. Azathioprine (AZA), if the dose is greater than 150 mg / day and if there is a new dose change or initiation within 4 weeks prior to ICF signing through randomization (Day 1), and if there is a change in route of administration. d. Leflunomide, if the dose is greater than 20 mg / day; or if there has been any change or initiation of a new dose within 4 weeks prior to ICF signing through randomization (Day 1). e. Mycophenolate mofetil (MMF), if the dose is >2 mg / day; or if there has been any change or initiation of a new dose within 4 weeks prior to ICF signing through randomization (Day 1). f. Any other DMARD, immunosuppressant, or antiproliferative agent (if last dose was administered within the following period): - 4 weeks prior to signing the ICF, or - Drug-specific 5 half-life elimination period (if greater than 4 weeks). g. Any medication that, in the opinion of the Investigator, interferes with the evaluation of VIB4920 or the subject's safety or interpretation of the study results. h.- Increase or initiation of a new dose of cevimeline or pilocarpine and cyclosporine eye drops (Restasis) within 2 weeks prior to ICF signing through randomization (Day 1). 18. Subject has received prior treatment with an anti-CD40L compound at any time prior to screening. 19.Subjects who had any of the following blood tests at screening: Aspartate aminotransferase (AST) > 2 × upper limit of normal (ULN) Alanine aminotransferase (ALT) > 2 × ULN Total bilirubin (TBL) > 2 × ULN Hemoglobin < 75g / L ●Neutrophil<1.0×109 / L ●Platelets<100×109 / L Prothrombin or partial thromboplastin time (PTT) > ULN

[0180] Inclusion criteria for Population #2 To be included in Population #2 of this study, each individual met all of the following criteria: 1. Adults aged 18 years or older at the time of informed consent (in countries with different regulations, the minimum age for adult participants may be greater than 18 years). 2. SS was diagnosed based on fulfilling the 2016 ACR / EULAR classification criteria. 3. ESSPRI score ≥ 5 at screening. 4. ESSDAI score <5 at screening. 5. Positive anti-Ro autoantibodies or RF, or both, at screening according to available standard central clinical laboratory definitions. 6. Residual salivary gland function defined by total stimulated salivary flow rate >0.1 mL / min. 7. Written informed consent and any locally required authorizations (e.g., Health Insurance Portability and Accountability Act in the United States and European Union Data Privacy Directive in the EU) obtained from subject / legal representative prior to performing any protocol-related procedures, including screening assessments. 8. Women of childbearing potential who are sexually active with an unsterilized male partner must use highly effective contraception from the time of signing the ICF and agree to continue such precautions until the end of study follow-up. Discontinuation of contraception after this point should be discussed with their responsible physician. Highly effective contraception methods include: Combined (estrogen and progestogen-containing) hormonal contraceptive methods associated with the inhibition of ovulation: -Oral -In the vagina -Transdermal Progestogen-only hormonal contraception associated with inhibition of ovulation: -Oral -Injectable -Portable ●Intrauterine device (IUD) Intrauterine hormone releasing system (IUS) Bilateral fallopian tube obstruction Partner who has had a vasectomy ●Sexual abstinence Sexual abstinence will be considered a highly effective method only if it is the subject's preference and usual lifestyle and the subject agrees to abstain from heterosexual intercourse from ICF signing until the end of study follow-up. Periodic abstinence, rhythm methods, and withdrawal methods are not acceptable contraceptive methods. Female partners (of childbearing potential) of male study participants are encouraged to use a highly effective method of contraception other than a barrier method. - A woman of childbearing potential is defined as a woman who is not surgically infertile (sterilization includes bilateral tubal ligation, bilateral oophorectomy, or hysterectomy) or who is not postmenopausal (defined as 12 months of absence of menstruation without another medical cause). -The vasectomized partner is a highly effective method of contraception only if he or she is the only sexual partner of the female study participant of childbearing potential and if the vasectomized partner has been medically evaluated for surgical success. 9. Non-infertile male subjects who are sexually active with a female partner of childbearing potential must use spermicide-containing condoms from day 1 through the end of the study. 10. Meet all of the following criteria for tuberculosis: i. No history of latent or active TB prior to screening, except for latent TB with documented completion of appropriate treatment. j. There are no signs or symptoms suggestive of active tuberculosis based on medical history or physical examination. k. No recent (within 12 weeks of screening) close contact with a person with active TB (close contact is defined as more than 4 hours per week or living in the same household or living in a home frequently visited by a person with active TB). l. Negative IGRA test result for TB obtained within 12 weeks prior to randomization. Subjects with indeterminate test results may have repeat testing, but will be excluded if repeat testing is also indeterminate. m. Chest radiograph (taken during the screening period or any time within 12 weeks prior to signing of the ICF) showing no evidence of current active TB or other infection, or old active TB, malignancy, or clinically significant abnormalities suggestive of an active process (other than attributable to SS).

