CD40L-specific Tn3-derived scaffold for the treatment and prevention of Sjögren's syndrome

Abstract

A composition and method comprising a CD40L-specific Tn3 scaffold are provided. Methods for the prevention and treatment of Sjögren's syndrome utilizing the same are also provided. Sjögren's syndrome (SS) is a systemic autoimmune disease characterized by chronic lymphocytic inflammation of the exocrine glands, primarily the salivary and lacrimal glands, which leads to loss of function and manifests as excessive dryness. The subjective aspects of SS, including the perception of dryness, musculoskeletal pain, and fatigue, are often described as debilitating and have been shown to have a significant negative impact on quality of life (QoL).

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. applications No. 63 / 492,715 filed on 28 March 2023, No. 63 / 504,003 filed on 24 May 2023, No. 63 / 584,134 filed on 20 September 2023, and No. 63 / 624,959 filed on 25 January 2024, each of which is incorporated herein by reference in its entirety for any purpose.

[0002] Reference to electronic sequence listings The contents of the electronic sequence listing (HOPA_067_04WO_SeqList_ST26.xml; size: 23,046 bytes; and creation date: February 16, 2024) are incorporated herein by reference in their entirety.

[0003] This disclosure relates to compositions comprising a Tn3 scaffold and to methods of using the same in the treatment and prevention of Sjögren'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, which leads to loss of function and manifests as excessive dryness. The subjective aspects of SS, including the perception of dryness, musculoskeletal pain, and fatigue, are often described as debilitating and have been shown to have a significant negative impact on quality of life (QoL). Dryness and fatigue are major contributing factors to the decline in QoL. QoL is also affected by psychological and emotional challenges and social impairments associated with reliance on family members for daily life and difficulties in work and other tasks.

[0005] Currently, there are no approved immunomodulatory agents or evidence-based treatment guidelines available for the treatment of extraglandular symptoms of Sjögren's syndrome (SS). Therefore, new treatments for Sjögren's syndrome are needed. [Brief explanation of the drawing]

[0006] [Figure 1] An exemplary study flowchart is shown. Δ=delta; D=day; Dazo=dazodalibep; EoS=end of study; EP=endpoint; DASPRI=Sjögren's Syndrome Patient Report Index Assessment Log; ESSDAI=EULAR Sjögren's Syndrome Disease Activity Index; EULAR=European Alliance of Associations for Rheumatology; n=number of subjects in the treatment group; PBO=placebo; q4wk=once every 4 weeks; q12wk=once every 12 weeks; wk=week. Note: Day 1 randomization was stratified by geographical location (North America and Europe, Japan, and other regions), coexistence of RA or SLE (present, absent), and screening of ESSDAI score (<10, ≥10). [Figure 2] An exemplary study flowchart is shown. D = Day; Dazo = Dazodalibep; EP = Endpoint; ESSPRI = EULAR Sjögren's Syndrome Patient Report Index; EULAR = European Alliance of Associations for Rheumatology; n = Number of subjects in the treatment group; PBO = Placebo; q4wk = Once every 4 weeks; q12wk = Once every 12 weeks; wk = Week. Randomization on day 1 was stratified based on geographical location (North America and Europe, Japan, and other regions) and screening of the ESSPRI score (<7.5, ≥7.5). [Figure 3] An exemplary study flowchart is shown. DAZ = dazodalibep, ESSDAI = EULAR Sjögren's Syndrome Disease Activity Index; EULAR = European League Against Rheumatism. Arrows indicate the days of administration of dazodalibep or placebo. [Figure 4]Exemplary changes from baseline in the ESSDAI total score are shown. The change from baseline in the ESSDAI total score is plotted as a function of time (days). The dosing schedules for dazodalibep and placebo are shown in Figure 3. Analysis was performed using mixed model repeated measures (MMRM). *p<0.1; DAZ=dazodalibep; ESSDAI=EULAR Sjögren's Syndrome Disease Activity Index; LS=least squares; MCID=minimally important difference; SE=standard error. [Figure 5] Exemplary changes from baseline in the ESSPRI total score are shown. Changes from baseline in the ESSPRI total score are plotted as a function of time (days). The dosing schedules for dazodalibep and placebo are shown in Figure 3. Analysis was performed using mixed model repeated measures (MMRM). DAZ = dazodalibep; ESSDAI = EULAR Sjögren's Syndrome Disease Activity Index; LS = least squares; MCID = clinically important minimum difference; SE = standard error. [Figure 6A] Typical changes from baseline in the FACIT fatigue score (Figure 6A), OSDI (Figure 6B), and PGIS (Figure 6C) are shown. Changes from baseline are plotted as a function of time (days). The administration schedules for dazodalibep and placebo are shown in Figure 3. [Figure 6B] Same as above. [Figure 6C] Same as above. [Figure 7A-B]Figure 3 shows the time-course changes in baseline blood biomarkers of B cell and T cell co-stimulation as a function of dazodalibep or placebo administration (from baseline to day 365): CXCL13 (Figure 7A), rheumatoid factor (RF, Figure 7B); Ki67+ post-switch memory B cells (Figure 7C), phenotypic cells (Figure 7D); CD11cbr+ B cells (Figure 7E); Ki67+ T cells (Figure 7F); TFH cells (Figure 7G). The administration schedules for dazodalibep and placebo are shown in Figure 3. Data are presented as median multiplier change from baseline (FC) ± IQR. Black symbols represent the placebo group (subjects who received placebo in stage I and dazodalibep in stage II). Pink symbols represent the dazodalibep group (subjects who received dazodalibep in stage I and placebo in stage II). The statistical significance of the difference in FC from baseline between treatment groups was assessed using the Mann-Whitney U test. Subjects were included in the RF analysis only if they were positive at baseline. *p<0.05;**p<0.01;**p<0.001;DAZ=Dazodarivep;FC=Factor-Factor-Factor;IQR=Interquartile Range, PBO=Placebo, RF=Rheumatoid Factor. [Figure 7C-D] Same as above. [Figure 7E-F] Same as above. [Figure 7G] Same as above. [Figure 8] Figures 7A-7G show exemplary biomarker heatmaps illustrating the median cumulative change (FC) from baseline up to day 365, using the biomarkers and ESSDAI total score. DAZ = dazodarivep, ESSDAI = EULAR Sjögren's Syndrome Disease Activity Index; PBO = placebo. [Figure 9] An exemplary study flowchart is shown. DAZ = dazodalibep, ESSPRI = EULAR Sjögren's Syndrome Patient Reporting Index; EULAR = European League Against Rheumatism. Arrows indicate the days of administration of dazodalibep or placebo. [Figure 10]The following shows an exemplary change from baseline in the ESSPRI total score. The change from baseline in the ESSPRI total score is plotted as a function of time (days). The administration schedules for dazodalibep and placebo are shown in Figure 9. Analysis was performed using the mixed model repeated measures (MMRM). DAZ = dazodalibep; ESSDAI = EULAR Sjögren's Syndrome Disease Activity Index; LS = least squares; MCID = clinically important minimum difference; SE = standard error. [Figure 11A] Exemplary changes from baseline in dryness (Figure 11A), fatigue (Figure 11B), and pain (Figure 11C) are shown. Changes from baseline are plotted as a function of time (days). The dosing schedules for dazodalibep and placebo are shown in Figure 9. Data are plotted for each trial visit and analyzed using MMRM. **p<0.01; BSL=baseline; DAZ=dazodalibep; LS=least squares; PBO=placebo; SE=standard error. [Figure 11B] Same as above. [Figure 11C] Same as above. [Figure 12] This shows the exemplary proportion of subjects who achieved an ESSPRI response by day 169 in the dazodarivep treatment group and the placebo group. The ESSPRI response rate is plotted as a function of days. An ESSPRI response is defined as an ESSPRI score of ≥1 point or a 15% decrease from baseline, provided that the study was not discontinued early and no salvage therapy was received. Data were analyzed using a logistic regression model. ***p<0.001. CI = confidence interval. DAZ = dazodarivep. ESSPRI = EULAR Sjoegren's Syndrome Patient Reported Index. EULAR = European Alliance of Associations for Rheumatology. [Figure 13A] Typical changes from baseline in the FACIT fatigue score (Figure 13A), OSDI (Figure 13B), and PGIS (Figure 13C) are shown. Changes from baseline are plotted as a function of time (days). The administration schedules for dazodalibep and placebo are shown in Figure 9. [Figure 13B] Same as above. [Figure 13C] Same as above. [Overview of the project] [Means for solving the problem]

[0007] A method for treating Sjögren's syndrome (SS) in subjects requiring treatment for SS is provided herein, comprising administering a Tn3 scaffold, wherein the Tn3 scaffold comprises a CD40L-specific monomer subunit, the CD40L-specific monomer subunit comprising seven β-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, the Tn3 scaffold is administered once every four weeks at a dose of approximately 1500 mg, the subjects having a moderate to severe symptomatic state as defined by an ESSPRI score ≥ 5 and low systemic disease activity as defined by an ESSDAI score < 5, and the subjects experience a decrease in the Sjögren's Syndrome Patient Reported Index Assessment Diary (DASPRI) score after administration. In one embodiment, at least three loading doses of 1500 mg each were administered before a single dose every four weeks. In another embodiment, at least three loading doses were administered in weeks 0, 2, and 4.

[0008] A method for treating Sjögren's syndrome (SS) in a subject who needs treatment for SS, the method comprising administering a Tn3 scaffold, where the Tn3 scaffold comprises a CD40L-specific monomeric subunit, and the CD40L-specific monomeric subunit comprises seven β-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, the FG loop comprises SEQ ID NO: 16, the Tn3 scaffold is administered at a dose of about 3000 mg once every 12 weeks, the subject has moderate to severe symptom status defined by an ESSPRI score ≧5 and low systemic disease activity defined by an ESSDAI score <5, and the Sjögren's Syndrome Patient Reported Index Assessment Diary (DASPRI) score in the subject decreases after administration. In an aspect, at least three loading doses of 3000 mg each are administered to the subject prior to each administration once every 12 weeks. In an aspect, at least three loading doses are administered at week 0, week 4, and week 12.

[0009] In an aspect, the salivary gland function of the subject is improved by about 3 weeks, 1 month, 2 months, or 4 months after administration of the Tn3 scaffold. In an aspect, the salivary gland function is determined by the total stimulated saliva flow rate. In an aspect, the ESSPRI score decreases after administration. In an aspect, the ESSPRI score decreases by at least about 1.5, 2, 3, 4, or 5 points. In an aspect, the DASPRI score decreases by 2 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months after administration. In an aspect, the DASPRI score decreases by at least about 5, 10, 15, or 20 points. In an aspect, administration of the Tn3 scaffold is effective in reducing the baseline score of tender and swollen joints in the subject after administration.

[0010] In an embodiment, administration of the Tn3 scaffold is effective to decrease the baseline score of the Short Form 36 (SF-36) health survey of the subject after administration. In an embodiment, administration of the Tn3 scaffold is effective to improve the baseline score of the subject, where the baseline score is selected from the group consisting of the Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-fatigue), PROMIS Fatigue Short Form 10a, Ocular Surface Disease Index (OSDI), EQ-5D-5L, and Patient's Global Impression of Severity (PGIS). In an embodiment, administration of the Tn3 scaffold is effective to decrease the baseline level of an inflammatory marker after administration, where the marker is selected from the group consisting of immunoglobulins, β-2 microglobulin, C-reactive protein, and combinations thereof. In an embodiment, administration of the Tn3 scaffold is effective to decrease the baseline level of a biomarker, where the biomarker is selected from the group consisting of plasma soluble CD40L, Ki67+CD27+ memory B cells, CD19, CD20, CD27, CD38, CD138, CD11c high-expressing / high (bright / high) B cells, CD3, CD4, CD8, follicular helper T (Tfh) cells, serum CXCL13, rheumatoid factor, anti-SSA autoantibody, anti-Ro autoantibody, anti-SSB autoantibody, anti-La autoantibody, and combinations thereof. In an embodiment, administration of the Tn3 scaffold is effective to decrease the baseline level of a disease symptom, where the disease symptom is selected from the group consisting of fatigue, dry mouth, dry eyes, vaginal dryness, pain, and combinations thereof. In an embodiment, the expression level of a gene associated with SS, or the level of a protein encoded by the gene, in the blood sample of the subject decreases by 48 weeks after administration. In an embodiment, the level of B cells selected from the group consisting of CD27+ memory B cells, marginal zone B cells, plasmablasts, plasma cells, and combinations thereof decreases in the blood sample of the subject by 48 weeks after administration. In an embodiment, the subject is positive for anti-Ro autoantibody, rheumatoid factor (RF), or both anti-Ro autoantibody and RF. In an embodiment, the Tn3 scaffold is administered intravenously.

[0011] In the methods disclosed herein, the Tn3 scaffold comprises two CD40L-specific monomer subunits linked in tandem. In one embodiment, each of the two CD40L-specific monomer subunits comprises SEQ ID NO: 3. In one embodiment, the CD40L-specific monomer subunits are linked by a linker. In one embodiment, at least one CD40L-specific monomer subunit is directly fused to or conjugated to polyethylene glycol (PEG). In one embodiment, at least one CD40L-specific monomer subunit is fused to or conjugated to polyethylene glycol (PEG) via a linker. In one embodiment, the linker comprises a peptide linker. In one embodiment, the linker comprises SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, or SEQ ID NO: 10. In one embodiment, at least one CD40L-specific monomer subunit is fused to or conjugated to albumin. In one embodiment, albumin is human serum albumin (HSA). In one embodiment, the HSA is a variant HSA containing sequence number 4. In another embodiment, the Tn3 scaffold contains sequence number 1.

[0012] In some embodiments, the subject matter of this disclosure has coexisting autoimmune indicators. In some embodiments, the coexisting autoimmune indicators are rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), or both RA and SLE. In some embodiments, the coexisting autoimmune indicator is rheumatoid arthritis. In some embodiments, the coexisting autoimmune indicator is systemic lupus erythematosus. [Modes for carrying out the invention]

[0013] Simple explanation definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which the subject matter pertains. All publications, patent applications, patents, and other references referred to herein are expressly incorporated by reference in their entirety. In case of any conflict, this specification, including its definitions, shall prevail. Furthermore, the materials, methods, and examples described herein are illustrative and not intended to be limiting.

[0014] As used herein and in the appended claims, the singular forms "a," "an," and "the" refer to multiple subjects unless the context explicitly indicates otherwise.

[0015] The terms “about” or “approximately” when preceding a number mean a range (e.g., plus or minus 10% of that value). For example, “about 50” can mean 45 to 55 unless the context of this disclosure specifically indicates otherwise or is inconsistent with such interpretation, and “about 25,000” can mean 22,500 to 27,500. For example, in a list of numbers such as “about 49, about 50, about 55,…”, “about 50” means a range extending to less than half the interval between the preceding and succeeding values, e.g., greater than 49.5 to less than 52.5. Furthermore, the phrases “about less than” or “about greater than” should be understood in consideration of the definition of the term “about” provided herein. Similarly, the term “about” when preceding a series of numbers or a range of values ​​(e.g., “about 10, 20, 30” or “about 10 to 30”) refers to all the values ​​in that series or to the two endpoints of the range, respectively.

[0016] As used herein, the term “subject” refers to any subject, e.g., human or non-human mammal, for which diagnosis, prognosis, or therapy is desired. The term “subject” may also mean a human or non-human mammal that is, may be, or suspected of being affected by a disease. In some embodiments, the subject is a mammal. Mammals include primates such as humans, monkeys, chimpanzees, and apes, as well as non-primates such as livestock.

[0017] When used herein, the term “subjects in need of it” includes subjects who may or would benefit from the methods described herein. Subjects in need of treatment include, without limitation, subjects who already have a condition or disorder, subjects prone to developing a condition or disorder, subjects suspected of having a condition or disorder, and subjects whose condition or disorder should be prevented, improved, or cured.

[0018] As used herein, “fused” means that at least two polypeptides are recombinantly linked together. As used herein, “conjugated” means that a bond is formed between two components by a chemical reaction. Typically, two components that are conjugated to each other are chemically linked by a covalent bond.

[0019] As used herein, “to treat” or “to cure” means the management and care of an object aimed at combating a disease, condition, or disorder, and includes the reduction of symptoms or complications of a disease, condition, or disorder, or the elimination of a disease, condition, or disorder, by administration of a Tn3 scaffold used in the manner described herein. Thus, the term “to treat” or “to cure” means treatment, and refers to treatment aimed at slowing (reducing) or improving the progression of a disease (e.g., an autoimmune disease or disorder). Beneficial or desired clinical outcomes include, but are not limited to, symptom reduction, reduction in the severity of the disease, stabilization of the disease state (i.e., not worsening), delay or slowing of disease progression, improvement or mitigation of the disease state, and improvement of the disease (whether partial or complete).

[0020] As used herein, “effective amount” is the amount of Tn3 scaffold used in the method herein that reduces or eliminates one or more symptoms of a disease, condition, or disorder.

[0021] When referring to nucleic acid sequences or protein sequences, the term “identity” is used to mean the similarity between two sequences. Unless otherwise specified, the percent identity described herein is determined using the BLAST algorithm, available at the worldwide web address:blast.ncbi.nlm.nih.gov / Blast.cgi, with default parameters.

[0022] Tn3 scaffolding This specification provides compositions that bind to CD40L. In some embodiments, the provided compositions include a CD40L antagonist. In some embodiments, this specification provides compositions including a Tn3 scaffold protein (e.g., "Tn3 scaffold") containing a CD40L-specific monomer subunit. In some embodiments, this specification provides compositions including a Tn3 scaffold containing two CD40L-specific monomer subunits. In some embodiments, the CD40L-specific monomer subunit is also known as a CD40L-specific Tn3 monomer. As used herein, the term "Tn3 scaffold" refers to a molecule containing at least one FnIII scaffold, where the Aβ strand includes SEQ ID NOs. 5, 23, or 24, the Bβ strand includes SEQ ID NOs. 6, the Cβ strand includes SEQ ID NOs. 17, the Dβ strand includes SEQ ID NOs. 18, the Eβ strand includes SEQ ID NOs. 19, the Fβ strand includes SEQ ID NOs. 20, and the β strand G includes SEQ ID NOs. 21.

[0023] In some embodiments, the provided composition may comprise any of the Tn3 scaffolds having the amino acid sequences described in PCT / US2012 / 059477 and PCT / US2019 / 052997 (which are incorporated herein by reference in their entirety). In some embodiments, the provided composition may comprise a Tn3 scaffold having the amino acid sequence shown in Sequence ID No. 1 (referred herein to as dazodalibep). Dazodalibep may also be referred to as VIB4920, MEDI4920, or HZN-4920.

[0024] In one embodiment, the CD40L monomer subunit of the Tn3 scaffold comprises seven β-strands designated A, B, C, D, E, F, and G, and six loop regions designated AB, BC, CD, DE, EF, and FG. In another embodiment, the Tn3 scaffold comprises a single CD40L-specific monomer subunit. In another embodiment, the Tn3 scaffold comprises two CD40L-specific monomer subunits. In another embodiment, the two CD40L-specific monomer subunits are linked in tandem. In another embodiment, the two CD40L-specific monomer subunits are linked by a linker. In another embodiment, the linker comprises a peptide linker, which may be a mobile peptide linker. In one embodiment, the peptide linker comprises a (GmX)n sequence (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).

[0025] In one embodiment, the Tn3 scaffold comprises a linker containing a functional group moiety. In another embodiment, this functional group moiety is an immunoglobulin or a fragment thereof. In another embodiment, this immunoglobulin or fragment thereof contains an Fc domain. In another embodiment, this Fc domain is unable to induce at least one FcγR-mediated effector function (e.g., Fc deficiency). In another embodiment, this at least one FcγR-mediated effector function is antibody-dependent cell-mediated cytotoxicity (ADCC).

[0026] In one embodiment, the Tn3 scaffold comprises a CD40L-specific monomer subunit including seven β 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 includes or consists of SEQ ID NO: 11, the BC loop includes or consists of SEQ ID NO: 12, the CD loop includes or consists of SEQ ID NO: 13, the DE loop includes or consists of SEQ ID NO: 14, the EF loop includes or consists of SEQ ID NO: 15, and the FG loop includes or consists of SEQ ID NO: 16. In another embodiment, the Tn3 scaffold includes or consists of SEQ ID NO: 1 (also known as VIB4920). In this embodiment, β-strand A includes or consists of SEQ ID NO: 5, β-strand B includes or consists of SEQ ID NO: 6, β-strand C includes or consists of SEQ ID NO: 17, β-strand D includes or consists of SEQ ID NO: 18, β-strand E includes or consists of SEQ ID NO: 19, β-strand F includes or consists of SEQ ID NO: 20, and β-strand G includes or consists of SEQ ID NO: 21.

[0027] In one embodiment, one or more CD40L-specific Tn3 monomers include or have a β-strand A consisting of IEV (SEQ ID NO: 5), RLDAPSQIEV (SEQ ID NO: 23), or SQIEV (SEQ ID NO: 24). In another embodiment, the Tn3 scaffold may include one or more CD40L-specific Tn3 monomers having the same or different β-strand A sequences. For example, the first CD40L-specific Tn3 monomer β-strand A may include or consist of IEV (SEQ ID NO: 5), and the second CD40L-specific Tn3 monomer β-strand A may include or consist of RLDAPSQIEV (SEQ ID NO: 23) or SQIEV (SEQ ID NO: 24).

[0028] The Tn3 scaffold may have the amino acid sequence shown in SEQ ID NO: 1 and as described above, or it may have one or more amino acid residue changes compared to the amino acid sequence shown in SEQ ID NO: 1. For example, if the scaffold has an amino acid sequence change compared to that shown in SEQ ID NO: 1, the change may be a change in one of the linkers. The Tn3 scaffold may include a Gly15 linker that separates two CD40L-specific monomers and a Gly10 linker that separates the CD40L-specific monomer from the HSA sequence. Both or one of these linkers may be modified and replaced with the amino acid sequence (GmX)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). For example, one or both linkers may be modified to have an amino acid sequence containing one of the following: GGGGSGGGGS (SEQ ID NO: 7), GGGGSGGGGSGGGGS (SEQ ID NO: 8), GGGGGGGGGG (SEQ ID NO: 9), or GGGGGGGGGGGGGGG (SEQ ID NO: 10). If the Tn3 scaffold has a certain amino acid sequence compared to the amino acid sequence provided in SEQ ID NO: 1, this may be due to one or more changes in the HSA amino acid sequence fused to the two CD40L-specific monomers. HSAs fused to two CD40L-specific monomers may be modified, compared to HSAs fused to two CD40L-specific Tn3 monomers, except for at least one amino acid substitution at a position 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 based on their position in a fully matured HSA; where the at least one amino acid substitution does not involve lysine (K) to glutamic acid (E) at position 573.

[0029] Table 1 shows exemplary sequences of Tn3 scaffolds. In some embodiments, a Tn3 scaffold contains at least about or at most about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or up to about 100% identity with any one of sequence numbers 1 to 25 shown in Table 1. In some embodiments, any one of the sequences from Table 1 may be modified. In some embodiments, modifications include one or more truncations, deletions, insertions, and combinations thereof. Modifications can be made to any of the residues provided in Table 1 and any number of residues from Table 1. In some embodiments, the modification 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, the modification may be carried out to a maximum of 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.

[0030] [Table 1-1]

[0031] [Table 1-2]

[0032] [Table 1-3]

[0033] If the Tn3 scaffold has an amino acid sequence change compared to that shown in SEQ ID NO: 1, the change may be a change in the amino acid sequence of one or both CD40L-specific Tn3 monomers, provided that it does not adversely affect the in vivo efficacy of the scaffold, for example, a change in the amino acid sequence such that one or both CD40L-specific Tn3 monomers have the amino acid sequence 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 amino acid residues (SQ) on the N-terminal side may be absent and / or substituted with alternative amino acid residues. In some embodiments, the Tn3 scaffold includes monomer subunits containing SEQ ID NO: 22, SEQ ID NO: 25, or both SEQ ID NO: 22 and SEQ ID NO: 25.

[0034] In one embodiment, the Tn3 scaffold comprises at least one CD40L-specific monomer subunit bound to a heterologous portion. In another embodiment, the heterologous portion is selected from the group consisting of proteins, peptides, protein domains, linkers, drugs, toxins, cytotoxic agents, contrast agents, radionuclides, radiocompounds, organic polymers, inorganic polymers, polyethylene glycol (PEG), biotin, albumin, HSA FcRn binding portions, antibodies or fragments thereof, single-chain antibodies, domain antibodies, albumin-binding domains, enzymes, ligands, receptors, binding peptides, non-FnIII scaffolds, epitope tags, recombinant polypeptide polymers, cytokines, and two or more combinations of the said portions. In another embodiment, the heterologous portion is albumin, and the albumin comprises human serum albumin. In another embodiment, the heterologous portion is an antibody. In another embodiment, the antibody is selected from the group consisting of an antibody Fc domain, an antibody fragment, and a single-chain antibody.