[0181] Exclusion Criteria for Population #2 If an individual in population #2 meets any of the following criteria, he or she is ineligible: 1. Patients with a history of confirmed deep vein thrombosis or arterial thromboembolism within 2 years after signing of the ICF. 2. Patients with risk factors for venous thromboembolism or arterial thrombosis (e.g., fixation or major surgery within 12 weeks prior to screening), prothrombotic conditions (including but not limited to congenital or inherited deficiencies of antithrombin III, protein C, protein S, or a confirmed diagnosis of fulminant antiphospholipid syndrome). 3. Patients who require treatment with anticoagulants (clopidogrel, prasugrel, warfarin, low molecular weight heparin, etc.). Low-dose aspirin therapy (up to 325 mg / day) is permitted. 4. Concomitant polymyositis, dermatomyositis, or systemic sclerosis. 5. Active malignancy or history of malignancy, except for the following: n. Cervical intraepithelial neoplasia with demonstrable success with curative therapy >12 months prior to screening; or Basal cell carcinoma of the skin with apparent success in curative treatment 6. Subjects who are pregnant, lactating, or planning to become pregnant during the study period. 7. Subjects who have tested positive for or are receiving treatment for Hepatitis B, Hepatitis C, or HIV infection. With regard to hepatitis B, a positive test for chronic hepatitis B infection at the time of screening was defined as detection of either (1) a positive hepatitis B surface antigen (HBsAg) or (2) a positive hepatitis B core antibody (anti-HBc). 8. Subjects with the following: a.- History of multiple episodes of herpes zoster and / or opportunistic infections during the past 12 months, excluding oral candidiasis, vaginal candidiasis, and fungal skin infections. b.- Active viral, bacterial, or other infection requiring systemic treatment at screening or throughout randomization, or history of more than two infections requiring IV antibiotics within 12 months prior to ICF signing. c. The epidemiological risk of COVID-19 (recent exposure, high-risk residence), and health-related risk of severity of COVID-19, based on current understanding of risk factors for severe disease, in making decisions regarding the risk of participation for each individual subject. Subjects with active COVID-19 infection or disease, or other significant infectious diseases, or who, in the investigator's judgment, may be at unacceptable risk of COVID-19 or its complications, should not be randomized. d. Documented positive SARS-CoV-2 test within 2 weeks prior to randomization. Subjects who test positive for SARS-CoV-2 may be rescreened at least 2 weeks after the positive test if asymptomatic and at least 3 weeks after the onset of symptomatic COVID-19 infection. 9. Subject with a known history of severe allergy or reaction to any component of the VIB4920 formulation or any other biologic therapy. 10.- Subject with severe cardiovascular, respiratory, endocrine, gastrointestinal, hematological, neurological, psychiatric, or systemic disease, or any other condition that, in the Investigator's opinion, interferes with the evaluation of VIB4920, or the subject's safety or interpretation of the study results. 11. Subjects unable or unwilling to comply with protocol requirements (e.g., drug or alcohol abuse). 12.Subject has received a live (attenuated) vaccine within 4 weeks prior to signing of the ICF. 13. The last dose of an experimental biological agent (except those listed in point 14) or oral medication was received less than 3 months or 5 half-lives prior to randomization. 14.- Subject has received biologic B-cell depleting therapy (e.g., rituximab, ocrelizumab, or ofatumumab) within 12 months prior to randomization, or other B-cell targeted therapy (e.g., belimumab) within 3 months. 15. Use of the following medications: If antimalarial medication (e.g., chloroquine, hydroxychloroquine, quinacrine) was initiated or the dose was changed within 8 weeks prior to signing the ICF or during the screening period. b. Oral, intramuscular, IV, or intra-articular corticosteroids within 4 weeks prior to ICF signing through randomization (Day 1). c. MTX, AZA, leflunomide, other cDMARDs, or immunosuppressants or antiproliferative medications (if last dose was administered within the following time periods): - 4 weeks prior to signing the ICF, or - Drug-specific 5 half-life elimination period (if greater than 4 weeks). d. Medications that, in the Investigator's opinion, may interfere with the evaluation of VIB4920, or with the subject's safety or interpretation of the study results. e.- Increased dose or initiation of a new dose of a regularly scheduled non-inflammatory drug within 2 weeks prior to ICF signing through randomization (Day 1). f.- Increase or initiation of a new dose of cevimeline or pilocarpine and cyclosporine eye drops (Restasis) within 2 weeks prior to ICF signing through randomization (Day 1). 16. Subject has received prior treatment with an anti-CD40L compound at any time prior to screening. 17.Subjects who had any of the following blood tests at screening: ●AST>2×ULN ●ALT>2×ULN ●TBL>2×ULN Hemoglobin < 75g / L ●Neutrophil<1.0×109 / L ●Platelets<100×109 / L ● Prothrombin or PTT>ULN

[0182] Safety-related screening assessments included adverse events (AEs), safety laboratory tests (serum chemistry, hematology, and urinalysis), coagulation parameters, chest radiograph, thyroid function tests, and a serum β-human chorionic gonadotropin (β-hCG) pregnancy test in women of childbearing potential.