[0035] In one embodiment, the heterogeneous portion is an antibody. In another embodiment, the antibody is selected from the group consisting of the antibody's Fc domain, antibody fragments, and single-chain antibodies.

[0036] In some embodiments, the heterogeneous portion is a contrast agent; for example, a radionuclide or biotin. In other embodiments, the heterogeneous portion is a drug; for example, a cytotoxic agent or a radiocompound.

[0037] In one embodiment, the heterogeneous portion includes PEG. In one embodiment, the Tn3 scaffold includes at least one CD40L-specific monomer subunit that is fused to or conjugated with PEG directly or via a linker. In one embodiment, both CD40L-specific monomer subunits are fused to, conjugated to, or bound to PEG via a linker. In one embodiment, the Tn3 scaffold includes at least one (e.g., two) CD40L-specific monomer subunits that are fused to or conjugated with PEG directly or via a linker.

[0038] In one embodiment, the heterogeneous portion comprises albumin. In one embodiment, the Tn3 scaffold comprises at least one CD40L-specific monomeric subunit that is fused to or conjugated with albumin directly or via a linker. In one embodiment, this albumin is HSA. In one embodiment, this HSA is a mutant HSA. In one embodiment, the amino acid sequence of the mutant HSA is SEQ ID NO: 4. In one embodiment, the mutant HSA has at least one improved property compared to natural HSA or a natural HSA fragment. In one embodiment, the amino acid sequence of the mutant HSA is a sequence that is at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or up to 100% identical to SEQ ID NO: 4. In one embodiment, the improved property is a modified plasma half-life compared to the plasma half-life of natural HSA or a natural HSA fragment. In one embodiment, the modified plasma half-life is a longer plasma half-life compared to that of natural HSA or natural HSA fragments. In another embodiment, the modified plasma half-life is a shorter plasma half-life compared to that of natural HSA or natural HSA fragments.

[0039] Dose setting In some embodiments, any composition comprising the Tn3 scaffold of this disclosure may be administered in any form. In some embodiments, the Tn3 scaffold is administered intravenously, subcutaneously, orally, intramuscularly, subarachnoidally, 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.

[0040] The Tn3 scaffold of this disclosure can be administered in any dose. In some embodiments, the Tn3 scaffold may be administered in doses of approximately 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, 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, and 24 50mg, 2500mg, 2550mg, 2600mg, 2650mg, 2700mg, 2750mg, 2800mg, 2850mg, 2900mg, 2950mg, 3000mg, 3050mg, 3100mg, 3150mg, 3200mg, 3250mg, 3300 mg, 3350mg, 3400mg, 3450mg, 3500mg, 3550mg, 3600mg, 3650mg, 3700mg, 3750mg, 3800mg, 3850mg, 3900mg, 3950mg, 4000mg, 4050mg, 4100mg, 4150mg , 4200mg, 4250mg, 4300mg, 4350mg, 4400mg, 4450mg, 4500mg, 4550mg, 4600mg, 4650mg, 4700mg, 4750mg, 4800mg, 4850mg, 4900mg, 4950mg, or from approximately 5000mg and / or up to 800mg, 850mg, 900mg, 950mg, 1000mg, 1050mg, 1100mg, 1150mg, 1200mg, 1250mg, 1300mg, 1350mg, 1400mg, 1450mg, 1500mg, 1550mg, 160 0mg, 1650mg, 1700mg, 1750mg, 1800mg, 1850mg, 1900mg, 1950mg, 2000mg, 2050mg, 2100mg, 2150mg, 2200mg, 2250mg, 2300mg, 2350mg, 2400mg, 2450m g, 2500mg, 2550mg, 2600mg, 2650mg, 2700mg, 2750mg, 2800mg, 2850mg, 2900mg, 2950mg, 3000mg, 3050mg, 3100mg, 3150mg, 3200mg, 3250mg, 3300mg,It is administered in doses of 3350 mg, 3400 mg, 3450 mg, 3500 mg, 3550 mg, 3600 mg, 3650 mg, 3700 mg, 3750 mg, 3800 mg, 3850 mg, 3900 mg, 3950 mg, 4000 mg, 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 approximately 5000 mg. Any of the aforementioned dosages may be effective for methods including treatment, reduction, or elimination.

[0041] In this embodiment, the Tn3 scaffold is administered in doses between approximately 800-5000 mg, 900-4900 mg, 1000-4800 mg, 1100-4700 mg, 1200-4600 mg, 1300-4500 mg, or 1500-3000 mg. In this configuration, the Tn3 scaffolding is available in the following quantities: 1300mg, 1350mg, 1400mg, 1450mg, 1500mg, 1550mg, 1600mg, 1650mg, 1700mg, 1750mg, 1800mg, 1850mg, 1900mg, 1950mg, 2000mg, 2050mg, 2100mg, 2150mg, 2200mg, 2250mg, 2300mg, 2350mg, 2400mg, 2450mg, 2500mg, 2550mg, 2600mg, 2650mg, 2700mg, 2750mg, 2800mg, 2850mg, 2900mg, 2 The drug is administered in doses selected from the group consisting of 950 mg, 3000 mg, 3050 mg, 3100 mg, 3150 mg, 3200 mg, 3250 mg, 3300 mg, 3350 mg, 3400 mg, 3450 mg, 3500 mg, 3550 mg, 3600 mg, 3650 mg, 3700 mg, 3750 mg, 3800 mg, 3850 mg, 3900 mg, 3950 mg, 4000 mg, 4050 mg, 4100 mg, 4150 mg, 4200 mg, 4250 mg, 4300 mg, 4350 mg, 4400 mg, 4450 mg, and 4500 mg. In this embodiment, the Tn3 scaffold is administered in doses of approximately 1500 mg to 3000 mg. In one embodiment, the Tn3 scaffold is administered in a dose of 1500 mg or 3000 mg. In another embodiment, the Tn3 scaffold is administered in a dose of approximately 1500 mg. In yet another embodiment, the Tn3 scaffold is administered in a dose of approximately 3000 mg.

[0042] Frequency of administration In some embodiments, the Tn3 scaffold of the Disclosure is administered on a schedule that yields optimal results. In some embodiments, the Tn3 scaffold is administered to subjects in need of it approximately once a week, twice a week, every two weeks, every month, every month, every four weeks, every two months, every three months, every twelve weeks, every fifteen weeks, every sixteen weeks, every four months, every five months, every six months, or every six months. Any number of doses may be provided to subjects in need of it. In some embodiments, the Tn3 scaffold of the Disclosure is administered as a loading dose. The loading dose is also called the induction dose. In some embodiments, the Tn3 scaffold is administered as a maintenance dose.

[0043] The Tn3 scaffolds of this disclosure can be administered in total doses of approximately 1 to 10, 10 to 50, 50 to 75, 75 to 100, 100 to 200, or 200 to 300 doses, or for the lifetime of the subject. In some embodiments, the Tn3 scaffolds are administered in doses of approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, or more. In some embodiments, the Tn3 scaffolds are administered in total doses of at least approximately or at most approximately 2, 3, 4, or 5 doses. In some embodiments, the Tn3 scaffolds are administered in total doses of at least approximately or at most approximately 10, 11, 12, or 13 doses.

[0044] In one configuration, the subject receives an effective dose approximately 1, 2, 3, 4, 5, 6 days after the start of treatment, 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 for the lifetime of the subject. In another configuration, the subject receives an effective dose on 1, 15, 29, 57, 85, 113, 141, 169, 197, 225, 253, 281, and 309 days after the start of treatment. In this configuration, the subjects are administered 1500 mg to 3000 mg of Tn3 scaffold on days 1, 15, 29, 57, 85, 113, 141, 169, 197, 225, 253, 281, and 309 after the start of treatment.

[0045] In one embodiment, the subject is administered approximately 1500 mg to 3000 mg of Tn3 scaffolding every two weeks for approximately three doses, followed by doses every four weeks thereafter. In another embodiment, the subject is administered approximately 1500 mg of Tn3 scaffolding every two weeks for approximately three doses, followed by doses every four weeks thereafter. In yet another embodiment, the subject is administered approximately 3000 mg of Tn3 scaffolding at weeks 0, 4, and 12, followed by doses every 12 weeks thereafter. In yet another embodiment, the subject is administered approximately 1500 mg of Tn3 scaffolding every four weeks. In yet another embodiment, the subject is administered approximately 3000 mg of Tn3 scaffolding every 12 weeks. In yet another embodiment, the subject is administered an initial dose of approximately 1500 mg to 3000 mg of the Tn3 scaffolding of this disclosure every two weeks for at least two, at least three, or more doses, followed by doses every four weeks thereafter. In one embodiment, the subject is administered an initial dose of approximately 1500 mg of the Tn3 scaffold of the Disclosure over at least two, at least three, or more doses every two weeks, and thereafter every four weeks. In another embodiment, the subject is administered an initial dose of approximately 3000 mg of the Tn3 scaffold of the Disclosure over at least two, at least three, or more doses every two weeks, and thereafter every 12 weeks. In yet another embodiment, the subject is administered an initial dose of approximately 3000 mg of the Tn3 scaffold of the Disclosure over at least two, at least three, or more doses every four weeks, and thereafter every 12 weeks. In yet another embodiment, the administration treats SS patients with low systemic disease activity but moderate to severe symptomatic status. In yet another embodiment, the administration treats SS subjects with moderate systemic disease activity. In yet another embodiment, the administration treats SS subjects with severe systemic disease activity. In one embodiment, the administration treats SS subjects with moderate to severe systemic disease activity. In another embodiment, the administration of the Tn3 scaffold treats SS patients with moderate or severe systemic disease activity, as defined by an ESSDAI score of ≥ 5. In yet another embodiment, the administration of the Tn3 scaffold treats SS patients with moderate to severe systemic disease activity, as defined by an ESSDAI score of ≥ 5. In yet another embodiment, the administration of the Tn3 scaffold treats SS patients with moderate to severe symptomatic activity, as defined by an ESSPRI score of ≥ 5, and low systemic disease activity, as defined by an ESSDAI score < 5.In one embodiment, administration of the Tn3 scaffold treats SS patients with moderate or severe systemic disease activity, as defined by an ESSDAI score of ≥ 5. In another embodiment, administration of the Tn3 scaffold treats SS patients with moderate or severe systemic disease activity, as defined by an ESSDAI score of ≥ 5. In yet another embodiment, administration of the Tn3 scaffold treats SS patients with moderate or severe symptomatic activity, as defined by an ESSPRI score of ≥ 5, and low systemic disease activity, as defined by an ESSDAI score < 5.

[0046] A therapeutic or preventive method of the present disclosure includes administering the Tn3 scaffold of the present disclosure to a subject in need of it. In one embodiment, the therapeutic method includes administering an effective dose of the Tn3 scaffold to a subject in need of it in approximately three doses every two weeks, followed thereafter by administering the Tn3 scaffold every four weeks. In another embodiment, the therapeutic method includes administering an effective dose of the Tn3 scaffold to a subject in need of it at weeks 0, 4, and 12, followed thereafter by administering the Tn3 scaffold every 12 weeks. In another embodiment, the therapeutic method includes administering approximately 1400 mg to approximately 1600 mg of the Tn3 scaffold to a subject in need of it in approximately three doses every two weeks, followed thereafter by administering the Tn3 scaffold every four weeks. In another embodiment, the therapeutic method includes administering approximately 2000 mg to approximately 4000 mg of the Tn3 scaffold to a subject in need of it at weeks 0, 4, and 12, followed thereafter by administering the Tn3 scaffold every 12 weeks.

[0047] In one embodiment, the treatment method includes administering approximately 1500 mg of Tn3 scaffold to a subject requiring approximately 1500 mg over seven doses every two weeks. In another embodiment, the treatment method includes administering approximately 1500 mg of Tn3 scaffold to a subject requiring approximately 1500 mg over five doses every four weeks. In yet another embodiment, the treatment method includes administering approximately 1500 mg of Tn3 scaffold to a subject requiring approximately 1500 mg over three doses every two weeks, followed by administration of Tn3 scaffold every four weeks thereafter. In yet another embodiment, the treatment method includes administering approximately 3000 mg of Tn3 scaffold to a subject requiring approximately 3000 mg of Tn3 scaffold at weeks 0, 4, and 12, followed by administration of Tn3 scaffold every 12 weeks thereafter. In yet another embodiment, administration is performed every four weeks and then continues for up to approximately 1, 2, 3, 4, or 5 years, or for the lifetime of the subject. In yet another embodiment, any of the aforementioned doses may be spaced out by approximately 1 to 4 days, 3 to 7 days, or 1 to 7 days. Depending on the circumstances, any of the aforementioned doses may be delayed by approximately 1 day, 3 days, 4 days, or 7 days. Depending on the circumstances, any of the aforementioned doses may be delayed by approximately 1 day. Depending on the circumstances, any of the aforementioned doses may be delayed by approximately 3 days. Depending on the circumstances, any of the aforementioned doses may be delayed by approximately 4 days. Depending on the circumstances, any of the aforementioned doses may be delayed by approximately 7 days.

[0048] In one embodiment, the subject receives an effective dose of Tn3 scaffolding on day 1, day 15 (-3 to +1 day), day 29 (±4 days), and day 57 (±7 days) after the start of treatment. In another embodiment, subjects who require it receive 1500 mg of Tn3 scaffolding on day 1, day 15 (-3 to +1 day), day 29 (±4 days), and day 57 (±7 days) after the start of treatment, and then every four weeks thereafter as needed. In yet another embodiment, subjects who require it receive 1500 mg of Tn3 scaffolding on day 1, day 15 (±1 day), and day 29 (±3 days) after the start of treatment. In yet another embodiment, subjects who require it receive 1500 mg of Tn3 scaffolding on day 1 and day 57 (±7 days) after the start of treatment. In one embodiment, subjects requiring it are administered 1500 mg of Tn3 scaffolding on day 1, day 15 (±1 day), day 29 (±3 days), day 57 (±7 days), day 85 (±7 days), day 113 (±7 days), and day 141 (±7 days) post-treatment. In another embodiment, subjects requiring it are administered 1500 mg of Tn3 scaffolding on day 169 (±7 days), day 197 (±7 days), day 225 (±7 days), day 253 (±7 days), and day 281 (±7 days) post-treatment. In yet another embodiment, subjects requiring it are administered 3000 mg of Tn3 scaffolding on day 1, day 15 (-3 days to +1 day), day 29 (±4 days), and day 57 (±7 days) post-treatment, and then every 6 months thereafter as needed. In one embodiment, a 3000 mg Tn3 scaffold is administered to subjects requiring it on day 1, day 15 (-3 to +1 day), and day 29 (±4 days) after the start of treatment. In another embodiment, a 3000 mg Tn3 scaffold is administered to subjects requiring it on day 1 and day 57 (±7 days) after the start of treatment, and then administered every 12 weeks thereafter as needed.

[0049] In one embodiment, subjects requiring it receive a certain dose of the Tn3 scaffold on day 1, day 15 (-3 to +1 day), day 29 (±4 days), day 57 (±7 days), day 85 (±7 days), day 113 (±7 days), and day 141 (±7 days). In another embodiment, subjects requiring it receive an effective dose of the Tn3 scaffold on day 169 (±7 days), day 197 (±7 days), day 225 (±7 days), day 253 (±7 days), day 281 (±7 days), and day 309 (±7 days).

[0050] In one embodiment, an effective dose of Tn3 scaffolding is administered to subjects who require it, once every 2 to 4 weeks. In another embodiment, an effective dose of Tn3 scaffolding is administered to subjects who require it, once every 2 weeks, 4 weeks, 6 weeks, 8 weeks, or 12 weeks. In another embodiment, 1500 mg of Tn3 scaffolding is administered to subjects who require it, in at least 3 doses every 2 weeks, in at least 12 doses every 4 weeks, in at least 13 doses every 4 weeks, or in combination thereof. In yet another embodiment, 3000 mg of Tn3 scaffolding is administered to subjects who require it, in at least 3 doses every 2 weeks, in at least 4 doses every 4 weeks, in at least 5 doses every 4 weeks, or in combination thereof. In yet another embodiment, 3000 mg of Tn3 scaffolding is administered every 3 months. In yet another embodiment, 3000 mg of Tn3 scaffolding is administered every 12 weeks.

[0051] In one embodiment, the Tn3 scaffold is administered at a dose of approximately 1500 mg once every two weeks for at least two doses, and thereafter administered approximately once a month. In another embodiment, the Tn3 scaffold is administered at a dose of approximately 1500 mg once every two weeks for at least three doses, and thereafter administered approximately once a month. In yet another embodiment, the Tn3 scaffold is administered at a dose of approximately 1500 mg once every two weeks for at least three doses, and thereafter administered every four weeks. In yet another embodiment, the Tn3 scaffold is administered at a dose of approximately 1500 mg once every month, once every two months, or once every three months. In yet another embodiment, the Tn3 scaffold is administered at a dose of approximately 3000 mg once every two weeks for at least two doses, and thereafter administered approximately once a month, every two months, or every three months, or a combination thereof. In one embodiment, the Tn3 scaffold is administered at a dose of approximately 3000 mg once every four weeks for at least two doses, and thereafter at a dose of approximately once a month, every two months, or every three months, or a combination thereof. In another embodiment, the Tn3 scaffold is administered at a dose of approximately 3000 mg once every four weeks for at least two doses, and thereafter at a dose of approximately every 12 weeks. In yet another embodiment, the Tn3 scaffold is administered at a dose of approximately 3000 mg once every month, every two months, or every three months. In yet another embodiment, the Tn3 scaffold is administered at a dose of two or more doses. In yet another embodiment, the subject is administered 1500 mg of the Tn3 scaffold of this disclosure every two weeks. In yet another embodiment, the subject is administered 1500 mg of the Tn3 scaffold of this disclosure every four weeks. In one embodiment, the subject is administered 3000 mg of the Tn3 scaffold of this disclosure every 12 weeks.

[0052] In some embodiments, the method of the present disclosure includes administration of a Tn3 scaffold at a dose of 3000 mg every 12 weeks, and at weeks 0 and 4. In some embodiments, the method of the present disclosure includes administration of a Tn3 scaffold at a dose of 1500 mg every 4 weeks. In some embodiments, the method of the present disclosure includes administration of a Tn3 scaffold containing SEQ ID NO: 1 at a dose of 3000 mg every 12 weeks, and at weeks 0 and 4. In some embodiments, the method of the present disclosure includes administration of a Tn3 scaffold containing SEQ ID NO: 1 at a dose of 1500 mg every 2 weeks. In some embodiments, the method of the present disclosure includes administration of a Tn3 scaffold containing SEQ ID NO: 1 at a dose of 1500 mg every 4 weeks. In one embodiment, the method of the present disclosure includes administering a Tn3 scaffold containing SEQ ID NO: 1 at a dose of 1500 mg of Tn3 scaffold every two weeks for three doses, and then every four weeks thereafter. In another embodiment, the method of the present disclosure includes administering a Tn3 scaffold containing SEQ ID NO: 1 at a dose of 3000 mg of Tn3 scaffold every two weeks for three doses, and then every 12 weeks thereafter.

[0053] In some embodiments, the method of the present disclosure includes administration of Tn3 scaffold at a dose of 3000 mg every 12 weeks, and at a dose of 3000 mg every 0 and 4 weeks. In some embodiments, the method of the present disclosure includes administration of Tn3 scaffold at a dose of 1500 mg every 4 weeks. In some embodiments, the method of the present disclosure includes administration of Tn3 scaffold containing SEQ ID NO: 22 or SEQ ID NO: 25 at a dose of 3000 mg every 12 weeks, and at a dose of 3000 mg every 0 and 4 weeks. In some embodiments, the method of the present disclosure includes administration of Tn3 scaffold containing SEQ ID NO: 22 or SEQ ID NO: 25 at a dose of 1500 mg every 2 weeks. In some embodiments, the method of the present disclosure includes administration of Tn3 scaffold containing SEQ ID NO: 22 or SEQ ID NO: 25 at a dose of 1500 mg every 4 weeks. In one embodiment, the method of the present disclosure includes administering a Tn3 scaffold containing SEQ ID NO: 22 or SEQ ID NO: 25 at a dose of 1500 mg of Tn3 scaffold every two weeks for three doses, and then every four weeks thereafter. In another embodiment, the method of the present disclosure includes administering a Tn3 scaffold containing SEQ ID NO: 22 or SEQ ID NO: 25 at a dose of 3000 mg of Tn3 scaffold every two weeks for three doses, and then every twelve weeks thereafter.

[0054] In some embodiments, the method of the present disclosure includes administering a Tn3 scaffold to a subject requiring it at a dose of 3000 mg every 12 weeks, and at week 0 and week 4. In some embodiments, the method of the present disclosure includes administering a Tn3 scaffold to a subject requiring it at a dose of 1500 mg every 4 weeks. In some embodiments, the method of the present disclosure includes administering a Tn3 scaffold containing SEQ ID NO: 1 to a subject requiring it at a dose of 3000 mg every 12 weeks, and at week 0 and week 4. In some embodiments, the method of the present disclosure includes administering a Tn3 scaffold containing SEQ ID NO: 1 to a subject requiring it at a dose of 1500 mg every 2 weeks. In one embodiment, the method of the present disclosure includes administering a Tn3 scaffold containing SEQ ID NO: 1 to a subject requiring it at a dose of 1500 mg of Tn3 scaffold every four weeks. In another embodiment, the method of the present disclosure includes administering a Tn3 scaffold containing SEQ ID NO: 1 to a subject requiring it at a dose of 1500 mg of Tn3 scaffold every two weeks for three doses, and then every four weeks thereafter. In yet another embodiment, the method of the present disclosure includes administering a Tn3 scaffold containing SEQ ID NO: 1 to a subject requiring it at a dose of 1500 mg of Tn3 scaffold every two weeks for seven doses. In yet another embodiment, the method of the present disclosure includes administering a Tn3 scaffold containing SEQ ID NO: 1 to a subject requiring it at a dose of 1500 mg of Tn3 scaffold every four weeks for five doses. In yet another embodiment, the method of the present disclosure includes administering a Tn3 scaffold containing SEQ ID NO: 1 to a subject requiring it at a dose of 3000 mg of Tn3 scaffold every two weeks for three doses, and then every twelve weeks thereafter.

[0055] In some embodiments, the method of the present disclosure includes administering a Tn3 scaffold to a subject requiring it at a dose of 3000 mg every 12 weeks, and at weeks 0 and 4. In some embodiments, the method of the present disclosure includes administering a Tn3 scaffold to a subject requiring it at a dose of 1500 mg every 2 weeks. In some embodiments, the method of the present disclosure includes administering a Tn3 scaffold to a subject requiring it at a dose of 1500 mg every 4 weeks. In some embodiments, the method of the present disclosure includes administering a Tn3 scaffold containing SEQ ID NO: 22 or SEQ ID NO: 25 to a subject requiring it at a dose of 3000 mg every 12 weeks, and at weeks 0 and 4. In some embodiments, the method of the present disclosure includes administering a Tn3 scaffold containing SEQ ID NO: 22 or SEQ ID NO: 25 at a dose of 1500 mg every two weeks to a subject requiring it. In some embodiments, the method of the present disclosure includes administering a Tn3 scaffold containing SEQ ID NO: 22 or SEQ ID NO: 25 at a dose of 1500 mg every four weeks to a subject requiring it. In some embodiments, the method of the present disclosure includes administering a Tn3 scaffold containing SEQ ID NO: 22 or SEQ ID NO: 25 at a dose of 1500 mg every two weeks over seven doses to a subject requiring it. In some embodiments, the method of the present disclosure includes administering a Tn3 scaffold containing SEQ ID NO: 22 or SEQ ID NO: 25 at a dose of 1500 mg every four weeks over five doses to a subject requiring it. In some embodiments, the method of the present disclosure includes administering a Tn3 scaffold containing SEQ ID NO: 22 or SEQ ID NO: 25 at a dose of 1500 mg to a subject requiring it, over three doses every two weeks, and thereafter every four weeks. In some embodiments, the method of the present disclosure includes administering a Tn3 scaffold containing SEQ ID NO: 22 or SEQ ID NO: 25 at a dose of 3000 mg to a subject requiring it, over three doses every two weeks, and thereafter every 12 weeks.