[0183] Safety assessment Safety evaluations were performed during the active treatment period according to the assessments shown in Table 5 and consisted of the following: - Monitoring and recording of all adverse events (AEs) (including significant AEs) and serious AEs - Safety laboratory tests (serum chemistry, hematology, and urinalysis) - Concomitant medication - Vital signs, physical examination (full or symptom-specific depending on visit), and weight -ECG -Urine pregnancy test (for women of childbearing age) -Coagulation tests

[0184] Adverse Events (AEs) An AE is any untoward medical occurrence associated with the use of an intervention in humans, whether or not it is considered related to the intervention.

[0185] Serious Adverse Events (SAEs) An SAE is considered "serious" if it results in any of the following outcomes: -death - Life-threatening AE (An event is considered "life-threatening" if, from the perspective of either the investigator or sponsor, its occurrence places the patient or subject at risk of immediate death. This does not include AEs or suspected adverse reactions (SARs) that could have caused death if they occurred in a more severe form.) - Inpatient hospitalization or extension of current hospitalization - Persistent or significant inability or substantial disruption of the ability to carry out normal life functions. -Congenital abnormalities / birth defects - A serious medical event that may not result in death, be life-threatening, or require hospitalization may be considered serious if, based on sound medical judgment, it may endanger the patient or subject and may require medical or surgical intervention to prevent one of the outcomes described in this definition. Examples of such medical events include allergic bronchospasm requiring intensive care in an emergency room or at home, blood disorders or seizures that do not result in inpatient hospital care, or the development of drug addiction or abuse.

[0186] Causation or association The assessment of the relationship of AEs and SAEs to VIB4920 was determined. An event was considered "unrelated" to the use of VIB4920 if any of the following tests were met: An unreasonable temporal relationship between administration of VIB4920 and the onset of the event (e.g., an event occurring too long before or after administration of VIB4920 to be considered VIB4920-related) b. The causal relationship between VIB4920 and the event is biologically improbable (e.g., death as a passenger in a car accident). c. There is a clearly more likely alternative explanation for the event (e.g., a typical adverse reaction [AR] to a concomitant medication and / or a typical disease-related event).

[0187] If the criteria for "unrelated" were not met, the individual AE / SAE reports were considered to be "related" to the use of VIB4920. "Related" means that the event was considered "related to the use of the drug" and there is a "reasonable possibility" that the event may have been caused by the product (i.e., there are facts, evidence, or evidence to suggest a possible causal relationship).

[0188] Severity / Intensity Severity was assessed according to the following scale: Grade 1: An event of mild intensity that is usually transient and may require only minimal treatment or therapeutic intervention. The event does not usually interfere with normal activities of daily living. Grade 2: An event of moderate intensity that is usually mitigated by additional special therapeutic intervention. The event interferes with normal activities of daily living and causes discomfort, but does not pose a risk of serious or permanent harm to the subject. Grade 3: A severe event requiring intensive therapeutic intervention. The event interrupts normal activities of daily living or has a significant impact on the subject's clinical condition. Grade 4: The event and / or its direct sequelae, associated with imminent risk of death or physical or mental impairment that affects or limits the subject's ability to perform daily living activities (eating, walking, toileting, etc.). Grade 5: Death (loss of life) as a result of the event.

[0189] Adverse Events of Special Interest (AESI) Adverse events of special interest (AESIs) were evaluated. AESIs are of scientific and medical concern specific to the understanding of VIB4920 and may require close monitoring and collection of additional information. AESIs may or may not be serious.

[0190] The following AESIs were monitored: Thrombotic and embolic events - Liver dysfunction (meeting the definition of High's Law (HL)) Anaphylaxis and clinically significant (grade 3 or higher) hypersensitivity reactions ●Severe infusion-related reactions (Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or higher). Severity was assessed according to CTCAE v5. - Grade 1: Mild, transient reaction; interruption of infusion not indicated; intervention not indicated. - Grade 2: Treatment or infusion interruption required but responds promptly to symptomatic treatment (e.g., antihistamines, NSAIDS, narcotics, IV fluids); administration of indicated prophylactic medications within 24 hours - Grade 3: Prolonged (e.g., not responding rapidly to symptomatic medication and / or brief cessation of infusion); recurrence of symptoms after initial improvement; clinical sequelae requiring hospitalization - Grade 4: Fatal outcome; urgent intervention indicated Malignant neoplasms ●Immune complex disease ●Infectious diseases: - Clinically significant symptoms (grade 3 or higher) - Opportunistic infections include, but are not limited to, reactivation of latent viral infections, invasive fungal infections, and tuberculosis.