[0056] In one embodiment, the Tn3 scaffold is administered in a dose of approximately 1500 mg. In another embodiment, the Tn3 scaffold is administered in a dose of approximately 3000 mg. In another embodiment, the Tn3 scaffold is administered in a dose of approximately 1500 mg every two weeks. In another embodiment, the Tn3 scaffold is administered in a dose of approximately 1500 mg every four weeks. In another embodiment, the Tn3 scaffold is administered in a dose of approximately 1500 mg once every two weeks for at least two doses. In yet another embodiment, the Tn3 scaffold is administered in a dose of approximately 1500 mg twice every two weeks for at least two doses. In yet another embodiment, the Tn3 scaffold is administered in a dose of approximately 1500 mg once every four weeks for at least two doses. In yet another embodiment, the Tn3 scaffold is administered in a dose of approximately 1500 mg twice every four weeks for at least two doses. In one embodiment, the Tn3 scaffold is administered in doses of approximately 1500 mg twice, every four weeks thereafter. In another embodiment, the Tn3 scaffold is administered in doses of approximately 1500 mg every two weeks for three doses, and then every four weeks thereafter. In another embodiment, the Tn3 scaffold is administered in doses of approximately 1500 mg every two weeks for two doses, and then every four weeks thereafter. In yet another embodiment, the Tn3 scaffold is administered in doses of approximately 3000 mg every two weeks. In yet another embodiment, the Tn3 scaffold is administered in doses of approximately 3000 mg every four weeks for at least two doses, every two weeks. In yet another embodiment, the Tn3 scaffold is administered in doses of approximately 3000 mg every four weeks for at least two doses, every two weeks. In one embodiment, the Tn3 scaffold is administered at a dose of approximately 3000 mg twice every 12 weeks for at least two doses. In another embodiment, the Tn3 scaffold is administered at a dose of approximately 3000 mg twice every 12 weeks thereafter. In yet another embodiment, the Tn3 scaffold is administered at a dose of approximately 3000 mg three times every two weeks, and then every 12 weeks thereafter. In yet another embodiment, the Tn3 scaffold is administered at a dose of approximately 3000 mg at a dose of at least two times every four weeks, and then every 12 weeks thereafter.

[0057] method In aspects of this specification, the method is intended to treat, alleviate, or eliminate an autoimmune disease or disorder. In aspects, the method includes administering the Tn3 scaffold of this disclosure. In aspects, the Tn3 scaffold is used to treat SS. In aspects, the Tn3 scaffold is administered to a subject in need for the treatment of SS using one of the dosing schedules disclosed herein. In aspects, the Tn3 scaffold is administered in doses of about 1500 mg once every two weeks for at least two doses, and thereafter administered about once a month. In aspects, the Tn3 scaffold is administered in doses of about 1500 mg once every two weeks for at least three doses, and thereafter administered about once a month or once every four weeks. In aspects, the Tn3 scaffold is administered in doses of about 1500 mg once every month, once every two months, or once every three months. In one embodiment, the Tn3 scaffold is administered at a dose of approximately 3000 mg once every month, once every two months, or once every three months. In another embodiment, the Tn3 scaffold is administered at a dose of approximately 3000 mg once every two weeks for at least three doses, and thereafter at a dose of approximately once every three months. In yet another embodiment, the Tn3 scaffold is administered at a dose of approximately 3000 mg once every four weeks for at least two doses, and thereafter at a dose of approximately once every three months. In yet another embodiment, the Tn3 scaffold is administered at a dose of approximately 3000 mg once every four weeks for at least two doses, and thereafter at a dose of approximately once every twelve weeks. In yet another embodiment, the Tn3 scaffold is administered at a dose of approximately 3000 mg, followed by additional doses at four and twelve weeks, and thereafter at a dose of approximately once every three months or once every twelve weeks. In this embodiment, the Tn3 scaffold is administered in two or more doses.

[0058] In some embodiments, the method includes treating SS subjects. In some embodiments, the method includes treating SS subjects with a European Alliance of Associations for Rheumatology (EULAR) Sjögren's Syndrome Disease Activity Index (ESSDAI) score of approximately 1, approximately 2, approximately 3, approximately 4, approximately 5, approximately 6, approximately 7, approximately 8, approximately 9, approximately 10, approximately 11, approximately 12, approximately 13, approximately 14, approximately 15, approximately 20, approximately 25, approximately 30, approximately 40, approximately 50, approximately 60, approximately 70, approximately 80, approximately 90, approximately 100, approximately 110, or approximately 120 points or higher. In one embodiment, the method includes treating SS subjects with a EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) score of approximately 1, 2, 4, 5, 6, 7, 8, 9, or 10 points.

[0059] In some embodiments, the method includes treating a subject in need of it. In some embodiments, the method includes treating an SS subject. In some embodiments, the method includes treating an SS subject with low systemic disease activity. In some embodiments, the method includes treating an SS patient with low systemic disease activity but a moderate to severe symptomatic state. In some embodiments, the method includes treating an SS subject with moderate systemic disease activity. In some embodiments, the method includes treating an SS subject with severe systemic disease activity. In some embodiments, the method includes treating an SS subject with moderate to severe systemic disease activity. In some embodiments, the method includes treating an SS subject with moderate to severe systemic disease activity by administering any dose of the Tn3 scaffold disclosed herein on any schedule. In some embodiments, the method includes treating a subject with SS and co-occurring rheumatoid arthritis (RA). In some embodiments, the method includes treating a subject with SS and co-occurring systemic lupus erythematosus (SLE). In one embodiment, moderate to severe systemic disease activity may be defined by a EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) ≥ 5. In another embodiment, moderate to severe systemic disease activity may be defined by a EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) ≥ 5. In another embodiment, low systemic disease activity may be defined by an ESSDAI ≤ 5. In one embodiment, the method includes treating an SS subject with low subjective symptoms by administering a Tn3 scaffold. In another embodiment, the method includes treating an SS subject with moderate to severe subjective symptoms by administering a Tn3 scaffold. In another embodiment, the subject has moderate to severe symptomatic activity defined by an ESSPRI score ≥ 5, but low systemic disease activity defined by an ESSDAI score < 5. In another embodiment, moderate to severe systemic disease activity may be defined by an ESSDAI score ≥ 5. In another embodiment, the method includes treating a severe SS subject. In one embodiment, the method includes treating SS subjects with an ESSDAI of 14 or more. In another embodiment, the method includes treating SS subjects with an ESSDAI of ≥ 14.In one embodiment, the method includes treating SS subjects with ESSDAI doses of 14-20, 14-30, 14-40, 14-50, 14-60, 15-40, 20-70, 30-80, 40-90, 50-100, 60-110, 70-120, or 80-123. In one embodiment, the Tn3 scaffold is administered at a dose of 1500 mg. In another embodiment, the Tn3 scaffold is administered at a dose of 3000 mg.

[0060] In one embodiment, the treatment method in a subject requiring treatment includes administering an effective dose of Tn3 scaffolding. In one embodiment, the administration is effective in reducing the disease or disability compared to a) a subject equivalent to a subject lacking the administration; or b) a subject requiring treatment compared to a baseline measurement of the disease or disability. In one embodiment, the administration is effective as assessed by the Sjögren's Syndrome Patient Reported Index Assessment Log (DASPRI). In one embodiment, in subjects administered Tn3 scaffolding, the DASPRI score decreases by at least or up to approximately 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100%. In one embodiment, the administration is effective as assessed by the Sjögren's Response Assessment Tool (STAR). In one embodiment, in subjects administered the Tn3 scaffold, the STAR score increases by at least approximately 1, 2, 3, 4, 5, 6, 7, or 8 points, or up to approximately 1, 2, 3, 4, 5, 6, 7, or 8 points. In another embodiment, administration is effective in reducing the ESSPRI score in subjects requiring it compared to the subject's baseline level. In another embodiment, in subjects administered the Tn3 scaffold, the ESSPRI score decreases by at least approximately 1, 5, 10, 25, 50, 75, 100, 150, or 250 times, or up to approximately 1, 5, 10, 25, 50, 75, 100, 150, or 250 times, compared to the subject's baseline level. In some embodiments, in subjects administered the Tn3 scaffold, the ESSPRI score decreases by at least approximately 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10 points compared to the subject's baseline level, or by up to approximately 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10 points, or more.In some embodiments, subjects treated with the Tn3 scaffold showed an ESSPRI score of at least approximately 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 22%, 24%, 26%, 28%, 30%, 32%, 34%, 36%, 38%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, and 7% compared to the baseline level of the subjects. The reduction is 5%, 80%, 85%, 90%, 95%, or up to approximately 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 22%, 24%, 26%, 28%, 30%, 32%, 34%, 36%, 38%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or up to 100%. In some embodiments, administration is effective in reducing the ESSDAI score in subjects requiring it compared to the subject's baseline level. In one embodiment, in subjects administered the Tn3 scaffold, the ESSDAI score decreases by at least approximately 1, 5, 10, 25, 50, 75, 100, 150, or 250 times, or up to approximately 1, 5, 10, 25, 50, 75, 100, 150, or 250 times, compared to the baseline level of the subject. In some embodiments, in subjects administered the Tn3 scaffold, the ESSDAI score decreases by at least approximately 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 80, 90, or 100 points, or up to approximately 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 80, 90, or 100 points, or more, compared to the baseline level of the subject.In some embodiments, subjects treated with the Tn3 scaffold showed an ESSDAI score of at least approximately 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 22%, 24%, 26%, 28%, 30%, 32%, 34%, 36%, 38%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, and 7% compared to the baseline level of the subjects. It decreases by 5%, 80%, 85%, 90%, 95%, or up to approximately 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 22%, 24%, 26%, 28%, 30%, 32%, 34%, 36%, 38%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or up to 100%.

[0061] In some embodiments, the Tn3 scaffold of the Disclosure increases the response rate in domains selected from the group consisting of constitution, lymphadenopathy, glands, joints, skin, lungs, kidneys, muscles, peripheral nervous system, central nervous system, blood, and biological domains, compared to subjects administered with a control. In some embodiments, the response rate increases by at least about 5%, 10%, 15%, 20%, 30%, 40%, or 50% compared to subjects administered with a control. In some embodiments, subjects administered with the Tn3 scaffold of the Disclosure to constitutional domains show an increased response rate compared to subjects administered with a control. In some embodiments, subjects administered with the Tn3 scaffold of the Disclosure to lymphadenopathy domains show an increased response rate compared to subjects administered with a control. In some embodiments, subjects administered with the Tn3 scaffold of the Disclosure to glandular domains show an increased response rate compared to subjects administered with a control. In some embodiments, subjects administered the Tn3 scaffold of the present disclosure to the articular domain show an increased response rate compared to subjects administered the control. In some embodiments, subjects administered the Tn3 scaffold of the present disclosure to the cutaneous domain show an increased response rate compared to subjects administered the control.

[0062] In one embodiment, the Tn3 scaffold is administered intravenously at a dose of approximately 1500 mg. In another embodiment, the Tn3 scaffold is administered intravenously at a dose of approximately 3000 mg. In another embodiment, the Tn3 scaffold is administered intravenously at a dose of approximately 1500 mg once every two weeks. In another embodiment, the Tn3 scaffold is administered intravenously at a dose of approximately 1500 mg once every four weeks. In yet another embodiment, the Tn3 scaffold is administered intravenously at a dose of approximately 1500 mg twice thereafter, every four weeks. In yet another embodiment, the Tn3 scaffold is administered intravenously at a dose of approximately 1500 mg every two weeks for three doses, and then every four weeks thereafter. In yet another embodiment, the Tn3 scaffold is administered at a dose of approximately 1500 mg at weeks 0, 2, and 4, and then every four weeks thereafter (Q4W). In one configuration, the Tn3 scaffold is administered intravenously at doses of approximately 1500 mg at weeks 0, 2, and 4, and thereafter once every 4 weeks (Q4W). In another configuration, the Tn3 scaffold is administered at doses of approximately 1500 mg every 2 weeks for 7 doses. In yet another configuration, the Tn3 scaffold is administered intravenously at doses of approximately 1500 mg every 2 weeks for 7 doses. In yet another configuration, the Tn3 scaffold is administered at doses of approximately 1500 mg every 4 weeks for 5 doses. In yet another configuration, the Tn3 scaffold is administered intravenously at doses of approximately 1500 mg every 4 weeks for 5 doses. In yet another configuration, the Tn3 scaffold is administered twice every 12 weeks at doses of approximately 3000 mg, and thereafter administered intravenously. In one embodiment, the Tn3 scaffold is administered intravenously at a dose of approximately 3000 mg every two weeks for three doses, and thereafter administered every 12 weeks. In another embodiment, the Tn3 scaffold is administered intravenously at a dose of approximately 3000 mg every two weeks for at least two doses, and thereafter administered every 12 weeks. In yet another embodiment, the Tn3 scaffold is administered intravenously at a dose of approximately 3000 mg every four weeks for at least two doses, and thereafter administered every 12 weeks.

[0063] In some embodiments, the method of the present disclosure includes intravenous administration of a Tn3 scaffold in doses of 3000 mg every 12 weeks, and in doses of 3000 mg every 0 and 4 weeks, to subjects who require it. In some embodiments, the method of the present disclosure includes intravenous administration of a Tn3 scaffold in doses of 1500 mg every 4 weeks, and in doses of 1500 mg every 0 and 2 weeks, to subjects who require it. In some embodiments, the method of the present disclosure includes intravenous administration of a Tn3 scaffold containing SEQ ID NO: 22 or SEQ ID NO: 25 in doses of 3000 mg every 12 weeks, and in doses of 3000 mg every 0 and 4 weeks, to subjects who require it. In some embodiments, the method of the present disclosure includes intravenous administration of a Tn3 scaffold containing SEQ ID NO: 22 or SEQ ID NO: 25 at a dose of 1500 mg every four weeks to a subject requiring it. In some embodiments, the method of the present disclosure includes intravenous administration of a Tn3 scaffold containing SEQ ID NO: 22 or SEQ ID NO: 25 at a dose of 1500 mg to a subject requiring it, over three doses every two weeks, and thereafter every four weeks. In some embodiments, the method of the present disclosure includes intravenous administration of a Tn3 scaffold containing SEQ ID NO: 22 or SEQ ID NO: 25 at a dose of 3000 mg to a subject requiring it, over three doses every two weeks, and thereafter every twelve weeks.

[0064] In one embodiment, a composition containing a Tn3 scaffold was formulated for administration. In another embodiment, the Tn3 scaffold was present in at least about, or up to about 1 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL, 35 mg / mL, 40 mg / mL, 45 mg / mL, 50 mg / mL, 55 mg / mL, 60 mg / mL, 65 mg / mL, 70 mg / mL, 75 mg / mL , 80mg / mL, 85mg / mL, 90mg / mL, 95mg / mL, 100mg / mL, 105mg / mL, 110mg / mL, 115mg / mL, 120mg / mL, 125mg / mL, 130mg / mL, 135 mg / mL, 140mg / mL, 145mg / mL, 150mg / mL, 155mg / mL, 160mg / mL, 165mg / mL, 170mg / mL, 175mg / mL, 180mg / mL, 185mg / mL, 190m g / mL, 195mg / mL, 200mg / mL, 205mg / mL, 210mg / mL, 215mg / mL, 220mg / mL, 225mg / mL, 230mg / mL, 235mg / mL, 240mg / mL, 245m g / mL, 250mg / mL, 255mg / mL, 260mg / mL, 265mg / mL, 270mg / mL, 275mg / mL, 280mg / mL, 285mg / mL, 290mg / mL, 295mg / mL, 300mg The formulation is prepared at concentrations of 100 mg / mL, 305 mg / mL, 310 mg / mL, 315 mg / mL, 320 mg / mL, 325 mg / mL, 330 mg / mL, 335 mg / mL, 340 mg / mL, 345 mg / mL, 350 mg / mL, 355 mg / mL, 360 mg / mL, 365 mg / mL, 370 mg / mL, 375 mg / mL, 380 mg / mL, 385 mg / mL, 390 mg / mL, 395 mg / mL, or up to 400 mg / mL. In one embodiment, the effective dose of the Tn3 scaffold can be formulated at a concentration of approximately 100 mg / mL.

[0065] In some embodiments, administration of a Tn3 scaffold is effective in eliminating the disease in subjects requiring it. In some embodiments, administration of a Tn3 scaffold is effective in reducing the disease in subjects requiring it. In some cases, administration of a Tn3 scaffold is effective in eliminating or reducing the disease in subjects requiring disease elimination or reduction for at least about 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 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, at least about 5 years, or over the lifetime of the subject. In some embodiments, administration of a Tn3 scaffold is effective in eliminating the disease in subjects requiring disease elimination for at least about 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, or at least about 12 weeks. In some embodiments, administration of a Tn3 scaffold is effective in eliminating or reducing a disease in subjects requiring elimination or reduction of the disease for at least about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or at least about 12 months. In some embodiments, administration of a Tn3 scaffold is effective in eliminating or reducing a disease in subjects requiring elimination or reduction of the disease for at least about 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, or at least about 10 years. In some embodiments, administration of a Tn3 scaffold is effective in eliminating or reducing a disease over the lifetime of subjects requiring it.

[0066] In one embodiment, the subject requiring treatment is administered a Tn3 scaffold. In another embodiment, the subject requiring treatment is administered a Tn3 scaffold as first-line therapy. In another embodiment, the subject has not received one or more prior and / or combination therapies for the treatment of SS prior to administration of the Tn3 scaffold of this disclosure. In another embodiment, the subject requiring it has received one or more prior and / or combination therapies for the treatment of SS prior to administration of the Tn3 scaffold. In another embodiment, the prior and / or combination therapy includes drugs and / or vaccines (e.g., over-the-counter [OTC] or prescription drugs, recreational drugs, vitamins, and / or herbal supplements). Exemplary prior and / or combination therapies are described below.

[0067] Biological B-cell depletion therapy In one aspect, the subject was previously treated with biological B-cell depletion therapy (e.g., rituximab, ocrelizumab, inebilizumab, ofatumumab, belimumab, or ianarumab, or a combination thereof). In another aspect, the subject was treated with biological B-cell depletion therapy approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or approximately 12 months prior to screening. In yet another aspect, the subject was treated with biological B-cell depletion therapy approximately 3 months prior to screening. In yet another aspect, the subject was treated with biological B-cell depletion therapy approximately 12 months prior to screening. In yet another aspect, the subject was treated with belimumab approximately 3 months prior to screening. In this study, subjects were treated with rituximab, ocrelizumab, inebilizumab, ofatumumab, or inalumab, or a combination thereof, approximately 12 months prior to screening.

[0068] corticosteroids In some embodiments, the subject has been previously treated with corticosteroids. In some embodiments, the subject is treated with corticosteroids concurrently. In some embodiments, the corticosteroid is a glucocorticoid. In some embodiments, the subject has been previously treated with injectable corticosteroids (e.g., intra-articular [IA] or intramuscular [IM]) or orally administered prednisone (or equivalent) at doses greater than 10 mg per day. In some embodiments, the subject has been previously treated with injectable corticosteroids (e.g., intra-articular [IA] or intramuscular [IM]) or orally administered (e.g., prednisone or equivalent) at doses greater than 10 mg per day prior to 6 weeks before screening. In some embodiments, the subject has been treated with systemic corticosteroids for more than 2 weeks prior to 6 months before screening. In some embodiments, the subject is treated in combination with oral corticosteroids (prednisone or equivalent) at doses less than 10 mg / day, where the dose is stable for at least 2 weeks prior to screening. In one embodiment, the subject is simultaneously treated with a stable dose of inhaled corticosteroids, intranasal corticosteroids, or topical corticosteroids. In another embodiment, the subject is not treated with corticosteroids.

[0069] In one embodiment, subjects with an ESSDAI score of 5 or higher prior to administration were being treated with or had previously been treated with corticosteroids (e.g., at doses of less than 10 mg / day). In another embodiment, subjects were treated with a 1500 mg or 3000 mg Tn3 scaffold of the present disclosure.

[0070] In one embodiment, subjects with an ESSDAI score ≥ 5 and an ESSPRI score ≤ 5 prior to administration are not administered corticosteroids. In another embodiment, subjects are treated with a 1500 mg or 3000 mg Tn3 scaffold of the present disclosure.

[0071] antimalarial drugs In one embodiment, the subject is simultaneously treated with an antimalarial drug (e.g., chloroquine, hydroxychloroquine, quinacrine, etc.). In another embodiment, the subject has been previously treated with an antimalarial drug. In yet another embodiment, the subject is simultaneously treated with an antimalarial drug and has initiated treatment with the antimalarial drug more than 8 weeks prior to screening. In yet another embodiment, the subject is simultaneously treated with an antimalarial drug and has maintained a stable dose of the antimalarial drug more than 8 weeks prior to screening.

[0072] Immunomodulators In one embodiment, the subject has been previously treated with an immunomodulator. In another embodiment, the subject is simultaneously treated with an immunomodulator. In another embodiment, the immunomodulator is also a disease-modifying antirheumatic drug (DMARD) (e.g., methotrexate, sulfasalazine, leflunomide, hydroxychloroquine, plaquenil, cevimeline, pilocarpine, cyclosporine, etanercept, baricitinib, tofacitinib, upadacitinib, infliximab, adalimumab, certolizumab, golimumab, and combinations thereof). In another embodiment, the subject has been previously treated with a DMARD. In another embodiment, the subject was treated with a DMARD more than 4 weeks prior to screening. In another embodiment, the subject was treated with cevimeline, pilocarpine, and / or cyclosporine more than 2 weeks prior to screening. In this embodiment, the subjects are treated simultaneously with cevimeline, pilocarpine, and / or cyclosporine, with the doses stable at least two weeks prior to screening.

[0073] NSAID In one embodiment, the subject has been previously treated with a non-steroidal anti-inflammatory drug (NSAID). In another embodiment, the subject is treated with an NSAID concurrently. Exemplary NSAIDs may include, but are not limited to, aspirin, ibuprofen, naproxen, and nabumetone. In another embodiment, the subject is treated with an NSAID, and the NSAID dose is stable for at least two weeks prior to screening. In yet another embodiment, the subject is treated with an NSAID, and the NSAID is not administered for the first time at least two weeks prior to screening.

[0074] Cholinergic agonist In one embodiment, the subject has been previously treated with a cholinergic agonist. In another embodiment, the subject is simultaneously treated with a cholinergic agonist. Typical cholinergic agonists include, but are not limited to, cevimeline and pilocarpine.

[0075] In some embodiments, one or more prior / concurrent treatments are administered approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, or 52 weeks or more before the administration of the Tn3 scaffold. In some embodiments, one or more prior or concurrent treatments are administered approximately 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months or more before the administration of the Tn3 scaffold.

[0076] The doses and administration regimens of the Tn3 scaffolds of this disclosure may be such that any therapeutic effect achieved from the administration of the Tn3 scaffold to treat any autoimmune disease or disorder may be considered “long-lasting.” “Long-lasting” effect of a Tn3 scaffold in the treatment of an autoimmune disease or disorder means that the therapeutic effect achieved by the Tn3 scaffold is maintained for at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, at least 1 year, at least 2 years, or up to approximately 5 years after the last dose of a series of Tn3 scaffold administrations (although no further Tn3 scaffolds are administered). In some embodiments, it may be advantageous to reduce the frequency of administration of any of the compositions provided herein. Examples of the advantages of lower-frequency administration include, but are not limited to, a reduction in the frequency of side effects associated with the administered composition, a reduction in treatment-related toxicity, and an improvement in the quality of life of the treated subject.

[0077] evaluation In some embodiments, the subject is evaluated. In some embodiments, the subject is evaluated as part of the treatment. In some embodiments, subjects with confirmed or suspected autoimmune diseases or disorders (e.g., SS) are investigated as part of the procedure. The evaluation can be performed at any point before, during, or after administration of the Tn3 scaffold. In some embodiments, the investigation is performed before the start of administration. In some embodiments, the evaluation is performed simultaneously with administration. In some embodiments, the evaluation is performed after the completion of administration.

[0078] Any of the evaluations described below can be performed at any time. In some cases, the subject is evaluated every minute, every hour, every day, every week, every month, or every year. In other cases, the evaluation is completed twice a day, every other week, every other month, or every six months. In this configuration, the evaluations are -28, -27, -26, -25, -24, -23, -22, -21, -20, -19, -18, -17, -16, -15, -14, -13, -12, -11, -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, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 1 12, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 16 8, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224,225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 26 8, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 3 12, 313, 314, 315, 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 It is performed from day 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, ​​383, 384, 385, 386, 387, 388, 389, 390, 391, and 392, or for up to approximately 393 days ± 7 days after treatment.

[0079] In some embodiments, treatment of SS may be characterized by a reduction in clinical symptoms of the disease or disorder, or a reduction in inflammation, or a reduction in biomarkers of the disease or disorder, compared to the level before treatment with the Tn3 scaffold, of 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%. Any reduction in these symptoms, inflammation, or biomarkers may represent a reduction of at least approximately 10%, 15%, 20%, 25%, approximately 30%, approximately 40%, approximately 50%, approximately 60%, approximately 70%, approximately 75%, approximately 80%, approximately 85%, approximately 90%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or up to approximately 100% compared to their levels before the initiation of treatment with the Tn3 scaffold. The reduction may be one that characterizes SS being in remission.

[0080] In one embodiment, the subject is surveyed and baseline disease measurements are determined. In another embodiment, the subject is surveyed and baseline disease measurements are determined at any point before, during, or after administration of the Tn3 scaffold. In one embodiment, a survey is conducted and baseline disease measurements are determined before administration of the Tn3 scaffold. In another embodiment, a survey is conducted and baseline disease measurements are determined simultaneously with administration of the Tn3 scaffold. In another embodiment, a survey is conducted and baseline disease measurements are determined after administration of the Tn3 scaffold.