[0191] Table 3. Summary of study screening procedures. Multiple visits may be required to complete screening.

[0192] [Table 3-1]

[0193] [Table 3-2]

[0194] Formulation of administration (formulation of administration) The formulation of VIB4920 is shown in Table 4.

[0195] [Table 4]

[0196] VIB4920 is formulated at 100 mg / mL VIB4920 in 10 mM sodium phosphate buffer, 250 mM sucrose, 0.02% (weight / volume [w / v]) poloxamer 188, pH 7.4. The nominal volume of each vial is 5.0 mL. VIB4920 is a sterile liquid drug product (500 mg VIB4920 (nominal) per vial) intended for IV infusion after dilution with saline. VIB4920 should not be shaken and does not require special biohazard handling. It should be stored in a refrigerator at 2 °C to 8 °C (36 °F to 46 °F) with appropriate temperature monitoring. VIB4920 should not be frozen.

[0197] The placebo was 0.9% (w / v) saline provided by the site as a 250 mL prefilled IV bag.

[0198] treatment Both populations #1 and #2 received the following treatment regimen: Treatment group 1 received 1,500 mg VIB4920 as an IV infusion Q2W for 3 doses, then Q4W for 4 more doses (Stage I). Starting on day 169, subjects received placebo Q4W for 5 doses (Stage II). Treatment group 2 received placebo as an IV infusion Q2W for 3 doses, followed by 4 more doses Q4W (Stage I). Beginning on day 169, subjects received VIB4910 1500 mg Q4W for 5 doses (Stage II).

[0199] VIB4920 was infused using an IV infusion pump. During stage I, each subject received the entire volume of VIB4920 solution in the IV bag over at least 90 minutes (approximately 2.8 mL / min). VIB4920 was infused through a low protein binding 0.2-line or 0.22-line filter. Vital signs were obtained before the start of each IP infusion. During stage II, infusions were administered over at least 60 minutes (approximately 4.2 mL / min).

[0200] On the first two dosing days of both Stage I (Days 1 and 15) and Stage II (Days 169 and 197), vital signs were measured within 30 minutes before the start of the infusion, every 30 minutes (± 5 minutes) during the infusion, at the end of the infusion (+5 minutes), and then 1 and 2 hours (± 10 minutes) after the end of the infusion. On subsequent dosing days, vital signs were measured within 30 minutes before the start of the infusion, every 30 minutes (± 5 minutes), at the end of the infusion (+5 minutes), and 30 minutes (± 5 minutes) after the end of the infusion. At the end of these observation periods, subjects were discharged if their condition was stable.