[0081] In some embodiments, baseline disease levels increase or decrease in response to administration or absence thereof. In some embodiments, baseline disease levels may increase and indicate effective treatment of the disease or disorder. In some embodiments, baseline disease levels may decrease and indicate effective treatment of the disease or disorder. In some embodiments, baseline disease levels increase or decrease after administration of the Tn3 scaffold. In some embodiments, baseline disease levels may increase after administration of the Tn3 scaffold, indicating effective treatment of the disease or disorder. In some embodiments, baseline disease levels may decrease after administration of the Tn3 scaffold, indicating effective treatment of the disease or disorder.

[0082] In one embodiment, baseline values ​​of the disease are compared with values ​​of the target disease after administration of the Tn3 scaffold. In another embodiment, values ​​of the target disease after administration of the Tn3 scaffold increase compared with baseline values ​​of the disease measured before administration of the Tn3 scaffold. In yet another embodiment, values ​​of the target disease after administration of the Tn3 scaffold decrease compared with baseline values ​​of the disease measured before administration of the Tn3 scaffold. In yet another embodiment, values ​​of the target disease after administration of the Tn3 scaffold increase compared with baseline values ​​of the disease measured before administration of the Tn3 scaffold, indicating an effective treatment. In yet another embodiment, values ​​of the target disease after administration of the Tn3 scaffold decrease compared with baseline values ​​of the disease measured before administration of the Tn3 scaffold, indicating an effective treatment.

[0083] In some embodiments, the evaluation includes measuring the effectiveness of a treatment. Effectiveness may be measured by any of the evaluations in this disclosure. In some embodiments, the effectiveness of preventing, mitigating, or eliminating an autoimmune disease or disorder (e.g., SS) is determined by detecting a change in the European Alliance of Associations for Rheumatology (EULAR) Sjögren's Syndrome Disease Activity Index (ESSDAI) score. In some embodiments, the ESSDAI decreases by approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 points, or more from baseline. In some embodiments, the effectiveness of preventing, mitigating, or eliminating an autoimmune disease or disorder (e.g., SS) is determined by detecting a change in the EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) score. In some embodiments, ESSPRI decreases by approximately 1 point (ESSPRI[1]), 1.5 points (ESSPRI[1.5]), 2 points (ESSPRI[2]), 3 points (ESSPRI[3]), 4 points (ESSPRI[4]), 5 points (ESSPRI[5]), 6 points (ESSPRI[6]), 7 points (ESSPRI[7]), 8 points (ESSPRI[8]), 9 points (ESSPRI[9]), 10 points (ESSPRI

[10] ), or more from baseline. In some embodiments, efficacy in the prevention, reduction, or elimination of autoimmune disease or disorder is determined by evaluating the pharmacokinetic parameters of the Tn3 scaffold used to treat the subject in need, baseline changes in the subject's IgM, rheumatoid factor (RF), sCD40L, CXCL13 serum levels, the presence of anti-drug antibodies (ADAs), and combinations thereof. In some embodiments, the effectiveness of preventing, mitigating, or eliminating autoimmune diseases or disorders is determined by evaluating serum levels of target plasma immunoglobulins (IgM, IgG, and IgA), β-2 microglobulin, high-sensitivity CRP, serum C3, C4, free light chain, cryoglobulin, and anti-SSA (e.g., anti-Ro), anti-SSB (e.g., anti-La), and IgG.In some embodiments, the effectiveness in preventing, mitigating, or eliminating autoimmune diseases or disorders is determined by evaluating rheumatoid factor (RF). RF is an antibody with various isotypes and affinities directed towards the Fc portion of immunoglobulin G. The most common rheumatoid factor is IgM RF, but other immunoglobulin types, including IgG and IgA, can also be found.

[0084] In some embodiments, the effectiveness in preventing, mitigating, or eliminating an autoimmune disease or disorder is determined by evaluating a population of target leukocytes (e.g., B lymphocytes). Target B cells may be present in peripheral blood. In some embodiments, target B cells are present in salivary glands. In some embodiments, the subject of this disclosure is a disturbance of B cell homeostasis, including a decrease in the frequency and / or absolute number of peripheral CD27+ memory B cells, particularly a decrease in the circulating CD27+ IgM+ subpopulation. In some embodiments, the subject of this disclosure includes an increase in the number of naive, non-switched peripheral memory B cells (CD19+, CD27-, IgD+) and a decrease in the number of peripheral memory B cells (CD19+, CD27+, IgD-). In some embodiments, the subject of this disclosure includes an increase in the frequency of migratory B cells and mature naive B cells expressing multireactive antibodies in peripheral blood. The compositions and methods of this specification are effective in resolving the B cell level disturbances described herein. For example, a subject treated with the composition of the Disclosure may show an increase in the frequency and / or absolute number of peripheral CD27 memory B cells after administration of the composition of the Disclosure (e.g., Tn3 scaffold). In some embodiments, a subject administered with the composition of the Disclosure shows an increase in the CD27+IgM+ subpopulation compared to the baseline level of the subject. In some embodiments, a subject of the Disclosure shows a decrease in the number of naive non-switched peripheral memory B cells (CD19+, CD27-, IgD+) and an increase in the number of peripheral memory B cells (CD19+, CD27+, IgD-) compared to baseline.

[0085] In one embodiment, the effectiveness in preventing, mitigating, or eliminating autoimmune diseases or disorders is determined by evaluating the target population of CD27 memory B cells, marginal zone B cells, plasmablasts, plasma cells, and combinations thereof. In another embodiment, the effectiveness in preventing, mitigating, or eliminating autoimmune diseases or disorders is determined by evaluating the target B cell population, for example, Ki67-switched memory B cells (compared to CD27+ / IgD- / CD19+ cells), Ki67+ / CD27+ memory B cells, CD27br / CD38br / IgD- plasmablasts, CD11c high This is determined by evaluating memory B cells or CD11cbr atypical memory cells, or a combination thereof. In one embodiment, efficacy in the prevention, mitigation, or elimination of autoimmune disease or disorder is measured by evaluating the level of TfH cells in question. In one embodiment, the level of TfH cells in question is evaluated by evaluating the positivity rate of CXCR5+ and / or ICOS+ cells. In one embodiment, the level of TfH cells in question is evaluated by evaluating the positivity rate of CXCR5+ and / or ICOS+ cells among identified CD4+ and / or CD3+ cells.

[0086] In some embodiments, the subject of the present disclosure is a disturbance of B cells within an exocrine gland infiltration. For example, the disturbance may include one or more of the following: the presence of germinal center-like structures; an increased frequency of IgG plasma cells compared to a healthy subject; autoreactive B cells and / or plasma cells; increased levels of B cell-related cytokines and chemokines (e.g., IL-6, IL-21, BAFF, APRIL, CXCL12, CXCL13) compared to a healthy subject; the presence of clonal B cell populations and / or autoantibody-producing plasma cells; and any combination thereof. In some embodiments, a subject administered with the composition of the present disclosure shows a decrease in levels of B cell-related cytokines or chemokines selected from the group consisting of IL-6, IL-21, BAFF, APRIL, CXCL12, CXCL13, and combinations thereof. In some embodiments, the decrease is at least about, or up to about 5%, 10%, 20%, 40%, 60%, 80%, 100%, or 150%. In one embodiment, evaluating the level of one or more parameters (e.g., B cells) includes quantifying the number of such parameters in the sample under consideration.

[0087] Evaluation of the choice In this approach, the subjects requiring it are evaluated before initiating treatment.

[0088] Depending on the configuration, the subject requiring it may be either male or female. Depending on the configuration, the subject requiring it is an adult. Depending on the configuration, the subject requiring it may be at least about 18 years old. Depending on the configuration, the subject is between 18 and 100 years old.

[0089] In one instance, the subject requiring treatment has a diagnosis of SS. In another instance, the subject requiring treatment has a diagnosis of SS according to the American College of Rheumatology (ACR) criteria. In another instance, the subject requiring treatment has a diagnosis of SS according to the 2016 American College of Rheumatology (ACR) criteria. In another instance, the subject requiring treatment has an ESSPRI score of 5 or higher. In another instance, the subject requiring treatment has an ESSDAI score of less than 5. In another instance, the subject requiring treatment has an ESSDAI score greater than 5. In yet another instance, the subject requiring treatment is positive for anti-SSA (e.g., anti-Ro) autoantibodies. In yet another instance, the subject requiring treatment is positive for rheumatoid factor (RF). In yet another instance, the subject requiring treatment is positive for both anti-SSA (e.g., anti-Ro) autoantibodies and RF. In yet another instance, the subject requiring treatment has a diagnosis of rheumatoid arthritis (RA). In one embodiment, the subject requiring it has a diagnosis of systemic lupus erythematosus (SLE). In another embodiment, the subject requiring it has SS and coexisting RA. In yet another embodiment, the subject requiring it has SS and coexisting SLE. The evaluation of the choice of this disclosure can be evaluated at approximately -28, -27, -26, -25, -24, -23, -22, -21, -20, -19, -18, -17, -16, -15, -14, -13, -12, -11, -10, -9, -8, -7, -6, -5, -4, -3, -2, -1, and up to approximately 0 days after the start of treatment.

[0090] ESSPRI In some embodiments, the assessment may include the ESSPRI assessment. In some embodiments, the ESSPRI assessment is a self-assessment (Seror et al, 2011). In some embodiments, the ESSPRI assessment uses a numerical analog scale from 0 to 10 points (ranging from 0 points [no symptoms] to 10 points [highest possible severity]) and is a scale for assessing each of three domains: dryness, fatigue, and pain (joint and / or muscle). ESSPRI fatigue, along with pain, has been shown to be a major predictor of reduced quality of life (QoL) in SS patients. In some embodiments, the ESSPRI dryness domain has been shown to correlate with sleep quality, the presence and degree of anxiety and depression (Gandia et al., 2014), and overall QoL (Schmalz et al., 2020). In some embodiments, individuals requiring it have an ESSPRI score of 5 or higher, which may be considered the cutoff point for “insufficient symptomatic state” (Seror et al., 2016).

[0091] The domain weights may be identical, and the average of the scores from the three domains corresponds to the final score. A recall period may be specified for each question, such as "the last two weeks." In one embodiment, the subject has an ESSPRI score of about 1 to about 100 before administration of the composition of the disclosure. In another embodiment, the subject has an ESSPRI score of about 1 to 10, 5 to 15, 10 to 20, 15 to 25, 20 to 30, 25 to 35, 30 to 40, 35 to 45, 40 to 50, 45 to 55, 50 to 60, 55 to 65, 60 to 70, 65 to 75, 70 to 80, 75 to 85, 80 to 90, 85 to 95, 90 to 100, or about 95 to 100 before administration of the composition of the disclosure. In some embodiments, the subject has an ESSPRI score of about 5-6, 5-7, 6-8, 6-9, or about 5-10 before administration of the composition of the Disclosure.

[0092] ESSPRI[1.5] refers to a decrease of at least 1.5 points from the baseline in the ESSPRI score.

[0093] In some embodiments, treatment with the compositions of the Disclosure is effective in reducing the ESSPRI score. In some embodiments, the ESSPRI score is reduced by at least about 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 3, 4, 5, 6, 7, 8, 9, or 10 points. In some embodiments, the ESSPRI score is reduced by up to about 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 3, 4, 5, 6, 7, 8, 9, or 10 points. In some embodiments, the ESSPRI score is reduced by about 0.6 to 5, 0.6 to 10, 1 to 10, 1 to 5, 2 to 10, or 5 to 10 points. In some embodiments, the ESSPRI score is reduced when compared to an equivalent method except in which the subject is not administered a Tn3 scaffold; for example, the reduction may be about 10%, 15%, 20%, 25%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or up to 100% when compared to the ESSPRI score in an equivalent method except in which the subject is not administered a Tn3 scaffold. In some embodiments, the ESSPRI score is reduced when compared to an equivalent method except in which the subject is not administered a Tn3 scaffold; for example, the reduction may be 10%, 15%, 20%, 25%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or up to 100% when compared to baseline.

[0094] In this configuration, the ESSPRI score is measured approximately at -28, -27, -26, -25, -24, -23, -22, -21, -20, -19, -18, -17, -16, -15, -14, -13, -12, -11, -10, -9, -8, -7, -6, -5, -4, -3, -2, -1, 0, 1, 2, 3, 4, 5, 6, 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, and 14 weeks after the start of treatment. Evaluation can be performed over 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, or at least approximately 56 weeks. In this configuration, the ESSPRI score is measured approximately at -28, -27, -26, -25, -24, -23, -22, -21, -20, -19, -18, -17, -16, -15, -14, -13, -12, -11, -10, -9, -8, -7, -6, -5, and -4 days after the start of treatment. The ESSPRI score is evaluated on day 1, -3, -2, -1, day 0, day 1, day 29 (±4 days), day 57 (±7 days), day 85 (±7 days), day 113 (±7 days), day 141 (±7 days), day 169 (±7 days), day 197 (±7 days), day 225 (±7 days), day 253 (±7 days), day 281 (±7 days), day 309 (±7 days), or approximately day 337 (±7 days). As described herein, the ESSPRI score can be evaluated at any time before, during, or after treatment using the Tn3 scaffold of this disclosure.

[0095] Patient-Reported Outcomes Measurement Information System (PROMIS) Short Form 10a Survey In some embodiments, the study includes the PROMIS Fatigue 10a survey, which can assess a range of self-reported symptoms, from mild subjective fatigue to overwhelming and debilitating persistent fatigue. In some embodiments, fatigue is divided into fatigue experience (frequency, duration, and intensity) and its impact on physical, mental, and social activities. In some embodiments, the PROMIS Fatigue 10a survey assesses symptoms over the past week. In some embodiments, the PROMIS Fatigue 10a survey may include evaluating subjects who have been administered the Tn3 scaffold of the Disclosure, or who require it, compared to baseline. In some embodiments, the subjects' self-reported symptoms are improved compared to an equivalent method, except that the subjects are not administered the Tn3 scaffold of the Disclosure.

[0096] In some embodiments, the PROMIS fatigue 10a study on the Tn3 scaffold of this disclosure was conducted approximately -28 days, -27 days, -26 days, -25 days, -24 days, -23 days, -22 days, -21 days, -20 days, -19 days, -18 days, -17 days, -16 days, -15 days, -14 days, -13 days, -12 days, -11 days, -10 days, -9 days, -8 days, -7 days, -6 days, -5 days, -4 days, -3 days, -2 days, -1 day, 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, and 12 weeks after the start of treatment. PROMIS fatigue can be assessed at intervals of 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 weeks, or at least approximately 56 weeks. In this mode, PROMIS fatigue is assessed at any time before, during, or after treatment using the Tn3 scaffold of this disclosure.

[0097] 5-Level EQ-ED (EQ-5D-5L) In some embodiments, the assessment may include an EQ-5D-5L survey. The EQ-5D-5L was provided to capture information covering five aspects of a subject's health: mobility, self-care, daily activities, pain / discomfort, and anxiety / depressive state. The EQ-5D-5L survey has five response levels: no problem (1), mild problem (2), moderate problem (3), major problem (4), and impossible / very problematic. Subjects indicate their health status by selecting the most appropriate response level for each of the five aspects. In some embodiments, the EQ-5D-5L survey investigates symptoms over the past week. In some embodiments, the EQ-5D-5L survey may include evaluating subjects who have been administered the Tn3 scaffold of this disclosure, or who require it, compared to baseline. In some embodiments, the subject's self-reported symptoms are improved compared to an equivalent method, except that the subject has not been administered the Tn3 scaffold of this disclosure.

[0098] In some embodiments, the EQ-5D-5L investigation of the Tn3 scaffold of this disclosure is performed approximately 28 days, 27 days, 26 days, 25 days, 24 days, 23 days, 22 days, 21 days, 20 days, 19 days, 18 days, 17 days, 16 days, 15 days, 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, 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 after the start of treatment. Evaluation can be performed at 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, or at least approximately 56 weeks. In this mode, EQ-5D-5L is evaluated at any time before, during, or after treatment using the Tn3 scaffold of this disclosure.

[0099] 36-item short form survey (SF-36) Depending on the context, the assessment may include the SF-36. The SF-36 (Immediate Retrieval) is a 36-item assessment of overall health that can capture information related to eight health domains: physical functioning, role functioning (physical), bodily pain, overall health perception, vitality, social functioning, role functioning (mental), and mental health. The SF-36 provides scores for each domain as well as a total score based on two psychometrics: the Physical Component Score (PCS) and the Mental Component Score (MCS). The recall period for the immediate version is one week (i.e., "last week"). The SF-36 is a widely used, validated, professional quality of life score that encompasses multiple domains, is sensitive to change (Hemingway et al, 1997). The SF-36 PCS is derived from multiple physical domains and has been validated and shown to respond in related autoimmune diseases (Kosinski et al, 1999; Devilliers et al, 2015). The SF-36 PCS score is based on an assessment of several symptoms similar to those of SS patients, including pain and mental and physical health, and therefore can comprehensively capture improvements in physical activity and mental function (Sjogren's Foundation 2021).

[0100] In some embodiments, the SF-36 study may include evaluating subjects who have been administered a Tn3 scaffold and those who require it, compared to baseline. In some embodiments, the functional health and well-being of the subjects are improved compared to an equivalent method, except that the subjects are not administered a Tn3 scaffold.

[0101] In some embodiments, SF-36 for the Tn3 scaffold of the present disclosure is applied approximately -28 days, -27 days, -26 days, -25 days, -24 days, -23 days, -22 days, -21 days, -20 days, -19 days, -18 days, -17 days, -16 days, -15 days, -14 days, -13 days, -12 days, -11 days, -10 days, -9 days, -8 days, -7 days, -6 days, -5 days, -4 days, -3 days, -2 days, -1 day, 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 after the start of treatment. Evaluation can be performed over 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, or at least approximately 56 weeks. In some embodiments, SF-36 on the Tn3 scaffold of the present disclosure can be evaluated approximately 1 day, 29 days (±4 days), 57 days (±7 days), 85 days (±7 days), 113 days (±7 days), 141 days (±7 days), 169 days (±7 days), 197 days (±7 days), 225 days (±7 days), 253 days (±7 days), 281 days (±7 days), 309 days (±7 days), or approximately 337 days (±7 days) after the start of treatment. In some embodiments, SF-36 can be evaluated at any time before, during, or after treatment using the Tn3 scaffold of the present disclosure.

[0102] Dry area improvement items The assessment in this disclosure may include items for improving dry areas. The dry area improvement items are a series of questions to assess dry areas. In one embodiment, the questions are completed during screening and ask subjects to rank the most important dry areas to improve (1 = most important area to improve, 4 = least important area to improve). Follow-up questions ask subjects to select the areas that have improved the most (if any) at two different time points: week 24 (question 2) and week 48 (question 3). Additional time points are construed herein, including 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, or at least about 56 weeks after the start of treatment. In some embodiments, improvement of the dry area is evaluated at any time before, during, or after treatment using the Tn3 scaffold of this disclosure.

[0103] In some embodiments, treatment with the compositions of the Disclosure is effective in reducing dryness, as determined by a dry site improvement assay. In some embodiments, a subject treated with the compositions of the Disclosure experiences a reduction in dryness in one or more sites where dryness was observed prior to treatment. Dryness can be self-identified or medically confirmed by a specialist. In some embodiments, the reduction in dryness is determined by self-identification and includes at least about, or up to about 1, 2, 3, 4, or 5 self-identified reductions.

[0104] Functional Assessment of Chronic Illness Therapy (FACIT) - Fatigue In some embodiments, the assessment may include the FACIT-Fatigue Assessment. The FACIT-Fatigue is a 13-item questionnaire completed by the subject and used to assess the effects of fatigue. The recall period for the FACIT-Fatigue is 7 days. Responses range from 0 (not at all) to 4 (very much). In some embodiments, the FACIT-Fatigue score for a question is approximately 0, 1, 2, 3, or a maximum of approximately 4. In some embodiments, the FACIT-Fatigue score for a given question is approximately 0 to approximately 4, or approximately 1 to approximately 4. When calculating the overall score, items with negative wording were reversed by subtracting the response from "4". The final score is the sum of the responses and ranges from 0 to 52. In some embodiments, the FACIT-Fatigue Total Score is approximately 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, or up to approximately 52. ​​A higher score indicates a better quality of life. In some embodiments, the FACIT-Fatigue assessment may include evaluating subjects who have been administered a Tn3 scaffold and require it, compared to baseline. In this embodiment, the subject's FACIT fatigue score increases compared to a method that is otherwise equivalent, except that the subject is not given a Tn3 scaffold.

[0105] In some embodiments, treatment with the compositions of the Disclosure is effective in reducing the FACIT fatigue score. In some embodiments, the FACIT fatigue score is reduced by at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, or 52 points. In some embodiments, the FACIT fatigue score is reduced by up to about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, or 52 points. In some embodiments, the FACIT fatigue score is reduced by about 1 to 5, 2 to 10, 5 to 10, 5 to 20, 10 to 20, 25 to 45, or 20 to 30 points.

[0106] In some embodiments, the FACIT fatigue evaluation of the Tn3 scaffold of this disclosure is performed approximately -28 days, -27 days, -26 days, -25 days, -24 days, -23 days, -22 days, -21 days, -20 days, -19 days, -18 days, -17 days, -16 days, -15 days, -14 days, -13 days, -12 days, -11 days, -10 days, -9 days, -8 days, -7 days, -6 days, -5 days, -4 days, -3 days, -2 days, -1 day, 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, 1 week Evaluation can be performed over 3 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, or at least approximately 56 weeks. In some embodiments, FACIT fatigue assessment for the Tn3 scaffold of this disclosure can be performed approximately 1 day, 29 days (±4 days), 57 days (±7 days), 85 days (±7 days), 113 days (±7 days), 141 days (±7 days), 169 days (±7 days), 197 days (±7 days), 225 days (±7 days), 253 days (±7 days), 281 days (±7 days), 309 days (±7 days), or approximately 337 days (±7 days) after the start of treatment. In some embodiments, FACIT fatigue can be assessed at any time before, during, or after treatment using the Tn3 scaffold of this disclosure.

[0107] Visual Analog Scale (VAS) for eye, oral, and / or vaginal dryness Depending on the configuration, the assessment may include a VAS for ocular, oral, and / or vaginal dryness. The VAS Oral / Ocular / Vaginal consists of three items that assess changes in the severity of oral, ocular, and vaginal dryness throughout the study using a continuous 100mm VAS (0mm = best, 100mm = worst). Participants are asked to draw lines perpendicular to the VAS line at points representing the intensity of their symptoms over the past two weeks. The VAS Oral assesses the question, "How dry do you usually feel your mouth is?" (Not dry at all; Desert dry at 100mm). The VAS Ocular assesses the question, "How dry do you usually feel your eyes are?" (Not dry at all; Very dry at 100mm). The VAS Vaginal assesses the symptoms of vaginal dryness (if necessary) (No symptoms at 0mm; Worst symptoms at 100mm). In some embodiments, the VAS oral / ocular / vaginal survey is evaluated on a scale of approximately 0 to 100, 1 to 100, 10 to 100, or 0 to 90. In other embodiments, the VAS oral / ocular / vaginal survey is evaluated on a scale of approximately 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, 5 The scores are assigned on a scale of 1, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 to a maximum of approximately 100. In some embodiments, the VAS oral / ocular / vaginal assessment may include evaluating subjects who have received and require the Tn3 scaffold compared to baseline. In some embodiments, the subjects' VAS oral / ocular / vaginal scores are reduced compared to subjects who have not received the Tn3 scaffold in a otherwise equivalent method. In some embodiments, baseline (VAS) oral / ocular / vaginal scores are reduced by approximately 3%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or up to approximately 100% compared to the subject's VAS oral / ocular / vaginal score before administration of the Tn3 scaffold.

[0108] In some embodiments, treatment with the compositions of the present disclosure is effective in reducing the VAS oral / ocular / vaginal score. In some embodiments, the VAS oral / ocular / vaginal score is reduced by at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, or 55 points. In some embodiments, the VAS oral / ocular / vaginal score is reduced by up to about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or up to about 100 points. In each case, the VAS oral / ocular / vaginal score decreases by approximately 1-5, 2-10, 5-10, 5-20, 10-20, 20-30, 30-40, 40-50, 50-60, 60-70, 70-80, 80-90, or approximately 90-100 points.