[0201] Post-treatment evaluation Following treatment, subjects in Population #1 were evaluated to determine one or more of the following: Change from baseline in ESSDAI at days 85, 169, and 309 Change from baseline in ESSPRI at days 85, 169, and 309 ● The proportion of subjects who achieved ESSDAI (i.e., at least a 3-point reduction) and ESSDAI[4] (i.e., at least a 4-point reduction) response, defined as a reduction of at least 3[4] points from baseline on the ESSDAI at Days 85, 169, and 309 without prematurely discontinuing the study or receiving rescue therapy. Change from baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score at days 85, 169, and 309 Change from baseline in Ocular Surface Disease Index (OSDI(c)) at Days 85, 169, and 309 Patient Global Impression of Severity (PGIS) on days 85, 169, and 309 - The safety and tolerability of multiple IV doses of VIB4920, as measured by the incidence of treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events (TESAEs), adverse events of special interest (AESIs), and laboratory, vital sign, and electrocardiogram (ECG) abnormalities. PK under study Percentage of subjects with a positive immunogenic response as measured by anti-VIB4920 antibodies by study completion Change from baseline in total stimulated salivary flow rate Change from baseline in Schirmer test Changes from baseline in SS-A, SS-B, and IgG and IgM rheumatoid factor (RF) autoantibodies Patient Global Impression of Change (PGIC) at 169 days Change from baseline in physician's global impression of severity Change from baseline in levels of inflammatory markers (immunoglobulins, beta2 microglobulin, C-reactive protein [CRP], CXCL13, C3, C4, and serum free light chains) The proportion of subjects who achieved a composite response, defined as either improvement in ESSDAI-3 or improvement in ESSPRI-1 plus no worsening in Physician's Global Impression of Disease from baseline, at Days 85, 169, and 309 Changes from baseline in SF36 physical and mental scores ● Visual Analog Scale (VAS) for dry mouth ●VAS xerophthalmia Patient-Reported Outcomes Measurement Information System (PROMIS-29 Profile v2.1) Biomarkers such as blood flow, cytometry for changes in T and B cell subsets, and salivary proteins Blood gene expression ● Changes in fecal microbiota (optional) ●Baseline and post-treatment DNA epigenetics (optional) Actigraphy: Changes in overall activity and sleep patterns during the study (optional) Change from baseline in the Clinical EULAR Sjögren's Syndrome Disease Activity Index (ClinESSDAI) at days 85, 169, and 309 ● The proportion of subjects who achieved ClinESSDAI and ClinESSDAI response, defined as at least a 3[4] point reduction from baseline on the ClinESSDAI at Days 85, 169, and 309, without prematurely discontinuing the study or receiving rescue therapy. This is in order to: 1. To evaluate the clinical efficacy of multiple doses of VIB4920 in treating glandular and extraglandular symptoms in patients with SS with moderate to severe systemic disease activity 2. Evaluate the effects of VIB4920 on systemic activity and patient-reported outcomes in subjects with SS 3. Evaluate the safety and tolerability of multiple doses of VIB4920 in subjects with SS 4. Characterize the pharmacokinetics (PK) of VIB4920 in subjects with SS 5. Evaluate the immunogenicity of VIB4920 in subjects with SS 6. Evaluate the pharmacodynamics of VIB4920 on the CD40 / CD40L pathway and disease biomarkers in subjects with SS 7. Evaluate changes in T and B cell populations, as well as biomarkers of inflammation and autoantibodies in subjects with SS upon treatment with VIB4920 8. Evaluate the effect of VIB4920 on systemic disease activity and salivary and lacrimal gland function in subjects with SS 9. Assess changes in major subjective complaints related to SS

[0202] Following treatment, subjects in Population #2 were evaluated to determine one or more of the following: Change from baseline in ESSPRI at days 85, 169, and 309 The proportion of subjects who achieved an ESSPRI response, defined as a ≥1-point or 15% decrease from baseline in ESSPRI score at Days 85, 169, and 309, without prematurely discontinuing the study or receiving rescue therapy. Change from baseline in FACIT-Fatigue at days 85, 169, and 309 Change from baseline in OSDI at days 85, 169, and 309 ●PGIS on days 85, 169, and 309 - The safety and tolerability of multiple IV doses of VIB4920 as measured by the incidence of TEAEs, TESAEs, AESIs, and laboratory, vital sign, and ECG abnormalities PK under study Percentage of subjects with a positive immunogenic response as measured by anti-VIB4920 antibodies by study completion Change from baseline in ESSDAI Change from baseline in total stimulated salivary flow rate Change from baseline in Schirmer test Changes from baseline in SS-A, SS-B, and IgG and IgM RF autoantibodies ● PGIC on the 169th day Change from baseline in physician's global impression of severity Change from baseline in levels of inflammatory markers (immunoglobulins, beta2 microglobulin, CRP, CXCL13, C3, C4 and serum free light chains) The proportion of subjects who achieved a composite response, defined as either improvement in ESSDAI-3 or improvement in ESSPRI-1 plus no worsening in Physician's Global Impression of Disease from baseline, at Days 85, 169, and 309 Changes from baseline in SF36 physical and mental scores ●VAS xerostomia ●VAS xerophthalmia PROMIS-29 Profile v2.1 Biomarkers such as blood flow, cytometry for changes in T and B cell subsets, and salivary proteins Blood gene expression ● Changes in fecal microbiota (optional) ●Baseline and post-treatment DNA epigenetics (optional) Actigraphy: Changes in overall activity and sleep patterns during the study (optional) Change from baseline in ClinESSDAI at days 85, 169, and 309 This is in order to: 1. Evaluate the clinical effects of multiple doses of VIB4920 on the major subjective complaints of SS (dryness, fatigue, and pain) 2. Evaluate the effects of VIB4920 on patient-reported outcomes in subjects with SS 3. Evaluate the safety and tolerability of multiple doses of VIB4920 in subjects with SS 4. Characterize the PK of VIB4920 in subjects with SS 5. Evaluate the immunogenicity of VIB4920 in subjects with SS 6. Evaluate the pharmacodynamics of VIB4920 on the CD40 / CD40L pathway and disease biomarkers in subjects with SS 7. Evaluate changes in T and B cell populations, as well as biomarkers of inflammation and autoantibodies in subjects with SS upon treatment with VIB4920 8. Evaluate the effect of VIB4920 on systemic disease activity and salivary and lacrimal gland function in subjects with SS 9. Assess changes in major subjective complaints related to SS

[0203] Clinical Laboratory After treatment, blood and urine samples were collected for laboratory safety testing. Hematology panel included complete blood count with differential (including basophils, eosinophils, lymphocytes, monocytes, and neutrophils), hemoglobin, hematocrit, platelets, and white blood cell count.

[0204] Serum chemistries were analyzed for: Creatinine, blood urea nitrogen, fasting blood glucose, total protein, creatine kinase and electrolytes (including sodium, potassium, chloride, calcium, bicarbonate and phosphorus) Liver profile: Albumin, TBL, indirect bilirubin, AST, ALT, alkaline phosphatase (ALP), and gamma-glutamyltransferase

[0205] Coagulation parameters were assessed. Subjects were assessed for prothrombin time and PTT at screening and at all study visits during and off-treatment periods (Tables 2 and 3, respectively).

[0206] Urinalysis included protein, glucose, blood, ketones, white blood cells, and pH by dipstick analysis. If abnormalities were observed, microscopic examination (crystals, casts, white blood cells, red blood cells) was performed.

[0207] Tests for SARS-COV-2 were conducted.

[0208] Vital signs were measured, including systolic and diastolic blood pressure (mmHg), pulse rate (beats / min), respiratory rate (breaths / min), temperature (°C), and weight (kg).

[0209] Twelve-lead ECGs were performed during screening, treatment, and off-treatment periods. Each ECG included ventricular rates and intervals (PR, QRS, QT, QTc).

[0210] Serum β-hCG pregnancy testing was completed for all women of childbearing potential during the screening period (before day 0), along with urine pregnancy tests at visits during the treatment and off-treatment periods.

[0211] Safety assessment Adverse Events (AEs) and Serious Adverse Events (SAEs)

[0212] The schedules of study assessments during the active treatment and off-treatment periods are shown in Tables 5 and 6, respectively. Table 6 also summarizes all assessments that could be performed during unscheduled visits during the study.

[0213] [Table 5-1]

[0214] [Table 5-2]

[0215] [Table 5-3]

[0216] [Table 5-4]

[0217] [Table 6-1]

[0218] [Table 6-2]

[0219] Results for subjects with moderate to high systemic disease activity (ESSDAI definition), "Population 1" The results of the change from baseline in ESSDAI at day 169 and the responder analysis are shown in Tables 7 and 8, respectively. The data in Table 7 show that at week 24, subjects treated with dazodaribep achieved a 6.3±0.6 point reduction in ESSDAI score and subjects treated with placebo achieved a 4.1±0.6 point reduction, resulting in a statistically significant least squares mean difference of 2.2 points (p=0.017). Dazodaribep achieved a statistically significant primary endpoint in subjects with ESSDAI-defined moderate-to-high systemic disease activity, signifying a significant achievement in the development of a treatment for Sjogren's syndrome, a disease with no FDA-approved treatment.

[0220] [Table 7]

[0221] In addition to the primary endpoint analyses described above, key secondary, exploratory, and post-hoc analyses also showed numerical improvements. These included measures of dryness, an important symptom for subjects with Sjögren's syndrome because it affects chewing, swallowing, and dentition. Fatigue, as measured by the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), and physical function, as measured using the 36-Item Short Form Health Survey (SF-36), showed numerical improvements, as did the number of tender and swollen joints. Furthermore, a post-hoc responder analysis of subjects who achieved a high level of improvement on the ESSDAI favored dazodarivep over placebo. Furthermore, dazodarivep was well tolerated in the trial.

[0222] Additionally, numerically greater improvements were observed in the dazodarivep group compared to the placebo group by the EULAR Sjogren's Syndrome Patient-Reported Index score, Functional Assessment of Chronic Disease Therapy-Fatigue score, 36-Item Short Form Health Survey Physical Component Score (physical aspect score), and stimulated salivary flow rate. Additionally, post-hoc responder analyses of subjects who achieved high levels (5 and 6 points) of improvement on the ESSDAI favored dazodarivep over placebo.

[0223] [Table 8]

[0224] Example 2 - A Prospective Phase III Study to Evaluate the Efficacy and Safety of VIB4920 in Subjects with Sjogren's Syndrome (SS) A study will be conducted to evaluate the efficacy and safety of VIB4920 in subjects with Sjogren's syndrome (SS). The study will evaluate the effect of VIB4920 versus placebo on systemic symptoms in SS patients with moderate to high systemic disease activity, using two different dosing regimens.

[0225] research design Two populations of Sjogren's disease patients will be enrolled in this study. Population #1 includes SS patients with moderate to high systemic activity, defined by an ESSDAI ≥ 5. The following domains will be scored, but they may not contribute to the minimum ESSDAI score of 5 required for enrollment: peripheral nervous system, central nervous system, and lung. Population #2 includes SS patients with exocrine insufficiency and subjective symptoms, defined by an ESSPRI score ≥ 5, considered as the cutoff point for "inadequate symptom status," but with low systemic disease activity (ESSDAI score < 5).