[0109] In some embodiments, the VAS oral / ocular / vaginal evaluation of the Tn3 scaffold of this disclosure is performed approximately -28 days, -27 days, -26 days, -25 days, -24 days, -23 days, -22 days, -21 days, -20 days, -19 days, -18 days, -17 days, -16 days, -15 days, -14 days, -13 days, -12 days, -11 days, -10 days, -9 days, -8 days, -7 days, -6 days, -5 days, -4 days, -3 days, -2 days, -1 day, 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, 1 week Evaluation can be performed over 3 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, or at least approximately 56 weeks. In some embodiments, VAS oral / ocular / vaginal evaluations for the Tn3 scaffold of the present disclosure can be evaluated approximately 1 day, 29 days (±4 days), 57 days (±7 days), 85 days (±7 days), 113 days (±7 days), 141 days (±7 days), 169 days (±7 days), 197 days (±7 days), 225 days (±7 days), 253 days (±7 days), 281 days (±7 days), 309 days (±7 days), or approximately 337 days (±7 days) after the start of treatment. In some embodiments, VAS oral / ocular / vaginal dryness can be evaluated at any time before, during, or after treatment using the Tn3 scaffold of the present disclosure.

[0110] Patient's overall impression of severity (PGIS) In some embodiments, the assessment may include a PGIS survey. The PGIS is a single-item questionnaire designed to capture a subject's perception of the severity of their worst SS symptoms (e.g., pain, fatigue, dryness) over the past seven days on a 5-point categorical response scale (1=none, 2=mild, 3=moderate, 4=severe, 5=very severe). In some embodiments, the PGIS score may include evaluating subjects who have received and require the Tn3 scaffold compared to baseline. In some embodiments, a subject's PGIS score will decrease compared to subjects who do not receive the Tn3 scaffold in a otherwise equivalent manner. The decrease may range from approximately 1, 2, 3, or 4 points, or up to approximately 5 points. In some embodiments, subjects will receive three symptom-specific PGIS items (e.g., pain, fatigue, dryness) and a PGIS for overall symptoms. The PGIS for overall symptoms may include additional symptoms other than pain, fatigue, and / or dryness.

[0111] In some embodiments, treatment with the compositions of the Disclosure is effective in reducing the PGIS score. In some embodiments, the PGIS score is reduced by at least about 1, 2, 3, 4, or 5 points. In some embodiments, the PGIS score is reduced by up to about 1, 2, 3, 4, or 5 points. In some embodiments, the PGIS fatigue score is reduced by about 1 to 5, 2 to 5, 1 to 4, or 3 to 5 points.

[0112] In this pattern, the PGIS survey was conducted approximately 28 days, 27 days, 26 days, 25 days, 24 days, 23 days, 22 days, 21 days, 20 days, 19 days, 18 days, 17 days, 16 days, 15 days, 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, 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, and 14 weeks after the start of treatment. The evaluation can be conducted over a period of 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 weeks, or at least approximately 56 weeks. In this manner, the PGIS survey was conducted approximately 28 days, 27 days, 26 days, 25 days, 24 days, 23 days, 22 days, 21 days, 20 days, 19 days, 18 days, 17 days, 16 days, 15 days, 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, - It can be evaluated on day 3, -2 days, -1 day, day 0, day 1, day 29 (±4 days), day 57 (±7 days), day 85 (±7 days), day 113 (±7 days), day 141 (±7 days), day 169 (±7 days), day 197 (±7 days), day 225 (±7 days), day 253 (±7 days), day 281 (±7 days), day 309 (±7 days), or approximately day 337 (±7 days). In some embodiments, PGIS can be evaluated at any time before, during, or after treatment using the Tn3 scaffold of this disclosure.

[0113] Overall impression of changes observed by patients (PGIC) In some embodiments, the assessment may include a PGIC survey. The PGIC is a single-item questionnaire designed to capture a subject's perception of changes in SS symptoms (pain, fatigue, dryness, etc.) since the start of treatment. Changes in severity are captured using a 5-point scale (1=much ​​better, 2=somewhat better, 3=no change, 4=somewhat worse, or 5=much ​​worse). In some embodiments, the PGIC score may include evaluating subjects who have received and require the Tn3 scaffold compared to baseline. In some embodiments, a subject's PGIC score will decrease compared to subjects who do not receive the Tn3 scaffold in a otherwise equivalent manner. The decrease may range from approximately 1, 2, 3, or 4 points, or up to approximately 5 points. In some embodiments, subjects will receive three symptom-specific PGIC items (pain, fatigue, dryness) and a PGIC for overall symptoms.

[0114] In some embodiments, treatment with the compositions of the present disclosure is effective in reducing the PGIC score. In some embodiments, the PGIC score is reduced by at least about 1, 2, 3, 4, or 5 points. In some embodiments, the PGIC score is reduced by up to about 1, 2, 3, 4, or 5 points. In some embodiments, the PGIC fatigue score is reduced by about 1 to 5, 2 to 5, 1 to 4, or 3 to 5 points.

[0115] In this scenario, the PGIC survey was conducted approximately 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0, 1, 2, 3, 4, 5, 6, 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, and 14 weeks after the start of treatment. The evaluation can be conducted over a period of 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 weeks, or at least approximately 56 weeks. In some embodiments, the PGIC assessment can be evaluated approximately 15 days (-3 to +1 day), 29 days (±4 days), 57 days (±7 days), 85 days (±7 days), 113 days (±7 days), 141 days (±7 days), 169 days (±7 days), 197 days (±7 days), 225 days (±7 days), 253 days (±7 days), 281 days (±7 days), 309 days (±7 days), or approximately 337 days (±7 days) after the start of treatment. In some embodiments, the PGIC can be evaluated at any time before, during, or after treatment using the Tn3 scaffold of this disclosure.

[0116] Saliva flow rate without stimulation The evaluations described herein include unstimulated salivary flow assays. Unstimulated salivary flow assessment may be performed before stimulated salivary flow collection, but other periods are also intended. Participants receiving standard treatment for xerostomia at screening may discontinue the use of pilocarpine and / or cevimeline for at least approximately 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 hours prior to saliva collection, and / or discontinue the use of artificial saliva for at least approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours prior to saliva collection. Participants should refrain from eating or drinking for approximately 30, 60, 90, 120, or 175 minutes prior to saliva collection.

[0117] For non-stimulated saliva flow rate collection, subjects should refrain from swallowing or speaking during the collection period, except for one swallow immediately before the start of the collection time. In each case, the total duration of the procedure is approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 minutes, during which time the subject accumulates saliva in the oral cavity for 60 seconds before releasing it into a pre-measured container. This is repeated approximately 1, 2, 3, 4, 5, 6, 7, or 8 times in total during the test. The weight of the container must be recorded before the start and at the end of the procedure.

[0118] In some embodiments, a subject treated with the composition of the present disclosure experiences an increase in salivary flow as determined by an unstimulated salivary flow assay. In some embodiments, the subject exhibits an increase in salivary flow, and its container includes an increased weight compared to the weight of the container at baseline. In some embodiments, the weight increases by at least about, or up to about 5%, 10%, 20%, 30%, 40%, 50%, 75%, 100%, 120%, 150%, or up to about 200%.

[0119] Female Sexual Function Index (FSFI) In some cases, the assessment may include the FSFI survey. The FSFI survey is designed to define female sexual function in clinical and non-clinical samples by establishing clear assessment items and outcomes for the study of female sexual function (Rosen et al, 2000). The FSFI is a 19-item self-reported, validated questionnaire assessment function covering the past four weeks in the following domains: desire, arousal, lubrication, orgasm, satisfaction, and pain. Each question is scored on a scale from 0 (no sexual activity) or 1 (maximum impairment) to 5 (no sexual impairment). The final score is calculated as follows: To normalize each domain based on the item number, the sum of each domain score is first multiplied by the domain coefficient ratio (0.6 for desire; 0.3 for arousal; 0.3 for lubrication; 0.4 for orgasm; 0.4 for satisfaction; 0.4 for pain), and then the domain scores are added together to obtain the final score. In some embodiments, the FSFI survey is scored on a scale of approximately 0 to 36, 1 to 36, 2 to 36, 0 to 30, 1 to 30, or 2 to 30. In some embodiments, the FSFI survey is scored on a scale of approximately 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, or up to approximately 36. This questionnaire can be answered by female subjects. In some embodiments, the FSFI score may include evaluating subjects who have been administered a Tn3 scaffold and those who require it, compared to baseline. In this embodiment, the FSFI score of the subject increases compared to a method that is otherwise equivalent except that the Tn3 scaffold is not administered to the subject.

[0120] In some embodiments, treatment with the compositions of the present disclosure is effective in increasing the FSFI survey score. In some embodiments, the FSFI score increases by at least 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, and 35 up to approximately 36 points. In one embodiment, the PGIC score increases by a maximum of approximately 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, or 35, up to a maximum of approximately 36 points. In another embodiment, the FSFI score increases by approximately 1-36, 1-30, 1-20, 1-10, 5-10, 15-25, 20-36, or 25-36 points.

[0121] In this configuration, the FSFI survey was conducted approximately 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0, 1, 2, 3, 4, 5, 6, 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, and 14 weeks after the start of treatment. The evaluation can be conducted over a period of 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 weeks, or at least approximately 56 weeks. In some embodiments, the FSFI assessment can be evaluated approximately 1 day, 29 days (±4 days), 57 days (±7 days), 85 days (±7 days), 113 days (±7 days), 141 days (±7 days), 169 days (±7 days), 197 days (±7 days), 225 days (±7 days), 253 days (±7 days), 281 days (±7 days), 309 days (±7 days), or approximately 337 days (±7 days) after the start of treatment. In some embodiments, the FSFI can be evaluated at any time before, during, or after treatment using the Tn3 scaffold of this disclosure.

[0122] ESSDAI The assessments in this disclosure may include ESSDAI assessments. In some embodiments, the ESSDAI assessment includes a physical examination. ESSDAI is a systemic disease activity index that includes definitions of disease activity by organ (Seror et al, 2010). ESSDAI grades disease activity across 12 domains (skin, respiratory, renal, joints, muscle, peripheral nervous system, central nervous system, hematology, glands, constitution, lymphadenopathy, and biology). A physician's overall assessment of activity was used as the gold standard, and the weights for each domain were determined using a multiple regression model.

[0123] Each domain is assigned a weight from 1 (biological domain) to 6 (muscle domain), and each domain has 3 or 4 activity levels ranging from 0 (no activity) to 3 or 4 (high activity).

[0124] The theoretical range of the ESSDAI score is 0 to 123 points, and the final score is calculated as follows: 1) Final score = sum of all 12 domain scores; 2) Domain score = activity level × domain weight.

[0125] Low activity is defined as ESSDAI < 5, moderate activity as 5 ≤ ​​ESSDAI ≤ 13, and severe activity as ESSDAI ≥ 14 (Seror et al, 2016). ESSDAI is a validated and widely used measure of systemic disease activity in SS and therefore may be a suitable primary endpoint (Seror et al, 2015). Reliable scoring has shown good construct validity, and the systematic score has shown good sensitivity to changes in subjects with improved disease activity. ESSDAI[3] may refer to a 3-point decrease from baseline in the ESSDAI score of subjects who have previously received or require the Tn3 scaffold of the Disclosure. ESSDAI[4] may refer to a 4-point decrease from baseline in the ESSDAI score of subjects who have previously received or require the Tn3 scaffold of the Disclosure. ESSDAI[5] may refer to a 5-point decrease from baseline in the ESSDAI score of subjects who have previously received or require the Tn3 scaffold of the Disclosure. ESSDAI[6] may refer to a 6-point reduction from baseline in the ESSDAI score of a subject who has previously been administered the Tn3 scaffold of the present disclosure and is in need of it.

[0126] In each embodiment, the ESSDAI score is approximately 0-123, approximately 1-123, approximately 2-123, approximately 10-120, or approximately 5-120. In this configuration, the ESSDAI score is approximately 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, 60, 61, 62, 63, 64, 65, The scores are 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, 121, 122, or up to approximately 123. In some embodiments, the subject has an ESSDAI score of approximately 5–7, 5–10, 5–13, or 10–13 prior to treatment with the composition of the Disclosure.

[0127] In some embodiments, treatment with the compositions of the present disclosure is effective in reducing the ESSDAI score. In some embodiments, the ESSDAI score is reduced by at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, or 120 points. In some embodiments, the ESSDAI score is reduced by up to about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, or 120 points. In each case, the ESSDAI score decreases by approximately 1-5, 2-10, 5-10, 5-20, 10-20, 20-30, 30-40, 40-50, 50-60, 60-70, 70-80, 80-90, 90-100, 100-110, or 110-120 points.

[0128] In some embodiments, treatment with the compositions of the present disclosure is effective in reducing the ESSDAI score. In some embodiments, the ESSDAI score is reduced by at least about, or up to about 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% It decreases by %, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%. In some aspects, the ESSDAI score decreases by approximately 1-10%, 1-20%, 5-20%, 10-30%, 20-30%, 25-30%, 25-35%, 30-40%, 35-55%, 40-60%, 50-70%, 60-80%, 70-90%, 80-100%, or approximately 90-100%.

[0129] In this configuration, the ESSDAI evaluation was performed approximately 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0, 1, 2, 3, 4, 5, 6, 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, and 14 weeks after the start of treatment. Evaluation can be performed over 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, or at least approximately 56 weeks. In this configuration, ESSDAI evaluation was performed approximately 28 days, 27 days, 26 days, 25 days, 24 days, 23 days, 22 days, 21 days, 20 days, 19 days, 18 days, 17 days, 16 days, 15 days, 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, and 4 days after the start of treatment. It can be evaluated on day -3, day -2, day -1, day 0, day 1, day 29 (±4 days), day 57 (±7 days), day 85 (±7 days), day 113 (±7 days), day 141 (±7 days), day 169 (±7 days), day 197 (±7 days), day 225 (±7 days), day 253 (±7 days), day 281 (±7 days), day 309 (±7 days), or approximately day 337 (±7 days). In some embodiments, ESSDAI is evaluated at any time before, during, or after treatment using the Tn3 scaffold of this disclosure.

[0130] Clinical EULAR Sjogren's Syndrome Disease Activity Index (ClinESSDAI) In some aspects, the assessment may include the ClinESSDAI assessment. ClinESSDAI is a validated SS disease activity index based on ESSDAI, but excluding the biological domain and assigning different weights to each domain. ClinESSDAI was developed to reduce the possible correlation between B cell biomarkers measured by the ESSDAI biological domain and clinical activity measures (Seror et al, 2016). The theoretical range of ClinESSDAI is 0 to 135. Similar to ESSDAI, low activity is defined as <5, moderate activity as 5 ≤ ​​ClinESSDAI ≤ 13, and high activity as ≥ 14 (Seror et al, 2016). ClinESSDAI is validated and has shown good correlation with ESSDAI, and is considered a useful tool for detecting changes unrelated to the biological effects of drugs (Seror et al, 2016; Dumusc et al, 2018; Quartuccio et al, 2017).

[0131] In this embodiment, the ClinESSDAI score is approximately 0-135, approximately 1-135, approximately 2-135, approximately 10-130, or approximately 5-130. In this configuration, the ClinESSDAI score is approximately 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, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 7 3, 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, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, or up to approximately 135. In one embodiment, the ClinESSDAI score may include evaluating subjects who have been administered a Tn3 scaffold and those who require it, compared to baseline. In one embodiment, the subjects' ClinESSDAI score is reduced compared to a method that is otherwise equivalent, except that the subjects are not administered a Tn3 scaffold.

[0132] In some embodiments, treatment with the compositions of the present disclosure is effective in reducing the ClinESSDAI score. In some embodiments, the ClinESSDAI score is reduced to at least about 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, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 7 The score decreases by 3, 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, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, or 135 points. In this configuration, the ClinESSDAI score is approximately 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, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73 The points decrease by 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, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, or 135 points.In each case, the ClinESSDAI score decreases by approximately 1-5, 2-10, 5-10, 5-20, 10-20, 20-30, 30-40, 40-50, 50-60, 60-70, 70-80, 80-90, 90-100, 100-110, 110-120, 120-130, or 125-135 points.

[0133] In this configuration, ClinESSDAI evaluation is performed approximately 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0, 1, 2, 3, 4, 5, 6, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, and 13 weeks after the start of treatment. It can be used for 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, or at least about 56 weeks. In this configuration, ClinESSDAI is administered approximately on -28, -27, -26, -25, -24, -23, -22, -21, -20, -19, -18, -17, -16, -15, -14, -13, -12, -11, -10, -9, -8, -7, -6, -5, and -4 days after the start of treatment. It can be performed on day 1, day 3, day 2, day 1, day 0, day 1, day 29 (±4 days), day 57 (±7 days), day 85 (±7 days), day 113 (±7 days), day 141 (±7 days), day 169 (±7 days), day 197 (±7 days), day 225 (±7 days), day 253 (±7 days), day 281 (±7 days), day 309 (±7 days), or approximately day 337 (±7 days). In some embodiments, ClinESSDAI is evaluated at any time before, during, or after treatment using the Tn3 scaffold of this disclosure.

[0134] 28-joint evaluation (TJC and SJC) In some embodiments, the assessment may include a 28-joint assessment. In some embodiments, the 28-joint assessment may include the number of tender joints (TJC). In some embodiments, the 28-joint assessment may include the number of swollen joints (SJC). In some embodiments, the 28-joint assessment may include both TJC and SJC. The 28-joint assessment evaluates the following joints for tenderness and swelling: the left and right shoulder joints, elbow joint, wrist joint, metacarpophalangeal (MCP) 1, MCP 2, MCP 3, MCP 4, MCP 5, proximal interphalangeal (PIP) 1, PIP 2, PIP 3, PIP 4, PIP 5 joints of the upper limb, and the left and right knee joints of the lower limb. The presence of synovitis may be determined for each of the 28 joints. At the start of the 28-joint assessment (before the assessment of tenderness and swelling), subjects may be asked whether they have ever experienced pain in any of the 28 joints, or whether they are currently experiencing pain. In some embodiments, the 28-joint evaluation score ranges from approximately 0 to approximately 28. In some embodiments, the 28-joint evaluation score ranges from approximately 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, and 27 up to approximately 28. In some embodiments, the 28-joint evaluation may include evaluating subjects who have been administered a Tn3 scaffold and require it, compared to baseline. In some embodiments, the 28-joint evaluation score of a subject is reduced compared to a subject in an otherwise equivalent method, except that the subject is not administered a Tn3 scaffold.

[0135] In some embodiments, treatment with the compositions of the present disclosure is effective in reducing the 28-joint evaluation score. In some embodiments, the 28-joint evaluation score decreases by at least about 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, or 28 points. In some embodiments, the 28-joint evaluation score decreases by a maximum of about 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, or 28 points. In each case, the 28-joint evaluation score decreases by approximately 1-28, 1-5, 2-10, 5-10, 1-20, 5-20, 10-15, 10-20, 15-25, or 20-28 points.

[0136] In this configuration, the evaluation of the 28 joints was performed approximately at -28, -27, -26, -25, -24, -23, -22, -21, -20, -19, -18, -17, -16, -15, -14, -13, -12, -11, -10, -9, -8, -7, -6, -5, -4, -3, -2, -1, 0, 1, 2, 3, 4, 5, 6, 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, and 14 weeks after the start of treatment. It can be used for 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, or at least about 56 weeks. In some embodiments, the 28-joint evaluation can be performed approximately 1 day, 29 days (±4 days), 57 days (±7 days), 85 days (±7 days), 113 days (±7 days), 141 days (±7 days), 169 days (±7 days), 197 days (±7 days), 225 days (±7 days), 253 days (±7 days), 281 days (±7 days), 309 days (±7 days), or approximately 337 days (±7 days) after the start of treatment. In some embodiments, the number of 28 joints can be evaluated at any time before, during, or after treatment using the Tn3 scaffold of this disclosure.

[0137] Saliva flow rate during stimulation In some embodiments, the evaluation may include measurement of stimulated salivary flow rate. In some embodiments, total stimulated salivary flow rate is measured to objectively evaluate changes in salivary gland function during treatment with the Tn3 scaffold of this disclosure. Subjects receiving standard treatment for dry mouth at the time of screening may discontinue the use of pilocarpine or cevimeline for at least 12 hours and the use of artificial saliva for at least 3 hours prior to saliva collection. Subjects may be prohibited from eating or drinking for at least 90 minutes prior to saliva collection. Saliva may be collected simultaneously at all visits.

[0138] In measuring the total salivary flow rate during stimulation, a rolled-up piece of Parafilm approximately 5 x 5 cm in size is given to the subject to chew at a rate of approximately 60 chews per minute, similar to chewing gum. The subject must sit with their back straight, eyes open, and head slightly tilted forward as they begin chewing the Parafilm. After 60 seconds, while still holding the Parafilm in their mouth, they must spit all the collected saliva into an additional (unweighed) Falcon tube. This initial collection allows the subject to become familiar with the procedure. Three rounds of saliva collection are continued, with each round involving 20 seconds of chewing followed by collection into a pre-weighed Falcon tube. These rounds are performed consecutively, but timing is stopped during saliva collection and immediately resumed once saliva is in the pre-weighed Falcon tube, ensuring a total stimulation time of 60 seconds. If the subject is unable to complete 60 seconds of collection due to their inability, the total collection time must be recorded. The total amount of stimulated saliva collected is evaluated by subtracting the weight of the tube before collection from the final weight. In this embodiment, the change from baseline in stimulated salivary flow rate is determined.

[0139] In this configuration, salivary flow rate measurement at stimulation is performed approximately 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0, 1, 2, 3, 4, 5, 6, 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, and 14 weeks after the start of treatment. In some embodiments, stimulated salivary flow measurement can be evaluated at approximately 1 day, 85 days (±7 days), 169 days (±7 days), 253 days (±7 days), or approximately 337 days (±7 days) after the start of treatment. In some embodiments, salivary flow rate is evaluated at any time before, during, or after treatment using the Tn3 scaffold of this disclosure.

[0140] European Quality of Life 5-Dimension 5-Level Version (EQ-5D-5L) The assessment described in this disclosure may be EQ-5D-5L. The 5-domain, 5-level version of EQ (EQ-5D-5L) is a common PRO item for measuring health status. It consists of a descriptive system and an EQ visual analog scale (EQ VAS). The EQ-5D-5L descriptive system consists of five aspects of health: mobility, self-care, daily living activities, pain / discomfort, and anxiety / depression. For each dimension, the patient selects one of five severity levels: no problem, mild problem, moderate problem, major problem, and impossible / extremely problematic. The EQ VAS records the patient's self-reported health on a vertical visual analog scale from 0 to 100, with each assessment item labeled as the worst possible health condition and the best possible health condition.

[0141] In some embodiments, after treatment with the composition of the Disclosure, subjects report an increase in health level as determined by EQ-5D-5L. In some embodiments, health increases by at least approximately, or up to approximately 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90 percentage points. In some embodiments, the EQ-5D-5L test is evaluated at any point before, during, or after treatment using the Tn3 scaffold of the Disclosure.

[0142] Schirmer Test The evaluation in this disclosure may be the Schirmer test. In this embodiment, the Schirmer test is performed without local anesthesia. The Schirmer test measures lacrimal gland function. It measures tear flow using a calibrated test strip, which is a non-toxic filter paper. One end of the test strip is placed inside the lower eyelid. Both eyes must be measured simultaneously. After placement, the participant is asked to gently close their eyes, and after 5 minutes, the test strip is removed from the eyelid, and the degree to which each test strip is wet is recorded.

[0143] In some embodiments, an increase in wettability is detected after treatment with the composition of the Disclosure, compared to the level of wettability before treatment or to a baseline level. In some embodiments, the wettability increases by at least about, or up to about 5%, 10%, 20%, 30%, 40%, or 50% compared to the baseline. In some embodiments, the Schirmer test is evaluated at any point before, during, or after treatment using the Tn3 scaffold of the Disclosure.

[0144] Physician's overall impression of severity (MDGIS) In some embodiments, the assessment may include an MDGIS survey. The MDGIS represents an assessment of the severity of SS disease and is a 5-point category response scale (1=none, 2=mild, 3=moderate, 4=severe, 5=very severe). In some embodiments, the MDGIS score may range from approximately 0 to approximately 5, or from approximately 1 to approximately 5. In some embodiments, the MDGIS score may be approximately 1, 2, 3, 4, or up to approximately 5. In some embodiments, the MDGIS score may be approximately 0, 1, 2, 3, or up to approximately 4. In some embodiments, the MDGIS score may include an assessment of subjects who have received and require a Tn3 scaffold compared to baseline. In some embodiments, the MDGIS score of a subject is reduced compared to a subject who does not receive a Tn3 scaffold, except that the subject does not receive a Tn3 scaffold, in a otherwise equivalent manner.

[0145] In some embodiments, treatment with the compositions of the Disclosure is effective in reducing the MDGIS score. In some embodiments, the MDGIS score is reduced by at least about 1, 2, 3, 4, or 5 points. In some embodiments, the MDGIS score is reduced by up to about 1, 2, 3, 4, or 5 points. In some embodiments, the MDGIS fatigue score is reduced by about 1 to 5, 2 to 5, 1 to 4, or 3 to 5 points.