[0226] A complete physical examination will be performed including weight, height, and a 28-joint evaluation.

[0227] Dosage schedule Subjects will be split into three doses: Dose 1, 1500 mg of VIB4920 administered every 2 weeks for three doses, then every 4 weeks thereafter; Dose 2, 3000 mg of VIB4920 administered at weeks 1, 4, and 12, then every 12 weeks thereafter; and placebo. The expected total duration of each subject's participation in this study is 392±7 days. An exemplary dosing schedule is shown in Table 9.

[0228] [Table 9]

[0229] Incorporation by Reference All references, articles, publications, patents, patent publications, and patent applications cited herein are incorporated herein by reference in their entirety for all purposes. However, the mention of any reference, article, publication, patent, patent publication, or patent application cited herein is not, and should not be considered as, an admission or any suggestion that they constitute valid prior art or form part of the common general knowledge in any country in the world.

Claims

1. 1. A pharmaceutical composition for treating Sjogren's syndrome (SS), comprising a Tn3 scaffold comprising two CD40L-specific monomer subunits and human serum albumin, The monomer subunit contains seven beta strands designated A, B, C, D, E, F, and G, and six loop regions designated AB, BC, CD, DE, EF, and FG; the AB loop comprises SEQ ID NO:11, the BC loop comprises SEQ ID NO:12, the CD loop comprises SEQ ID NO:13, the DE loop comprises SEQ ID NO:14, the EF loop comprises SEQ ID NO:15, and the FG loop comprises SEQ ID NO:16; the Tn3 scaffold is administered every four weeks at a dose of about 1500 mg; The above pharmaceutical composition.

2. 2. The pharmaceutical composition of claim 1, wherein the Tn3 scaffold is administered to a subject with a European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index (ESSDAI) score of ≧5.

3. The Tn3 scaffold is as follows: (a) ESSDAI score <5, and (b) EULAR Sjögren's Syndrome Patient-Reported Index (ESSPRI) score ≥ 5; The pharmaceutical composition of claim 1 , wherein the composition is administered to a subject having

4. 4. The pharmaceutical composition of claim 3, wherein the subject has a total stimulated saliva flow rate > 0.1 mL / min.

5. 10. The pharmaceutical composition of claim 1, wherein the Tn3 scaffold is administered at a loading dose of 1500 mg at least three times about every two weeks.

6. 10. The pharmaceutical composition of claim 1, wherein the Tn3 scaffold is administered at a loading dose of 1500 mg approximately two weeks after the initial administration.

7. 2. The pharmaceutical composition of claim 1, wherein beta chain A comprises SEQ ID NO: 5, beta chain B comprises SEQ ID NO: 6, beta chain C comprises SEQ ID NO: 17, beta chain D comprises SEQ ID NO: 18, beta chain E comprises SEQ ID NO: 19, beta chain F comprises SEQ ID NO: 20, and beta chain G comprises SEQ ID NO:

21.

8. 2. The pharmaceutical composition of claim 1, wherein the Tn3 scaffold comprises two CD40L-specific monomer subunits connected in series.

9. 9. The pharmaceutical composition of claim 8, wherein the two CD40L-specific monomer subunits each comprise SEQ ID NO:

3.

10. The pharmaceutical composition of claim 8, wherein the two CD40L-specific monomer subunits are connected by a linker.

11. The pharmaceutical composition of claim 8, wherein at least one CD40L-specific monomer subunit is fused or conjugated to polyethylene glycol (PEG) via a linker selected from the group consisting of SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, and SEQ ID NO:

10.

12. 9. The pharmaceutical composition of claim 8, wherein at least one CD40L-specific monomeric subunit is fused or conjugated to albumin.

13. 9. The pharmaceutical composition of claim 8, wherein the albumin is human serum albumin (HSA).

14. 14. The pharmaceutical composition of claim 13, wherein the HSA is a variant HSA comprising SEQ ID NO:

4.

15. 2. The pharmaceutical composition of claim 1, wherein the Tn3 scaffold comprises SEQ ID NO:

1.

16. 1. A pharmaceutical composition for treating Sjogren's syndrome (SS), comprising a Tn3 scaffold comprising SEQ ID NO:1, The pharmaceutical composition, wherein the Tn3 scaffold is administered at a dose of about 1500 mg every four weeks.

17. 17. The pharmaceutical composition of claim 16, wherein the Tn3 scaffold is administered at a loading dose about once every two weeks for at least three doses prior to administration every four weeks at a dose of about 1500 mg.

18. 17. The pharmaceutical composition of claim 16, wherein the Tn3 scaffold is administered at a loading dose of 1500 mg approximately two weeks after the initial administration.

19. 1. A pharmaceutical composition for treating Sjogren's syndrome (SS), comprising a Tn3 scaffold comprising SEQ ID NO:1, the Tn3 scaffold is administered at a dose of 1500 mg every 4 weeks; The Tn3 scaffold is administered at a loading dose of 1500 mg two weeks after the first administration. The above pharmaceutical composition.

20. 1. A pharmaceutical composition for treating Sjogren's syndrome (SS), comprising a Tn3 scaffold comprising two CD40L-specific monomer subunits and human serum albumin, The monomer subunit contains seven beta strands designated A, B, C, D, E, F, and G, and six loop regions designated AB, BC, CD, DE, EF, and FG; the AB loop comprises SEQ ID NO:11, the BC loop comprises SEQ ID NO:12, the CD loop comprises SEQ ID NO:13, the DE loop comprises SEQ ID NO:14, the EF loop comprises SEQ ID NO:15, and the FG loop comprises SEQ ID NO:16; the Tn3 scaffold is administered at a dose of about 3000 mg every 12 weeks; The above pharmaceutical composition.

21. 21. The pharmaceutical composition of claim 20, wherein the Tn3 scaffold is administered to a subject with a European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index (ESSDAI) score of ≧5.

22. The target is as follows: (a) ESSDAI score <5, and (b) EULAR Sjögren's Syndrome Patient-Reported Index (ESSPRI) score ≥ 5; 22. The pharmaceutical composition of claim 21, having the formula:

23. 23. The pharmaceutical composition of claim 22, wherein the subject has a total stimulated saliva flow rate > 0.1 mL / min.

24. 21. The pharmaceutical composition of claim 20, wherein the Tn3 scaffold is administered at an initial dose of 3000 mg, followed by a second dose of 3000 mg four weeks later, and a third dose of 3000 mg approximately eight weeks after the second dose, prior to administration every 12 weeks at a dose of about 3000 mg.

25. 21. The pharmaceutical composition of claim 20, wherein the Tn3 scaffold is administered at a loading dose of 3000 mg about 4 weeks after the initial administration.

26. 21. The pharmaceutical composition of claim 20, wherein beta chain A comprises SEQ ID NO: 5, beta chain B comprises SEQ ID NO: 6, beta chain C comprises SEQ ID NO: 17, beta chain D comprises SEQ ID NO: 18, beta chain E comprises SEQ ID NO: 19, beta chain F comprises SEQ ID NO: 20, and beta chain G comprises SEQ ID NO:

21.

27. 21. The pharmaceutical composition of claim 20, wherein the Tn3 scaffold comprises two CD40L-specific monomer subunits connected in series.

28. 28. The pharmaceutical composition of claim 27, wherein the two CD40L-specific monomer subunits each comprise SEQ ID NO:

3.

29. 28. The pharmaceutical composition of claim 27, wherein the two CD40L-specific monomer subunits are connected by a linker.

30. 28. The pharmaceutical composition of claim 27, wherein at least one CD40L-specific monomer subunit is fused or conjugated to polyethylene glycol (PEG) via a linker selected from the group consisting of SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, and SEQ ID NO:

10.

31. 28. The pharmaceutical composition of claim 27, wherein at least one CD40L-specific monomeric subunit is fused or conjugated to albumin.

32. 32. The pharmaceutical composition of claim 31, wherein the albumin is human serum albumin (HSA).

33. 33. The pharmaceutical composition of claim 32, wherein the HSA is a variant HSA comprising SEQ ID NO:

4.

34. 21. The pharmaceutical composition of claim 20, wherein the Tn3 scaffold comprises SEQ ID NO:

1.

35. 1. A pharmaceutical composition for treating Sjogren's syndrome (SS), comprising a Tn3 scaffold comprising SEQ ID NO:1, the Tn3 scaffold is administered at a dose of about 3000 mg every 12 weeks; The above pharmaceutical composition.

36. 36. The pharmaceutical composition of claim 35, wherein the Tn3 scaffold is administered in a first dose, followed by a second dose four weeks later, and a third dose about eight weeks after the second dose, prior to administration every 12 weeks at a dose of about 3000 mg.

37. 36. The pharmaceutical composition of claim 35, wherein the Tn3 scaffold is administered at a loading dose of 3000 mg about 4 weeks after the initial administration.

38. 1. A pharmaceutical composition for treating Sjogren's syndrome (SS), comprising a Tn3 scaffold comprising SEQ ID NO:1, the Tn3 scaffold is administered at a dose of about 3000 mg every 12 weeks; The Tn3 scaffold is administered at a loading dose of 3000 mg approximately 4 weeks after the first administration. The above pharmaceutical composition.

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