[0146] In this configuration, the MDGIS survey was conducted approximately 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0, 1, 2, 3, 4, 5, 6, 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, and 14 weeks after the start of treatment. It can be used for 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, or at least about 56 weeks. In some embodiments, the MDGIS assessment can be performed approximately 1 day, 29 days (±4 days), 57 days (±7 days), 85 days (±7 days), 113 days (±7 days), 141 days (±7 days), 169 days (±7 days), 197 days (±7 days), 225 days (±7 days), 253 days (±7 days), 281 days (±7 days), 309 days (±7 days), or approximately 337 days (±7 days) after the start of treatment. In some embodiments, the MDGIS can be evaluated at any time before, during, or after treatment using the Tn3 scaffold of this disclosure.

[0147] Electrocardiogram (ECG) Depending on the configuration, the evaluation may include an ECG. A single 12-lead electrocardiogram may be performed with the subject in a supine position. ECG measurement may be delayed by at least 10 minutes if performed after venotomy. Each ECG may include ventricular heart rate and intervals (PR, QRS, QT, RR).

[0148] Depending on the circumstances, ECG evaluations may be performed approximately 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0, 1, 2, 3, 4, 5, 6, 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, and 14 weeks after the start of treatment. In this configuration, ECG evaluation can be performed at 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 weeks, or at least approximately 56 weeks. In this configuration, ECG evaluation can be performed at approximately 1 day, 169 days (±7 days), or approximately 337 days (±7 days) after the start of treatment. In some embodiments, the ECG is evaluated at any time before, during, or after treatment using the Tn3 scaffold of this disclosure.

[0149] Clinical safety laboratory testing Depending on the context, the evaluation may include clinical safety laboratory testing. Blood and urine samples may be collected for laboratory safety testing using clinically acceptable methods and equipment. Abnormal laboratory findings related to underlying conditions may not be considered clinically significant.

[0150] During participation in the study, or within the protocol follow-up period after the last dose of the Tn3 scaffold, any clinical laboratory tests with values ​​considered clinically significant may be repeated until the values ​​return to normal or baseline, or until they are no longer clinically significant. Additional tests may be performed at any point during the study.

[0151] In some embodiments, clinical safety laboratory tests may include hematological, clinical chemistry, urinalysis (urine analysis), pregnancy tests, and other screening tests. Exemplary hematological parameters include, but are not limited to, platelet count, red blood cell (RBC) count, RBC index (mean corpuscular volume [MCV] and mean corpuscular hemoglobin [MCH]), white blood cell (WBC) count and percentage (e.g., neutrophils, lymphocytes, monocytes, eosinophils, and / or basophils), hemoglobin, hematocrit, and immunoglobulins (IgG, IgM, and IgA). Exemplary clinical chemistry parameters include, but are not limited to, blood urea nitrogen (BUN), potassium, creatinine, sodium, calcium, chloride, bicarbonate, phosphorus, glucose, aspartate aminotransferase (AST) / serum glutamate oxaloacetate transaminase (SGOT), alanine aminotransferase (ALT) / serum glutamate pyruvate transaminase (SPGT), alkaline phosphatase, bilirubin, gamma glutamyltransferase, albumin, total protein, creatinine kinase, calculated estimated glomerular filtration rate (eGFR), uric acid, total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides. Exemplary urinalysis includes, but is not limited to, specific gravity, pH, glucose, protein, blood, ketones, microscopic examination (e.g., crystals, casts, WBC, RBC), and protein:creatinine ratio. Exemplary pregnancy test parameters include, but are not limited to, serum beta-human chorionic gonadotropin (β-hCG) pregnancy tests and urine pregnancy tests. Other screening test parameters include, but are not limited to, follicle-stimulating hormone, serological tests (e.g., hepatitis B virus [HBV], HCV, human immunodeficiency virus type 1 [HIV-1], HIV-2), rapid tests for severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), tuberculosis (TB) tests (e.g., interferon-gamma release assay (IGRA)), and coagulation panels (e.g., prothrombin time, international normalized ratio (INR), partial thromboplastin time (PTT)).In some embodiments, clinical safety laboratory testing may include evaluating subjects who have been administered the Tn3 scaffold and those requiring it, compared to baseline. In some embodiments, clinical safety laboratory testing of subjects is reduced compared to an otherwise equivalent method, except that subjects are not administered the Tn3 scaffold. In some embodiments, clinical safety laboratory testing of subjects is increased compared to an otherwise equivalent method, except that subjects are not administered the Tn3 scaffold.

[0152] Depending on the circumstances, clinical safety laboratory tests may be conducted approximately 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0, 1, 2, 3, 4, 5, 6, 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, and 14 weeks after the start of treatment. Evaluation can be performed over 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, or at least approximately 56 weeks. In this configuration, clinical safety laboratory tests are conducted approximately 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, and 1 Evaluation can be performed on day 1, day 0, day 1, day 15 (-3 to +1 day), day 29 (±4 days), day 57 (±7 days), day 85 (±7 days), day 113 (±7 days), day 141 (±7 days), day 169 (±7 days), day 197 (±7 days), day 225 (±7 days), day 253 (±7 days), day 281 (±7 days), day 309 (±7 days), day 337 (±7 days), or approximately day 393 (±7 days). In some embodiments, clinical examinations are performed at any time before, during, or after treatment using the Tn3 scaffold of this disclosure.

[0153] immunogenicity In some embodiments, the evaluation may include determining the level of immunogenicity if the anti-Tn3 scaffold of the Disclosure is immunogenic. Immunogenicity includes determining the presence of anti-drug antibodies (ADAs) against the Tn3 scaffold. The presence of ADAs can be determined using plasma samples from subjects administered with the Tn3 scaffold. Plasma samples of ADAs against the Tn3 scaffold of the Disclosure may be collected prior to IP administration upon hospital visit and evaluated using validated immunoassays. In some embodiments, ADAs are not detectable after administration of the Tn3 scaffold. In some embodiments, the ADA level is reduced compared to an equivalent method except that the subject is not subjected to a Tn3 scaffold, for example, the reduction may be about 10%, 15%, 20%, 25%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or up to 100% compared to the ADA level in an equivalent method except that the subject is not subjected to a Tn3 scaffold.

[0154] Antibodies against the Tn3 scaffold of this disclosure can be evaluated in plasma samples collected from all subjects. In addition, plasma samples should be collected at the time of the last visit from subjects who discontinued Tn3 scaffold administration or who were excluded from the study.

[0155] Plasma samples can be screened for antibody binding to the Tn3 scaffold of this disclosure, and the titers of confirmed positive samples can be reported. Other analyses may be performed to verify the stability of antibodies to the Tn3 scaffold of this disclosure and / or to further characterize the immunogenicity of the Tn3 scaffold of this disclosure.

[0156] The detection and characterization of antibodies against the Tn3 scaffold of this disclosure may be performed using validated assay methods. The ability of the antibodies to neutralize the activity of the research intervention can be further characterized and / or evaluated. To enable further analysis of the immune response to the Tn3 scaffold of this disclosure, samples may be stored for at least 15 years after the last hospital visit of the last subject in the study. The number and percentage of subjects who developed ADA, as well as ADA titers, can be compiled per hospital visit and per treatment group.

[0157] In this configuration, immunogenicity assessment is performed approximately 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0, 1, 2, 3, 4, 5, 6, 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, and 14 weeks after the start of treatment. It can be used for 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, or at least about 56 weeks. In some embodiments, immunogenicity assessment can be performed approximately 1 day, 15 days (-3 to +1 day), 29 days (±4 days), 57 days (±7 days), 85 days (±7 days), 113 days (±7 days), 141 days (±7 days), 169 days (±7 days), 197 days (±7 days), 225 days (±7 days), 253 days (±7 days), 281 days (±7 days), 309 days (±7 days), 337 days (±7 days), or approximately 393 days (±7 days) after the start of treatment. In some embodiments, immunogenicity or lack thereof can be assessed at any time before, during, or after treatment with the Tn3 scaffold of this disclosure.

[0158] Ultrasound image In some embodiments, the evaluation may include ultrasound images. In some embodiments, the ultrasound images may be images of one or more joints. In some embodiments, the ultrasound images may be images of one or more salivary glands.

[0159] Salivary gland ultrasound image Ultrasonography of the parotid and submandibular glands may be performed. Subjects with significant glandular disease may be selected for participation. The above glands can be evaluated longitudinally and transversely with the subject in a supine position. After image capture and quality assessment, the images are scored and the data are totaled. The echogenicity of each gland on the B-mode image can be scored on a 5-point scale (0-4) as described above (Gazeau et al, 2018). The evaluation criteria are as follows: Grade 0: Normal homogeneous gland, Grade 1: Small hypoechoic area with a hyperechoic band, Grade 2: Multiple hypoechoic areas less than 2 mm, Grade 3: Multiple hypoechoic areas between 2 and 6 mm, Grade 4: Multiple hypoechoic areas greater than 6 mm.

[0160] At each point in time being evaluated, a total of four scores may be collected: one for each parotid gland and one for each submandibular gland. The salivary gland ultrasound score for each evaluation is the sum of these grades.

[0161] Joint ultrasound imaging Ultrasound evaluation of peripheral small joints may be performed. Subjects with potential joint disorders may be selected. A modified German 7-joint US scoring system may be used (Backhaus et al, 2009). After image capture and quality assessment, images are transmitted, scored, and data is totaled.

[0162] Grayscale (GS) ultrasound may be performed on the following clinically significant hand and ankle joints: wrist (dorsal, palmar, ulnar plane), second and third MCPs (MCP2 and MCP3, palmar plane), PIPs (PIP2 and PIP3, palmar plane), and second and fifth metatarsophalangeal phalanges (MTP2 and MTP5, dorsal). In GS, synovitis can be semi-quantitatively scored for each joint and plane on a scale of 0 to 3: Grade 0 = no synovitis, Grade 1 = mild synovitis (small hypoechoic / anechoic line beneath the joint capsule), Grade 2 = moderate synovitis (joint capsule elevated parallel to the joint), Grade 3 = severe synovitis (maximal joint capsule expansion). The total GS score for synovitis is the sum of each joint or plane, with scores ranging from 0 to 27. In some cases, the total GS score for synovitis is approximately 0 to approximately 27, or approximately 1 to approximately 27. In this embodiment, the total GS score for synovitis is approximately 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, or up to approximately 27.

[0163] Powered Doppler ultrasound is performed on the following clinically significant hand and ankle joints: wrist (posterior, palmar, and ulnar plane), second and third MCPs (MCP2 and MCP3, palmar and posterior), PIPs (PIP2 and PIP3, palmar and posterior), and second and fifth metatarsophalangeal phalanges (MTP2 and MTP5, posterior only). Synovitis is assessed using powered Doppler on a scale of 0 to 3 as follows: Grade 0 = no IA color signal; Grade 1 = mild synovitis (maximum 3 color signals or 2 single signals and 1 confluent signal in the IA space); Grade 2 = moderate synovitis (greater than Grade 1, but color occupies less than 50% of the IA space); and Grade 3 = severe synovitis (more than 50% color in the IA space). The total GS score for synovitis is the sum of each joint or plane, with a score of 0 to 39. In one embodiment, the total GS score is approximately 0 to approximately 39, or approximately 1 to approximately 39. In another embodiment, the total GS score is scored as approximately 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, or up to approximately 39.

[0164] The total synovitis score is the sum of the GS score and the power Doppler score, and ranges from 0 to 66. In some embodiments, the total synovitis score is approximately 0 to approximately 66, or approximately 1 to approximately 66. In this configuration, the total synovitis score ranges from approximately 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, 60, 61, 62, 63, 64, 65 to a maximum of approximately 66.

[0165] In some embodiments, the synovitis score of the present disclosure may include evaluating subjects who have been administered a Tn3 scaffold and those who require it, compared to baseline. In some embodiments, the synovitis score of the present disclosure is reduced compared to a method otherwise equivalent, except that subjects are not administered a Tn3 scaffold.

[0166] In some embodiments, treatment with the compositions of the present disclosure is effective in reducing the synovitis score. In some embodiments, the synovitis score is reduced by at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, or 66 points. In some embodiments, the synovitis score is reduced by up to about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, or 66 points. In some embodiments, the synovitis score is reduced by 1-5, 2-10, 5-10, 5-20, 10-20, 20-30, 30-40, 40-50, 50-60, or 55-66 points.

[0167] In this configuration, ultrasound image evaluation is performed approximately 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0, 1, 2, 3, 4, 5, 6, 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, and 14 weeks after the start of treatment. In this approach, ultrasound imaging can be performed at approximately 1 week, 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, or at least approximately 56 weeks. In this approach, ultrasound imaging can be performed at approximately 1 day, 197 days (±7 days), or approximately 337 days (±7 days) after the start of treatment. In some embodiments, imaging is completed at any point before, during, or after treatment using the Tn3 scaffold of this disclosure.

[0168] Transcriptomics In some embodiments, the assessment may include transcriptomics assessment. In some embodiments, RNA testing is performed. In some embodiments, RNA testing is performed to measure the expression levels of genes related to disease activity, specific cell types (e.g., plasma cell gene signatures), T follicular helper gene signatures, and signaling (e.g., CD40L / CD40 pathways).

[0169] In one embodiment, blood RNA is used to measure the expression levels of genes associated with disease activity, specific cell types (e.g., plasma cell gene signatures), T follicular helper gene signatures, and signaling pathways, including the CD40L / CD40 pathway. In another embodiment, blood samples are collected using the PAXgene Blood RNA system for blood collection, transport, and storage, as well as for 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.

[0170] In some embodiments, the expression levels of disease activity-related genes using RNA analysis can be reduced by at least approximately 10%, 15%, 20%, 25%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or up to 100% compared to a comparable method except that the Tn3 scaffold is not administered to the same subjects.

[0171] In this configuration, transcriptomics evaluation is performed approximately 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0, 1, 2, 3, 4, 5, 6, 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 after the start of treatment. Evaluation can be performed over 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 weeks, or at least approximately 56 weeks. In some embodiments, transcriptomics evaluation can be performed approximately 1 day, 15 days (-3 to +1 day), 29 days (±4 days), 85 days (±7 days), 169 days (±7 days), or approximately 337 days (±7 days) after the start of treatment. In some embodiments, transcriptomics is performed at any point before, during, or after treatment using the Tn3 scaffold of this disclosure.

[0172] Genetic analysis In some embodiments, the assessments provided herein may include genetic assessments by DNA or RNA testing. In some embodiments, DNA testing is performed. In some embodiments, RNA testing is performed. In some embodiments, DNA testing may be performed to measure pharmacological genomic (single nucleotide polymorphism [SNP]) profiling of CD40 and other genes involved in the CD40 / CD40L axis. In some embodiments, DNA is collected for epigenetic analysis, such as DNA methylation of immune-related genes. In some embodiments, the investigation includes measuring the sequences of genes associated with disease activity by whole blood DNA analysis.

[0173] In some embodiments, whole blood can be collected and used to evaluate gene sequences before, during, and after treatment with the compositions provided herein. Gene sequences found to be regulated by the treatment can be analyzed in whole blood using quantitative methods. Samples can be used to examine gene sequences and their changes over time, which can be evaluated by NGS, Sanger sequencing, or PCR.

[0174] Depending on the configuration, gene analysis evaluation may be performed approximately 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0, 1, 2, 3, 4, 5, 6, 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, and 14 weeks after the start of treatment. The assessment can be performed in between, 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, or at least approximately 56 weeks. In this mode, the gene assessment is performed at any point before, during, or after treatment using the Tn3 scaffold of this disclosure.

[0175] Pharmacokinetics In some embodiments, the method provided herein may include determining the concentration of a Tn3 scaffold after administration in a subject requiring it. In some embodiments, the method includes a pharmacokinetic evaluation. In some embodiments, the sample is a blood sample, 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, and the plasma may be used to determine the maximum observed concentration (C) of the Tn3 scaffold. max ), area under the concentration-time curve (AUC), clearance (CL), and terminal elimination half-life (t 1 / 2 The concentration of anti-ILT7 antibody or its antigen-binding fragment is investigated by measuring the following:

[0176] The samples will be used to evaluate the pharmacokinetics (PK) of the Tn3 scaffold of this disclosure. Samples collected for the analysis of plasma concentrations of the Tn3 scaffold of this disclosure may also be used to evaluate aspects of safety and efficacy during or after the study.

[0177] In this configuration, pharmacokinetic evaluation is performed approximately 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0, 1, 2, 3, 4, 5, 6, 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, and 14 weeks after the start of treatment. In some cases, immunogenicity assessment can be performed at approximately 1 day, 85 days (±7 days), 169 days (±7 days), 253 days (±7 days), 337 days (±7 days), or approximately 393 days (±7 days) after the start of treatment. In some embodiments, pharmacokinetics are evaluated at any point before, during, or after treatment using the Tn3 scaffold of this disclosure.

[0178] Pharmacodynamics In some embodiments, the evaluation may include pharmacodynamic (PD) evaluation. In some embodiments, the investigation may be carried out over a period of time. Whole blood, plasma, urine, saliva, and serum samples may be collected to evaluate the PD of the Tn3 scaffold of this disclosure. In some embodiments, the samples may be evaluated by validated assays, including but not limited to flow cytometry.

[0179] Samples may be collected and the levels of biomarkers may be evaluated, including but not limited to immunoglobulins (IgM, IgG, and IgA), sCD40L, CXCL13, β-2 microglobulin, high-sensitivity CRP, serum C3, C4, free light chain, peripheral blood mononuclear cells (PBMCs), anti-SSA, anti-SSB, cryoglobulins, and serum and urine immunofixation. In some embodiments, immunoglobulins are plasma immunoglobulins. In some embodiments, biomarkers are cellular biomarkers, such as those expressed by a subset of B cells or T cells. Exemplary B and T cell subsets include, but are not limited to, plasmablasts (e.g., CD27br / CD38br / IgD- subsets of CD19+ cells), memory B progenitor cells (e.g., CD11cbr subsets of CD19+ cells), T follicular helper (Tfh) cells (e.g., CXCR5+ / ICOS+ subsets of CD3+ / CD4+ cells), post-switch memory B cells (e.g., Ki67+ subsets of CD27br / IgD- / CD19+ cells), and / or the proliferation of all T cells (e.g., Ki67+ subsets of CD3+ cells). In some embodiments, the assessment involves determining one or more levels of CD19, CD20, CD27, CD38, and CD138.

[0180] In some embodiments, the level of a biomarker increases in subjects requiring it after administration of the Tn3 scaffold of the Disclosure. In some embodiments, the level of a biomarker decreases in subjects requiring it after administration of the Tn3 scaffold of the Disclosure. In some embodiments, the decrease in the biomarker can be detected compared to an otherwise equivalent method, except that the subjects are not administered the Tn3 scaffold. In some embodiments, the removal of the biomarker can be detected compared to an otherwise equivalent method, and the subjects are not administered the Tn3 scaffold compared to an equivalent method, except that the administration of the Tn3 scaffold is absent. In some embodiments, the reduction in biomarkers is at least approximately, or up to approximately: 1x, 2x, 3x, 4x, 5x, 10x, 15x, 20x, 25x, 30x, 35x, 40x, 45x, 50x, 55x, 60x, 65x, 70x, 75x, 80x, 85x, 90x, 95x, 100x, 105x, 1 This includes 10x, 115x, 120x, 125x, 130x, 135x, 140x, 145x, 150x, 155x, 160x, 165x, 170x, 175x, 180x, 185x, 19x, 195x, 200x, 210x, 220x, 230x, 240x, 250x, 260x, 270x, 280x, 290x, or up to approximately 300x. In some embodiments, the therapeutic efficacy of the Tn3 scaffold on a biomarker can be investigated over time using a suitable immunoassay. In some embodiments, the effect of the Tn3 scaffold is evaluated over time using a qualified immunoassay.

[0181] This disclosure provides a Tn3 scaffold-containing composition that alters the CD40 / CD40L pathway in a subject. This disclosure provides a Tn3 scaffold-containing composition that effectively reduces or depletes soluble CD40L (sCD40L) in a subject. Since the Tn3 scaffold binds to a biomarker and depletes it, the reduction or removal of the biomarker can be used as a measure of therapeutic effect. In some embodiments, sCD40L is a measure of target binding. In some embodiments, suitable assays for investigating sCD40L levels may include flow cytometry, histology, immunohistochemistry, hematological analysis, microscopy, PCR, ELISA, and combinations thereof.

[0182] This disclosure provides Tn3 scaffold-containing compositions that effectively reduce, remove, or inhibit major leukocyte populations (e.g., B lymphocytes), anti-SSA(RO), anti-SSB(La), antinuclear antibodies, rheumatoid factor (RF), and combinations thereof. Suitable assays for evaluating leukocyte populations, anti-SSA(RO), anti-SSB(La), antinuclear antibodies, and rheumatoid factor (RF) include flow cytometry, histology, immunohistochemistry, hematological analysis, microscopy, PCR, ELISA, and combinations thereof.

[0183] In some embodiments, the Tn3 scaffold of the present disclosure can achieve a reduction of at least about 10%, 15%, 20%, 25%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or up to about 100% of CD40L compared to an equivalent method except that the subject is not administered the Tn3 scaffold. The reduction in major leukocyte counts can be prolonged. In some embodiments, depletion of the CD40L major leukocyte population, anti-SSA(Ro), anti-SSB(La), antinuclear antibodies, and rheumatoid factor (RF), or combinations thereof, can last for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 15 days, at least 20 days, at least 25 days, or at least 30 days. In some embodiments, depletion of CD40L, major leukocyte populations, anti-SSA(Ro), anti-SSB(La), antinuclear antibodies, and rheumatoid factor (RF), or combinations thereof, may persist for at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, at least six weeks, at least seven weeks, at least eight weeks, at least nine weeks, or at least ten weeks. In some embodiments, depletion of CD40L, major leukocyte populations, anti-SSA(RO), anti-SSB(La), antinuclear antibodies, and rheumatoid factor (RF), or combinations thereof, may persist for at least one month, at least two months, at least three months, at least four months, at least five months, at least six months, at least seven months, at least eight months, at least nine months, at least ten months, at least eleven months, or at least twelve months.

[0184] In this configuration, pharmacodynamic evaluations are performed approximately 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0, 1, 2, 3, 4, 5, 6, 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, and 14 weeks after the start of treatment. The evaluation can be performed over 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 weeks, or at least approximately 56 weeks. In this configuration, pharmacodynamic evaluations are performed approximately on -28, -27, -26, -25, -24, -23, -22, -21, -20, -19, -18, -17, -16, -15, -14, -13, -12, -11, -10, -9, -8, -7, -6, -5, -4, -3, and -2 days after the start of treatment. , can be evaluated on day -1, day 0, day 1, day 15 (-3 to +1), day 29 (±4), day 57 (±7), day 85 (±7), day 113 (±7), day 141 (±7), day 169 (±7), day 197 (±7), day 225 (±7), day 253 (±7), day 281 (±7), day 309 (±7), or approximately day 337 (±7). In some embodiments, pharmacodynamics are evaluated at any point before, during, or after treatment using the Tn3 scaffold of this disclosure.

[0185] Inflammatory markers In some embodiments, the assessment includes determining the levels of inflammatory markers. Exemplary inflammatory markers include, but are not limited to, immunoglobulins (IgM, IgG, IgA), β-2 microglobulin, C-reactive protein (CRP), CXCL13, serum C3, C4 and free light chains, cryoglobulins, and serum-urine immunofixation and combinations thereof. In some embodiments, whole blood, plasma, serum, and urine are collected to assess inflammatory markers. In some embodiments, the change compared to baseline is determined. In some embodiments, the change from baseline in the levels of inflammatory markers (immunoglobulins, β-2 microglobulin, CRP, CXCL13, serum C3, C4, and free light chains) is determined. In some embodiments, suitable assays for assessing inflammation levels include ELISA, high-sensitivity (hs)-CRP tests, CRP tests, Luminex, and combinations thereof. In some embodiments, administration of the Tn3 scaffold of the Disclosure includes reducing the level of an inflammatory biomarker in a subject by at least approximately or as much as approximately 20%, 30%, 40%, 45%, 50%, 60%, 75%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or up to 100% compared to the autoantibody level in a subject otherwise equivalent to the subject without administration of the Tn3 scaffold. In some embodiments, administration of the Tn3 scaffold of the Disclosure is effective in reducing the level of an inflammatory biomarker in a subject by at least approximately or as much as approximately 3% to 5%, 5% to 10%, 10% to 20%, or 5% to 25% compared to baseline levels before administration.

[0186] In this configuration, the evaluation of inflammatory markers is performed approximately 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0, 1, 2, 3, 4, 5, 6, 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, and 1 week after the start of treatment. It can be used for 4 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, or at least about 56 weeks. In some embodiments, inflammatory markers are evaluated approximately 1 day, 15 days (-3 to +1 day), 29 days (±4 days), 57 days (±7 days), 85 days (±7 days), 113 days (±7 days), 141 days (±7 days), 169 days (±7 days), 197 days (±7 days), 225 days (±7 days), 253 days (±7 days), 281 days (±7 days), 309 days (±7 days), or approximately 337 days (±7 days) after the start of treatment. In some embodiments, markers are evaluated at any point before, during, or after treatment using the Tn3 scaffold of this disclosure.

[0187] American College of Rheumatology / European Alliance of Associations for Rheumatology (ACR / EULAR) In some cases, the assessment includes the ACR / EULAR classification. In some cases, the assessment includes the 2016 ACR / EULAR classification. In some cases, the assessment includes the 2016 ACR / EULAR classification for primary Sjögren's syndrome. In some cases, the classification includes scores based on the following items: focal lymphocytic sialadenitis and lesion score of the oral salivary glands, anti-SSA(Ro) positivity, ocular staining score and / or van Bijsterveld score, Schirmer score, and a measure of unstimulated total salivary flow. In some cases, the focal lymphocytic sialadenitis and lesion score of the oral salivary glands is 1 or higher. In some cases, the ocular staining score is 5 or higher for at least one eye. In some cases, the van Bijsterveld score is 4 or higher. In some cases, the Schirmer score for at least one eye is 5 mm / 5 min or less. In some cases, the unstimulated total salivary flow is 0.1 mL / min or less. In this configuration, one or more scores from the ACR / EULAR classification are weighted. In this configuration, focal lymphocytic sialadenitis and lesions of the oral salivary glands are weighted 3. In this configuration, eye staining scores are weighted 3. In this configuration, the van Bijsterveld score is weighted 1. In this configuration, the Schirmer score is weighted 1. In this configuration, total unstimulated salivary flow is weighted 1. In this configuration, subjects requiring this are those with a total weighted score of 4 or higher. In this configuration, subjects requiring this may be asked at least one of the following questions: 1) Have you had persistent, unpleasant dry eye on a daily basis for more than three months? 2) Do you repeatedly experience a feeling of sand or gravel in your eyes? 3) Do you use artificial tears more than three times a day? 4) Do you experience thirst on a daily basis for more than three months? 5) Do you frequently drink liquids to make it easier to swallow dry food?

[0188] In this configuration, ACR / EULAR evaluations were performed approximately 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0, 1, 2, 3, 4, 5, 6, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, and 13 weeks after the start of treatment. It can be used for 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 weeks, or at least approximately 56 weeks. In some embodiments, the ACR / EULAR evaluation can be performed approximately on day -28, day -27, day -26, day -25, day -24, day -23, day -22, day -21, day -20, day -19, day -18, day -17, day -16, day -15, day -14, day -13, day -12, day -11, day -10, day -9, day -8, day -7, day -6, day -5, day -4, day -3, day -2, day -1, or approximately day 0 after the start of treatment. In some embodiments, the ACR / EULAR can be evaluated at any time before, during, or after treatment using the Tn3 scaffold of this disclosure.

[0189] Ocular Surface Disease Index (OSDI) In some embodiments, the assessment includes an OSDI assessment. In some embodiments, the OSDI assessment includes an OSDI questionnaire. The OSDI is effective in differentiating between normal, mild to moderate, and severe dry eye disease. In some embodiments, the OSDI assessment evaluates three subsets: visual-related function, ocular symptoms, environmental triggers, or a combination thereof.

[0190] In one embodiment, a score is generated by OSDI assessment. In one embodiment, the OSDI score is in the range of approximately 0 to approximately 100. 0 to 12 represents normal, 13 to 22 represents mild dry eye disease, 23 to 32 represents moderate dry eye disease, and 33 to 100 represents severe dry eye disease. In one embodiment, the OSDI score is in the range of approximately 0 to approximately 12, approximately 13 to approximately 22, approximately 23 to approximately 32, approximately 33 to approximately 100, approximately 20 to approximately 50, approximately 60 to approximately 100, approximately 40 to approximately 70, approximately 10 to approximately 30, or 5 to approximately 25.

[0191] In some embodiments, the OSDI score decreases in subjects requiring the Tn3 scaffold after administration of the Tn3 scaffold of the Disclosure. In some embodiments, the OSDI score may decrease compared to other equivalent methods, and subjects in other equivalent methods will not receive the Tn3 scaffold, except that the Tn3 scaffold administration is absent compared to the equivalent methods. In some embodiments, the OSDI score decreases by at least about, or up to about 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, The points decrease by 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 points.

[0192] In this scenario, OSDI evaluation is performed approximately 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0, 1, 2, 3, 4, 5, 6, 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, and 14 weeks after the start of treatment. In this mode, OSDI can be evaluated at any time before, during, or after treatment using the Tn3 scaffold of this disclosure.

[0193] Sjögren's response assessment tool (STAR) In some embodiments, the assessment may include the Sjögren's Response Assessment Tool (STAR). STAR is a composite responder index developed by the NECESSITY Consortium, supported by an international panel of pSS experts, scientists, methodologists, and patients, to assess therapeutic effects based on improvement in disease activity (Seror et al, 2022). STAR encompasses biomarkers in five domains: systemic activity, symptoms, lacrimal gland function, salivary gland function, and autoimmune activity. Each domain is weighted differently. In some embodiments, the STAR domains may include other assessments as described herein.

[0194] In some embodiments, the STAR survey is scored on a scale of approximately 1 to approximately 9. In some embodiments, the STAR survey is scored on a scale of approximately 1, 2, 3, 4, 5, 6, 7, 8, or approximately 9. In some embodiments, the STAR survey is scored on a scale of approximately 1 to approximately 3, approximately 1 to approximately 5, approximately 5 to approximately 9, approximately 6 to approximately 9, approximately 7 to approximately 9, or approximately 4 to approximately 9. In some embodiments, the STAR survey is scored on a scale of approximately 5 or higher. In some embodiments, the STAR survey may include evaluating subjects that have been administered the Tn3 scaffold of the Disclosure and those that require it, compared to a baseline. In some embodiments, the STAR score of a subject increases compared to a method that is otherwise equivalent, except that the subject is not administered the Tn3 scaffold of the Disclosure. In some embodiments, subjects that have been administered the Tn3 scaffold of the Disclosure and those that require it show an increase in their STAR score compared to a baseline. In some embodiments, the STAR score increases by 1, 2, 3, 4, 5, 6, 7, or 8 points.

[0195] In this manner, the STAR study was conducted approximately 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0, 1, 2, 3, 4, 5, 6, 1 week, 2 weeks, 3 weeks, 4 weeks, and 5 weeks after the start of treatment. The evaluation can be performed at 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, or at least approximately 56 weeks. In some embodiments, the STAR assessment can be evaluated approximately 1 day, 15 days (~3~1 days), 29 days ± 4 days, 57 days ± 7 days, 85 days ± 7 days, 113 days ± 7 days, 141 days ± 7 days, 169 days ± 7 days, 197 days ± 7 days, 225 days ± 7 days, 253 days ± 7 days, 281 days ± 7 days, 309 days ± 7 days, 337 days ± 7 days, or 421 days ± 7 days after the start of treatment. In some embodiments, the STAR assessment can be evaluated at any time before, during, or after treatment using the Tn3 scaffold of this disclosure.

[0196] Sjögren's Syndrome Patient Reporting Index Evaluation Log (DASPRI) In some embodiments, the assessment may include the Sjögren's Syndrome Patient Reported Index Assessment Diary (DASPRI). In some embodiments, the DASPRI is also known as the SS Symptom Diary (SSSD). The DASPRI is a questionnaire completed by participants to measure the severity of core symptoms in SS patients. It may have a 24-hour recall period. Participants assess the severity of each "worst-case" symptom using a numerical rating scale (0 [no symptoms] to 10 [highest imaginable severity]) in domains including dryness, fatigue (e.g., fatigue), and pain (joint or muscle pain in the arms and / or limbs). The dryness domain assesses the severity of site-specific dryness (mouth, eyes, skin, and genitals). In addition, participants are asked to rank their most bothersome dry areas. In some embodiments, the DASPRI-based assessment items are defined as the average daily score over a 7-day period.

[0197] In one embodiment, the DASPRI domain is scored on a scale of approximately 0 to 10. In another embodiment, the DASPRI questions are scored on a scale of approximately 0 to 2, 1 to 5, 2 to 7, 0 to 9, 1 to 10, 8 to 10, or 6 to 10. In yet another embodiment, the DASPRI composite score is approximately 0 to 100. In this embodiment, the DASPRI composite score is approximately 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, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or approximately 100. In this embodiment, the DASPRI composite score is approximately 0 to 10, 5 to 15, 20 to 20, 15 to 25, 20 to 30, 20 to 50, 30 to 60, 40 to 70, 50 to 80, 60 to 90, or 70 to 100.

[0198] In some embodiments, DASPRI may include evaluating subjects that have been administered the Tn3 scaffold of the Disclosure and require it compared to a baseline. In some embodiments, the DASPRI score of a subject is reduced compared to a method otherwise equivalent, except that the subject is not administered the Tn3 scaffold of the Disclosure. In some embodiments, subjects that have been administered the Tn3 scaffold of the Disclosure and require it have a reduced DASPRI compared to a baseline. In some embodiments, the DASPRI score is reduced by approximately 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 95, 96, 97, 98, 99, or 100.

[0199] In this context, the DASPRI study was conducted approximately 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0, 1, 2, 3, 4, 5, 6, 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, and 14 weeks after the start of treatment. Evaluation can be performed over 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, or at least approximately 56 weeks. In some embodiments, the DASPRI survey can be evaluated approximately -28, -27, -26, -25, -24, -23, -22, -21, -20, -19, -18, -17, -16, -15, -14, -13, -12, -11, -10, -9, -8, -7, -6, -5, -4, -3, -2, -1, 0 days, and approximately once, twice, three, four, five, six, or seven times per week after the start of treatment. In some embodiments, the DASPRI survey can be evaluated at any time before, during, or after treatment using the Tn3 scaffold of this disclosure.

[0200] Pharmaceutical composition In some embodiments, a pharmaceutical composition is provided. The pharmaceutical composition may include the Tn3 scaffold of the Disclosure. In some embodiments, the pharmaceutical composition is part of a therapeutic regimen comprising the Tn3 scaffold of the Disclosure and one or more additional therapeutic agents provided herein.

[0201] For subcutaneous routes, the needle is inserted into the adipose tissue just beneath the skin. After injection, the drug then moves into the microvessels (capillaries) and is carried away by the bloodstream. Alternatively, the drug reaches the bloodstream via the lymphatic vessels. Intramuscular routes are preferred over subcutaneous routes when a larger volume of drug product is required. Since muscles are located beneath the skin and adipose tissue, longer needles are used. Drugs are usually injected into the muscles 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 thinner the blood supply, the longer it takes for the drug to be absorbed. For intravenous routes, the needle is inserted directly into a vein. The drug-containing solution may be administered as 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 to a tube (catheter) inserted into a vein, usually in the forearm.

[0202] In some embodiments, the pharmaceutical compositions provided herein are administered by infusion. Infusions can be performed over a period of time. For example, an infusion may be the administration of a drug over a period of time ranging from about 5 minutes to about 10 hours. Infusions can be performed over periods of time ranging from 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 ensures that the precise dose is delivered rapidly and well-controlled throughout the body. Infusions are also used for irritating solutions that, if administered by subcutaneous or intramuscular injection, may cause pain and tissue damage. When administered intravenously, the drug is immediately delivered into the bloodstream and tends to take effect more rapidly than when administered by any other route. Consequently, healthcare professionals more closely monitor patients receiving intravenous injections for signs that the drug is working or causing undesirable side effects. Furthermore, the effects of drugs administered via this route tend to be short-lived. Therefore, some drugs must be administered by continuous infusion to maintain a consistent effect. In some cases, infusion reactions may occur, including headache, nausea, drowsiness, dyspnea, fever, muscle pain, rash, or other symptoms. Potential risks associated with administration of the Tn3 scaffold are infection, redness, swelling, pain, and hardening of the injection site. Before each intravenous infusion, the subject may receive prophylaxis with IV methylprednisolone, oral diphenhydramine, and oral acetaminophen, or one or more equivalent drugs, to reduce the risk or severity of potential reactions.

[0203] In some embodiments, a therapeutic regime comprising a pharmaceutical composition may be dose-configured according to the subject's body weight. For subjects classified as obese (BMI > 35), it may be necessary to use their actual body weight. In other embodiments, the dosage may be calculated using body surface area.

[0204] In some embodiments, the pharmaceutical composition may be administered by any route, either alone or in combination with a pharmaceutically acceptable carrier or excipient, and such administration may be carried out in both single and multiple doses. More specifically, the pharmaceutical composition may be in the form of tablets, capsules, lozenges, troches, hand candies, powders, sprays, aqueous suspensions, injectable solutions, elixirs, syrups, etc., and may be combined with a variety of pharmaceutically acceptable inert carriers. Such carriers include solid diluents or fillers, sterile aqueous media, and various non-toxic organic solvents. Furthermore, the pharmaceutical formulation may be suitably sweetened and / or flavored with a variety of agents of a type commonly used for such purposes. Exemplary carriers and excipients may include dextrose, monobasic sodium phosphate, dibasic sodium phosphate, monobasic / dibasic sodium phosphate, sodium chloride (NaCl), sucrose, lactose, cellulose, xylitol, sorbitol, maltitol, gelatin, PEG, PVP, histidine / histidine hydrochloride, trehalose dihydrate, polysorbate 80, poloxamer 188 (pH 7.4), and any combination thereof. In some embodiments, the pharmaceutical composition used in the method of the present invention comprises monobasic / dibasic sodium phosphate, sucrose, and poloxamer 188 (pH 7.4).

[0205] Numbered Embodiments Embodiment Set 1 1. A method for treating Sjögren's syndrome (SS) in patients requiring treatment for SS, comprising administering a Tn3 scaffold, the Tn3 scaffold comprising a CD40L-specific monomer subunit, the CD40L-specific monomer subunit comprising seven β-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 comprising SEQ ID NO: 11, the BC loop comprising SEQ ID NO: 12, the CD loop comprising SEQ ID NO: 13, the DE loop comprising SEQ ID NO: 14, the EF loop comprising SEQ ID NO: 15, and the FG loop comprising SEQ ID NO: 16. The Tn3 scaffold containing the CD40L-specific monomer subunit is administered in doses of approximately 1500 mg to approximately 3000 mg, and the target patients are those of the European Alliance of Associations for Rheumatism (EUR). A method for determining moderate to severe systemic disease activity as determined by the SS Disease Activity Index (ESSDAI) of Rheumatology (EULAR). 2. The method according to Embodiment 1, wherein the subject has an ESSDAI score of 5-7, 5-10, 5-13, or 10-13 before administration of the Tn3 scaffold. 3. The method according to Embodiment 2, wherein the subject has an ESSDAI score of 5 or higher. 4. The method according to any one of Embodiments 1 to 3, wherein administration of a Tn3 scaffold is effective in reducing the EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) score after administration. 5. The method according to Embodiment 4, wherein the ESSPRI score is reduced by at least about 2, 3, 4, or 5 points. 6. A method for treating Sjögren's syndrome (SS) in a subject requiring treatment for SS, comprising administering a Tn3 scaffold, the Tn3 scaffold comprising a CD40L-specific monomer subunit, the CD40L-specific monomer subunit comprising seven β-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 comprising SEQ ID NO: 11, the BC loop comprising SEQ ID NO: 12, the CD loop comprising SEQ ID NO: 13, the DE loop comprising SEQ ID NO: 14, the EF loop comprising SEQ ID NO: 15, and the FG loop comprising SEQ ID NO: 16, the Tn3 scaffold containing the CD40L-specific monomer subunit is administered in a dose of approximately 1500 mg to approximately 3000 mg, the subject having an ESSPRI score of 5 or higher, and the method. 7. The method according to Embodiment 6, wherein the subject has an ESSDAI score of less than 5 before administration of the Tn3 scaffold. 8. The method according to any one of Embodiments 6 to 7, wherein the subject has residual salivary gland function defined by a total stimulated salivary flow rate of more than 0.1 mL / min. 9. A method according to any one of Embodiments 1 to 8, wherein the subject is positive for anti-Ro autoantibody, rheumatoid factor, or both anti-Ro autoantibody and rheumatoid factor. 10. The method according to any one of Embodiments 1 to 9, wherein the dose is 1500 mg. 11. The method according to any one of Embodiments 1 to 9, wherein the dose is 3000 mg. 12. The method according to any one of Embodiments 2 to 11, wherein the change from baseline in ESSDAI is determined after administration of a Tn3 scaffold. 13. The method according to Embodiment 12, wherein the change from baseline is determined every four weeks up to 48 weeks after administration of the Tn3 scaffold. 14. The method according to any one of Embodiments 2 to 13, wherein administration of the Tn3 scaffold is effective in reducing the subject's ESSDAI score after administration. 15. The method according to Embodiment 14, wherein the ESSDAI score is reduced by at least about 1, 2, 3, 4, or 5 points. 16. The method according to Embodiment 14, wherein the ESSDAI score is reduced by at least about 5 points. 17. The method according to any one of Embodiments 1 to 16, wherein administration of the Tn3 scaffold is effective in reducing the baseline score of tenderness and swollen joints in the subject after administration. 18. The method according to any one of Embodiments 1 to 16, wherein administration of the Tn3 scaffold is effective in reducing the baseline score of the subject on the Short Form 36 (SF-36) Health Survey after administration. 19. A method according to any one of Embodiments 1 to 18, wherein administration of a Tn3 scaffold is effective in reducing baseline levels of inflammatory markers after administration, the markers being selected from the group consisting of immunoglobulins, β-2 microglobulins, C-reactive proteins, and combinations thereof. 20. A method according to any one of Embodiments 1 to 19, wherein administration of a Tn3 scaffold is effective in reducing baseline levels of a biomarker, the biomarker being selected from the group consisting of plasma-soluble CD40L, B cells, serum CXCL13, rheumatoid factor autoantibodies, anti-Ro autoantibodies, and combinations thereof. 21. A method according to any one of Embodiments 1 to 20, wherein administration of a Tn3 scaffold is effective in reducing the baseline level of disease symptoms, the disease symptoms being selected from the group consisting of fatigue, dry mouth, dry eyes, dry vagina, pain, and combinations thereof. 22. The method according to any one of Embodiments 1 to 21, wherein the expression level of SS-related genes in the target blood sample decreases by 48 weeks after administration. 23. A method according to any one of Embodiments 1 to 22, wherein the level of B cells selected from the group consisting of CD27+ memory B cells, marginal zone B cells, plasmablasts, plasma cells, and combinations thereof decreases in the blood sample of the subject by 48 weeks after administration. 24. The method according to any one of Embodiments 1 to 23, wherein Tn3 scaffold is administered as a loading dose and then as a maintenance dose. 25. The method according to Embodiment 24, wherein the loading dose includes administering the Tn3 scaffold once every two weeks for at least three doses. 26. The method according to Embodiment 24, wherein the maintenance dose comprises administering the Tn3 scaffold once every four weeks for at least four doses. 27. The method according to Embodiment 24, wherein the time between the final loading dose and the initial maintenance dose is approximately 4 weeks. 28. The method according to any one of Embodiments 1 to 27, wherein the Tn3 scaffold is administered once every four weeks, once every two months, once every three months, once every four months, or once every six months. 29. The method according to any one of Embodiments 1 to 28, wherein the Tn3 scaffold is administered over at least four doses. 30. The method according to any one of Embodiments 1 to 28, wherein the Tn3 scaffold is administered over at least 5 doses. 31. The method according to any one of Embodiments 1 to 30, wherein the Tn3 scaffold is administered by intravenous administration, subcutaneous administration, oral administration, intramuscular administration, subarachnoid administration, sublingual administration, rectal administration, vaginal administration, cutaneous administration, systemic administration, local administration, transdermal administration, or inhalation. 32. The method according to Embodiment 31, wherein the Tn3 scaffold is administered intravenously. 33. The method according to any one of embodiments 1 to 32, wherein the Tn3 scaffold comprises two CD40L-specific monomer subunits linked in tandem. 34. The method according to Embodiment 33, wherein each of the two CD40L-specific monomer subunits comprises Sequence ID No. 3. 35. The method according to any one of embodiments 33 to 34, wherein the CD40L-specific monomer subunits are linked by a linker. 36. The method according to any one of Embodiments 1 to 35, wherein at least 33 CD40L-specific monomer subunits are directly fused to or conjugated to polyethylene glycol (PEG). 37. The method according to any one of embodiments 33 to 35, wherein at least one CD40L-specific monomer subunit is fused to or conjugated to polyethylene glycol (PEG) via a linker. 38. The method according to Embodiment 37, wherein the linker comprises a peptide linker. 39. The method according to Embodiment 37, wherein the linker includes SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, or SEQ ID NO: 10. 40. The method according to any one of embodiments 33 to 39, wherein at least one CD40L-specific monomer subunit is fused to or conjugated to albumin. 41. The method according to Embodiment 40, wherein the albumin is human serum albumin (HSA). 42. The method according to Embodiment 41, wherein the HSA is a mutant HSA containing Sequence ID No. 4. 43. The method according to any one of embodiments 24 to 42, wherein the loading dose and the maintenance dose are the same. 44. The method according to any one of embodiments 24 to 42, wherein the loading dose and the maintenance dose are different. 45. The method according to any one of Embodiments 1 to 44, wherein the Tn3 scaffold includes Sequence ID No. 1. 46. ​​The method according to any one of Embodiments 10 to 45, wherein 1500 mg of Tn3 scaffold is administered intravenously at weeks 0, 2, and 4, and thereafter once every 4 weeks. 47. The method according to any one of Embodiments 11 to 45, wherein 3000 mg of Tn3 scaffold is administered intravenously at weeks 0, 4, and 12, and then once every 12 weeks thereafter. 48. A method for treating Sjögren's syndrome (SS) in a subject requiring treatment for SS, comprising administering a Tn3 scaffold containing SEQ ID NO: 1 to the subject, wherein the Tn3 scaffold is administered at a dose of approximately 1500 mg, the subject has an ESSDAI score of 5 or greater prior to administration, and the administration is effective in reducing the ESSDAI score compared to a subject that is otherwise equivalent, except that administered a placebo. 49. The method according to Embodiment 48, wherein 1500 mg is administered intravenously in weeks 0, 2, and 4, and then once every 4 weeks thereafter. 50. A method for treating Sjögren's syndrome (SS) in a subject requiring treatment for SS, comprising administering a Tn3 scaffold containing SEQ ID NO: 1 to the subject, wherein the Tn3 scaffold is administered at a dose of approximately 3000 mg, the subject has an ESSDAI score of 5 or greater prior to administration, and the administration is effective in reducing the ESSDAI score compared to a subject with equivalent status except that administered a placebo. 51. The method according to Embodiment 50, wherein 3000 mg of Tn3 scaffold is administered intravenously at weeks 0, 4, and 12, and then once every 12 weeks thereafter. 52. The method according to any one of embodiments 48 to 51, wherein the ESSDAI score decreases by approximately 2, 3, 4, or 5 points. 53. The method according to any one of embodiments 48 to 52, wherein the subject has an ESSDAI score of 5-7, 5-10, 5-13, or 10-13. 54. A method for treating Sjögren's syndrome (SS) in subjects requiring treatment for SS, comprising administering a Tn3 scaffold containing Sequence ID No. 1 to the subject, wherein the Tn3 scaffold is administered at a dose of approximately 1500 mg, the subject has a European Alliance of Associations for Rheumatology (EULAR) SS Disease Activity Index (ESSDAI) score of less than 5, and the subject has an EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) score of 5 or greater prior to administration. 55. The method according to Embodiment 54, wherein 1500 mg is administered intravenously in weeks 0, 2, and 4, and then once every 4 weeks thereafter. 56. A method for treating Sjögren's syndrome (SS) in subjects requiring treatment for SS, comprising administering a Tn3 scaffold containing Sequence ID No. 1 to the subject, wherein the Tn3 scaffold is administered at a dose of approximately 3000 mg, the subject has a European Alliance of Associations for Rheumatology (EULAR) SS Disease Activity Index (ESSDAI) score of less than 5, and the subject has an EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) score of 5 or greater prior to administration. 57. The method according to Embodiment 56, wherein 3000 mg of Tn3 scaffold is administered intravenously at weeks 0, 4, and 12, and then once every 12 weeks thereafter. 58. The method according to any one of embodiments 54 to 57, wherein the subject's ESSPRI score before administration is 5-6, 5-7, 6-8, 6-9, or 5-10.

[0206] Embodiment Set 2 1. A method for treating Sjögren's syndrome (SS) in patients requiring treatment for SS, comprising administering a Tn3 scaffold, the Tn3 scaffold comprising a CD40L-specific monomer subunit, the CD40L-specific monomer subunit comprising seven β-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 comprising SEQ ID NO: 11, the BC loop comprising SEQ ID NO: 12, the CD loop comprising SEQ ID NO: 13, the DE loop comprising SEQ ID NO: 14, the EF loop comprising SEQ ID NO: 15, and the FG loop comprising SEQ ID NO: 16. The Tn3 scaffold containing the CD40L-specific monomer subunit is administered in doses of approximately 1500 mg to approximately 3000 mg, and the target patients are those of the European Alliance of Associations for Rheumatism (EUR). A method for determining moderate to severe systemic disease activity as determined by the SS Disease Activity Index (ESSDAI) of Rheumatology (EULAR). 2. The method according to Embodiment 1, wherein the subject has an ESSDAI score of 5-7, 5-10, 5-13, or 10-13 before administration of the Tn3 scaffold. 3. The method according to Embodiment 2, wherein the subject has an ESSDAI score of 5 or higher. 4. The method according to any one of Embodiments 1 to 4, wherein administration of a Tn3 scaffold is effective in reducing the EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) score after administration. 5. The method according to Embodiment 4, wherein the ESSPRI score is reduced by at least about 2, 3, 4, or 5 points. 6. A method for treating Sjögren's syndrome (SS) in a subject requiring treatment for SS, comprising administering a Tn3 scaffold, the Tn3 scaffold comprising a CD40L-specific monomer subunit, the CD40L-specific monomer subunit comprising seven β-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 comprising SEQ ID NO: 11, the BC loop comprising SEQ ID NO: 12, the CD loop comprising SEQ ID NO: 13, the DE loop comprising SEQ ID NO: 14, the EF loop comprising SEQ ID NO: 15, and the FG loop comprising SEQ ID NO: 16, the Tn3 scaffold containing the CD40L-specific monomer subunit is administered in a dose of approximately 1500 mg to approximately 3000 mg, the subject having an ESSPRI score of 5 or higher, and the method. 7. The method according to Embodiment 6, wherein the subject has an ESSDAI score of less than 5 before administration of the Tn3 scaffold. 8. The method according to any one of Embodiments 6 to 7, wherein the subject has residual salivary gland function defined by a total stimulated salivary flow rate of more than 0.1 mL / min. 9. A method according to any one of Embodiments 1 to 8, wherein the subject is positive for anti-Ro autoantibody, rheumatoid factor, or both anti-Ro autoantibody and rheumatoid factor. 10. The method according to any one of Embodiments 1 to 9, wherein the dose is 1500 mg. 11. The method according to any one of Embodiments 1 to 9, wherein the dose is 3000 mg. 12. The method according to any one of Embodiments 2 to 11, wherein the change from baseline in ESSDAI is determined after administration of a Tn3 scaffold. 13. The method according to Embodiment 12, wherein the change from baseline is determined every four weeks up to 48 weeks after administration of the Tn3 scaffold. 14. The method according to any one of Embodiments 2 to 13, wherein administration of the Tn3 scaffold is effective in reducing the subject's ESSDAI score after administration. 15. The method according to Embodiment 14, wherein the ESSDAI score is reduced by at least about 1, 2, 3, 4, 5, 6, or 7 points. 16. The method according to Embodiment 14, wherein the ESSDAI score is reduced by at least about 6 points. 17. The method according to any one of Embodiments 1 to 16, wherein administration of the Tn3 scaffold is effective in reducing the baseline score of tenderness and swollen joints in the subject after administration. 18. The method according to any one of Embodiments 1 to 16, wherein administration of the Tn3 scaffold is effective in reducing the baseline score of the subject's Short Form 36 (SF-36) health survey by 48 weeks after administration. 19. A method according to any one of Embodiments 1 to 16, wherein administration of a Tn3 scaffold is effective in improving the baseline score of the subject, the baseline score being selected from the group consisting of the Functional Assessment of Chronic Disease Treatment - Fatigue (FACIT-fatigue), PROMIS Fatigue Short Form 10a, Ocular Surface Disease Index (OSDI), EQ-5D-5L, and Patient's General Impression of Severity (PGIS). 20. A method according to any one of Embodiments 1 to 18, wherein administration of a Tn3 scaffold is effective in reducing baseline levels of inflammatory markers after administration, the markers being selected from the group consisting of immunoglobulins, β-2 microglobulins, C-reactive proteins, and combinations thereof. 21. A method according to any one of Embodiments 1 to 19, wherein administration of a Tn3 scaffold is effective in reducing baseline levels of a biomarker, the biomarker being selected from the group consisting of plasma-soluble CD40L, B cells, serum CXCL13, rheumatoid factor autoantibodies, anti-SSA autoantibodies (i.e., anti-Ro autoantibodies), anti-SSB autoantibodies (i.e., anti-La autoantibodies), and combinations thereof. 22. A method according to any one of Embodiments 1 to 20, wherein administration of a Tn3 scaffold is effective in reducing the baseline level of disease symptoms, the disease symptoms being selected from the group consisting of fatigue, dry mouth, dry eyes, dry vagina, pain, and combinations thereof. 23. The method according to any one of Embodiments 1 to 21, wherein the expression level of SS-related genes in the target blood sample decreases by 48 weeks after administration. 24. A method according to any one of Embodiments 1 to 22, wherein the level of B cells selected from the group consisting of CD27+ memory B cells, marginal zone B cells, plasmablasts, plasma cells, and combinations thereof decreases in the blood sample of the subject by 48 weeks after administration. 25. The method according to any one of Embodiments 1 to 23, wherein Tn3 scaffold is administered as a loading dose and then as a maintenance dose. 26. The method according to Embodiment 24, wherein the loading dose includes administering the Tn3 scaffold once every two weeks for at least three doses. 27. The method according to Embodiment 24, wherein the maintenance dose comprises administering the Tn3 scaffold once every four weeks for at least four doses. 28. The method according to Embodiment 24, wherein the time between the final loading dose and the initial maintenance dose is approximately 4 weeks. 29. The method according to any one of Embodiments 1 to 27, wherein the Tn3 scaffold is administered approximately every four weeks, once every two months, once every three months, once every four months, or once every six months. 30. The method according to any one of Embodiments 1 to 28, wherein the Tn3 scaffold is administered over at least four doses. 31. The method according to any one of Embodiments 1 to 28, wherein the Tn3 scaffold is administered over at least 5 doses. 32. The method according to any one of Embodiments 1 to 30, wherein the Tn3 scaffold is administered by intravenous administration, subcutaneous administration, oral administration, intramuscular administration, subarachnoid administration, sublingual administration, rectal administration, vaginal administration, cutaneous administration, systemic administration, local administration, transdermal administration, or inhalation. 33. The method according to Embodiment 31, wherein the Tn3 scaffold is administered intravenously. 34. The method according to any one of embodiments 1 to 32, wherein the Tn3 scaffold comprises two CD40L-specific monomer subunits linked in tandem. 35. The method according to Embodiment 33, wherein each of the two CD40L-specific monomer subunits comprises Sequence ID No. 3. 36. The method according to any one of embodiments 33 to 34, wherein the CD40L-specific monomer subunits are linked by a linker. 37. The method according to any one of Embodiments 1 to 35, wherein at least 33 CD40L-specific monomer subunits are directly fused to or conjugated to polyethylene glycol (PEG). 38. The method according to any one of embodiments 33 to 35, wherein at least one CD40L-specific monomer subunit is fused to or conjugated to polyethylene glycol (PEG) via a linker. 39. The method according to Embodiment 37, wherein the linker comprises a peptide linker. 40. The method according to Embodiment 37, wherein the linker includes SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, or SEQ ID NO: 10. 41. The method according to any one of embodiments 33 to 39, wherein at least one CD40L-specific monomer subunit is fused to or conjugated to albumin. 42. The method according to Embodiment 40, wherein the albumin is human serum albumin (HSA). 43. The method according to Embodiment 41, wherein the HSA is a mutant HSA containing SEQ ID NO: 4. 44. The method according to any one of embodiments 24 to 42, wherein the loading dose and the maintenance dose are the same. 45. The method according to any one of embodiments 24 to 42, wherein the loading dose and the maintenance dose are different. 46. ​​The method according to any one of Embodiments 1 to 44, wherein the Tn3 scaffold includes Sequence ID No. 1. 47. The method according to any one of Embodiments 10 to 45, wherein 1500 mg of Tn3 scaffold is administered intravenously at weeks 0, 2, and 4, and thereafter every 4 weeks. 48. The method according to any one of Embodiments 11 to 45, wherein 3000 mg of Tn3 scaffold is administered intravenously at week 0, week 2, and week 4, and thereafter every four weeks. 49. A method for treating Sjögren's syndrome (SS) in a subject requiring treatment for SS, comprising administering a Tn3 scaffold containing SEQ ID NO: 1 to the subject, wherein the Tn3 scaffold is administered at a dose of approximately 1500 mg, the subject has an ESSDAI score of 5 or greater prior to administration, and the administration is effective in reducing the ESSDAI score compared to a subject that is otherwise equivalent except that administered a placebo. 50. The method according to Embodiment 48, wherein 1500 mg is administered intravenously in weeks 0, 2, and 4, and then once every 4 weeks thereafter. 51. A method for treating Sjögren's syndrome (SS) in subjects requiring treatment for SS, comprising administering a Tn3 scaffold containing SEQ ID NO: 1 to the subject, wherein the Tn3 scaffold is administered at a dose of approximately 3000 mg, the subject has an ESSDAI score of 5 or greater prior to administration, and the administration is effective in reducing the ESSDAI score compared to a subject that is otherwise equivalent, except that administered a placebo. 52. The method according to Embodiment 50, wherein 3000 mg of Tn3 scaffold is administered intravenously at weeks 0, 4, and 12, and then once every 12 weeks thereafter. 53. The method according to any one of Embodiments 48 to 51, wherein the ESSDAI score decreases by 2, 3, 4, 5, 6, or 7 points after administration. 54. The method according to any one of Embodiments 48 to 51, wherein, prior to administration, the subject has an ESSDAI score of 5-7, 5-10, 5-13, or 10-13. 55. A method for treating Sjögren's syndrome (SS) in a subject requiring treatment for SS, comprising administering a Tn3 scaffold containing Sequence ID No. 1 to the subject, wherein the Tn3 scaffold is administered at a dose of approximately 1500 mg, the subject has a European Alliance of Associations for Rheumatology (EULAR) SS Disease Activity Index (ESSDAI) score of less than 5, and the subject has an EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) score of 5 or greater prior to administration. 56. The method according to Embodiment 54, wherein 1500 mg is administered intravenously in weeks 0, 2, and 4, and then once every 4 weeks thereafter. 57. A method for treating Sjögren's syndrome (SS) in subjects requiring treatment for SS, comprising administering a Tn3 scaffold containing Sequence ID No. 1 to the subject, wherein the Tn3 scaffold is administered at a dose of approximately 3000 mg, the subject has a European Alliance of Associations for Rheumatology (EULAR) SS Disease Activity Index (ESSDAI) score of less than 5, and the subject has an EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) score of 5 or greater prior to administration. 58. The method according to Embodiment 56, wherein 3000 mg of Tn3 scaffold is administered intravenously at weeks 0, 4, and 12, and then once every 12 weeks thereafter. 59. The method according to any one of embodiments 54 to 57, wherein the subject's ESSPRI score before administration is 5-6, 5-7, 6-8, 6-9, or 5-10. 60. The method according to any one of Embodiments 5 to 58, wherein the administration is effective in reducing the ESSPRI score by at least 0.6 points, 0.8 points, 1 point, 1.8 points, or 2 points compared to baseline. 61. A method for treating Sjögren's syndrome (SS) in a subject requiring treatment for SS, comprising administering a Tn3 scaffold, the Tn3 scaffold comprising a CD40L-specific monomer subunit, the CD40L-specific monomer subunit comprising seven β-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 comprising SEQ ID NO: 11, the BC loop comprising SEQ ID NO: 12, the CD loop comprising SEQ ID NO: 13, the DE loop comprising SEQ ID NO: 14, the EF loop comprising SEQ ID NO: 15, and the FG loop comprising SEQ ID NO: 16, wherein the subject is positive for anti-SSA / Ro antibody. 62. A method for treating Sjögren's syndrome (SS) in a subject requiring treatment for SS, comprising administering a Tn3 scaffold, the Tn3 scaffold comprising a CD40L-specific monomer subunit, the CD40L-specific monomer subunit comprising seven β-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 comprising SEQ ID NO: 11, the BC loop comprising SEQ ID NO: 12, the CD loop comprising SEQ ID NO: 13, the DE loop comprising SEQ ID NO: 14, the EF loop comprising SEQ ID NO: 15, and the FG loop comprising SEQ ID NO: 16, wherein the subject is positive for RF antibody. 63. The method according to any one of Embodiments 1 to 60, wherein the administration is effective in achieving a reduction of 5%, 10%, 15%, 20%, 40%, or 60% or more in the ESSPRI score compared to a subject that received a placebo, or compared to the baseline level of the subject.

[0207] Embodiment Set 3 1. A method for treating Sjögren's syndrome (SS) in patients requiring treatment for SS, comprising administering a Tn3 scaffold, the Tn3 scaffold comprising a CD40L-specific monomer subunit, the CD40L-specific monomer subunit comprising seven β-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 comprising SEQ ID NO: 11, the BC loop comprising SEQ ID NO: 12, the CD loop comprising SEQ ID NO: 13, the DE loop comprising SEQ ID NO: 14, the EF loop comprising SEQ ID NO: 15, and the FG loop comprising SEQ ID NO: 16. The Tn3 scaffold containing the CD40L-specific monomer subunit is administered in doses of approximately 1500 mg to approximately 3000 mg, and the target patients are those of the European Alliance of Associations for Rheumatism (EUR). A method for determining moderate to severe systemic disease activity as determined by the SS Disease Activity Index (ESSDAI) of Rheumatology (EULAR). 2. The method according to Embodiment 1, wherein the subject has an ESSDAI score of 5-7, 5-10, 5-13, or 10-13 before administration of the Tn3 scaffold. 3. The method according to Embodiment 2, wherein the subject has an ESSDAI score of 5 or higher. 4. The method according to any one of Embodiments 1 to 3, wherein administration of a Tn3 scaffold is effective in reducing the EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) score after administration. 5. The method according to Embodiment 4, wherein the ESSPRI score is reduced by at least about 2, 3, 4, or 5 points. 6. The method according to any one of Embodiments 1 to 3, wherein administration of Tn3 scaffolding is effective in reducing the DASPRI score. 7. The method according to Embodiment 6, wherein the DASPRI score is reduced by at least about 5, 10, 15, or 20 points. 8. A method for treating Sjögren's syndrome (SS) in a subject requiring treatment for SS, comprising administering a Tn3 scaffold, the Tn3 scaffold comprising a CD40L-specific monomer subunit, the CD40L-specific monomer subunit comprising seven β-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 comprising SEQ ID NO: 11, the BC loop comprising SEQ ID NO: 12, the CD loop comprising SEQ ID NO: 13, the DE loop comprising SEQ ID NO: 14, the EF loop comprising SEQ ID NO: 15, and the FG loop comprising SEQ ID NO: 16, the Tn3 scaffold containing the CD40L-specific monomer subunit is administered in a dose of approximately 1500 mg to approximately 3000 mg, the subject having an ESSPRI score of 5 or higher, and the method. 9. The method according to Embodiment 8, wherein the subject has an ESSDAI score of less than 5 before administration of the Tn3 scaffold. 10. The method according to any one of Embodiments 8 to 9, wherein the subject has residual salivary gland function defined by a total stimulated salivary flow rate of more than 0.1 mL / min. 11. A method according to any one of Embodiments 1 to 10, wherein the subject is positive for anti-Ro autoantibody, rheumatoid factor autoantibody, or both anti-Ro autoantibody and rheumatoid factor autoantibody. 12. The method according to any one of Embodiments 1 to 11, wherein the dose is 1500 mg. 13. The method according to any one of Embodiments 1 to 11, wherein the dose is 3000 mg. 14. The method according to any one of Embodiments 2 to 13, wherein the change from baseline in ESSDAI is determined after administration of a Tn3 scaffold. 15. The method according to Embodiment 14, wherein the change from baseline is determined every four weeks up to 48 weeks after administration of the Tn3 scaffold. 16. The method according to any one of Embodiments 2 to 15, wherein administration of a Tn3 scaffold is effective in reducing the subject's ESSDAI score after administration. 17. The method according to Embodiment 16, wherein the ESSDAI score is reduced by at least about 1, 2, 3, 4, 5, 6, or 7 points. 18. The method according to Embodiment 16, wherein the ESSDAI score is reduced by at least about 6 points. 19. The method according to any one of Embodiments 8 to 18, wherein administration of Tn3 scaffolding is effective in reducing the DASPRI score. 20. The method according to Embodiment 19, wherein the DASPRI score is reduced by at least about 5, 10, 15, or 20 points. 21. The method according to any one of Embodiments 1 to 20, wherein administration of the Tn3 scaffold is effective in reducing the baseline score of tenderness and swollen joints in the subject after administration. 22. The method according to any one of Embodiments 1 to 21, wherein administration of the Tn3 scaffold is effective in reducing the baseline score of the subject's Short Form 36 (SF-36) Health Survey by 48 weeks after administration. 23. A method according to any one of Embodiments 1 to 22, wherein administration of a Tn3 scaffold is effective in improving the baseline score of the subject, the baseline score being selected from the group consisting of the Functional Assessment of Chronic Disease Treatment - Fatigue (FACIT-fatigue), PROMIS Fatigue Short Form 10a, Ocular Surface Disease Index (OSDI), EQ-5D-5L, and Patient's General Impression of Severity (PGIS). 24. A method according to any one of Embodiments 1 to 23, wherein administration of a Tn3 scaffold is effective in reducing baseline levels of inflammatory markers after administration, the markers being selected from the group consisting of immunoglobulins, β-2 microglobulins, C-reactive proteins, and combinations thereof. 25. A method according to any one of Embodiments 1 to 24, wherein administration of a Tn3 scaffold is effective in reducing baseline levels of a biomarker, the biomarker being selected from the group consisting of plasma-soluble CD40L, B cells, serum CXCL13, rheumatoid factor autoantibodies, anti-SSA autoantibodies (i.e., anti-Ro autoantibodies), anti-SSB autoantibodies (i.e., anti-La autoantibodies), and combinations thereof. 26. The method according to any one of Embodiments 1 to 25, wherein the administration of the Tn3 scaffold is effective to reduce the baseline level of disease symptoms, and the disease symptoms are selected from the group consisting of fatigue, dry mouth, dry eyes, vaginal dryness, pain, and combinations thereof. 27. The method according to any one of Embodiments 1 to 26, wherein the expression level of a gene related to SS in a blood sample of the subject decreases by 48 weeks after administration. 28. The method according to any one of Embodiments 1 to 27, wherein the level of B cells selected from the group consisting of CD27+ memory B cells, marginal zone B cells, plasmablasts, plasma cells, and combinations thereof decreases in a blood sample of the subject by 48 weeks after administration. 29. The method according to any one of Embodiments 1 to 28, wherein the Tn3 scaffold is administered as a loading dose and then as a maintenance dose. 30. The method according to Embodiment 29, wherein the loading dose comprises administering the Tn3 scaffold once every about two weeks for at least three doses. 31. The method according to Embodiment 30, wherein the maintenance dose comprises administering the Tn3 scaffold once every about four weeks for at least four doses. 32. The method according to Embodiment 31, wherein the time between the final loading dose and the first maintenance dose is about four weeks. 33. The method according to any one of Embodiments 1 to 31, wherein the Tn3 scaffold is administered once every about four weeks, once every about two months, once every about three months, once every about four months, or once every about six months. 34. The method according to any one of Embodiments 1 to 33, wherein the Tn3 scaffold is administered for at least four doses. 35. The method according to any one of Embodiments 1 to 33, wherein the Tn3 scaffold is administered for at least five doses. 36. The method according to any one of Embodiments 1 to 35, wherein the Tn3 scaffold is administered by intravenous administration, subcutaneous administration, oral administration, intramuscular administration, intrathecal administration, sublingual administration, rectal administration, vaginal administration, cutaneous administration, systemic administration, topical administration, transdermal administration, or inhalation. 37. The method according to embodiment 36, wherein the Tn3 scaffold is administered intravenously. 38. The method according to any one of embodiments 1 to 37, wherein the Tn3 scaffold comprises two CD40L-specific monomer subunits linked in tandem. 39. The method according to Embodiment 38, wherein each of the two CD40L-specific monomer subunits comprises Sequence ID No. 3. 40. The method according to any one of embodiments 38 to 39, wherein the CD40L-specific monomer subunits are linked by a linker. 41. The method according to any one of Embodiments 1 to 40, wherein at least 38 CD40L-specific monomer subunits are directly fused to or conjugated to polyethylene glycol (PEG). 42. The method according to any one of embodiments 38 to 40, wherein at least one CD40L-specific monomer subunit is fused to or conjugated to polyethylene glycol (PEG) via a linker. 43. The method according to Embodiment 42, wherein the linker comprises a peptide linker. 44. The method according to Embodiment 43, wherein the linker includes SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, or SEQ ID NO: 10. 45. The method according to any one of embodiments 38 to 40, wherein at least one CD40L-specific monomer subunit is fused to or conjugated to albumin. 46. ​​The method according to Embodiment 45, wherein the albumin is human serum albumin (HSA). 47. The method according to Embodiment 46, wherein the HSA is a mutant HSA containing SEQ ID NO: 4. 48. The method according to any one of embodiments 29 to 47, wherein the loading dose and the maintenance dose are the same. 49. The method according to any one of embodiments 29 to 47, wherein the loading dose and the maintenance dose are different. 50. The method according to any one of Embodiments 1 to 49, wherein the Tn3 scaffold includes Sequence ID No. 1. 51. The method according to any one of Embodiments 12 to 50, wherein 1500 mg of Tn3 scaffold is administered intravenously at weeks 0, 2, and 4, and thereafter every 4 weeks. 52. The method according to any one of Embodiments 13 to 50, wherein 3000 mg of Tn3 scaffold is administered intravenously at weeks 0, 2, and 4, and thereafter every 4 weeks. 53. A method for treating Sjögren's syndrome (SS) in a subject requiring treatment for SS, comprising administering a Tn3 scaffold containing SEQ ID NO: 1 to the subject, wherein the Tn3 scaffold is administered at a dose of approximately 1500 mg, the subject has an ESSDAI score of 5 or greater prior to administration, and the administration is effective in reducing the ESSDAI score compared to a subject that is otherwise equivalent except that administered a placebo. 54. The method according to Embodiment 49, wherein 1500 mg is administered intravenously in weeks 0, 2, and 4, and then once every 4 weeks thereafter. 55. A method for treating Sjögren's syndrome (SS) in subjects requiring treatment for SS, comprising administering a Tn3 scaffold containing SEQ ID NO: 1 to the subject, wherein the Tn3 scaffold is administered at a dose of approximately 3000 mg, the subject has an ESSDAI score of 5 or greater prior to administration, and the administration is effective in reducing the ESSDAI score compared to a subject with equivalent status except that administered a placebo. 56. The method according to Embodiment 55, wherein 3000 mg of Tn3 scaffold is administered intravenously at weeks 0, 4, and 12, and then once every 12 weeks thereafter. 57. The method according to any one of Embodiments 49 to 56, wherein the ESSDAI score decreases by 2, 3, 4, 5, 6, or 7 points after administration. 58. The method according to any one of Embodiments 49 to 57, wherein the subject has an ESSDAI score of 5-7, 5-10, 5-13, or 10-13 prior to administration. 59. A method for treating Sjögren's syndrome (SS) in a subject requiring treatment for SS, comprising administering a Tn3 scaffold containing Sequence ID No. 1 to the subject, wherein the Tn3 scaffold is administered at a dose of approximately 1500 mg, the subject has a European Alliance of Associations for Rheumatology (EULAR) SS Disease Activity Index (ESSDAI) score of less than 5, and the subject has an EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) score of 5 or greater prior to administration. 60. The method according to Embodiment 59, wherein 1500 mg is administered intravenously in weeks 0, 2, and 4, and then once every 4 weeks thereafter. 61. A method for treating Sjögren's syndrome (SS) in subjects requiring treatment for SS, comprising administering a Tn3 scaffold containing Sequence ID No. 1 to the subject, wherein the Tn3 scaffold is administered at a dose of approximately 3000 mg, the subject has a European Alliance of Associations for Rheumatology (EULAR) SS Disease Activity Index (ESSDAI) score of less than 5, and the subject has an EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) score of 5 or greater prior to administration. 62. The method according to Embodiment 61, wherein 3000 mg of Tn3 scaffold is administered intravenously at weeks 0, 4, and 12, and then once every 12 weeks thereafter. 63. The method according to any one of embodiments 59 to 62, wherein the subject's ESSPRI score before administration is 5-6, 5-7, 6-8, 6-9, or 5-10. 64. The method according to any one of Embodiments 4 to 63, wherein the administration is effective in reducing the ESSPRI score by at least 0.6 points, 0.8 points, 1 point, 1.8 points, or 2 points compared to baseline. 65. A method for treating Sjögren's syndrome (SS) in a subject requiring treatment for SS, comprising administering a Tn3 scaffold, the Tn3 scaffold comprising a CD40L-specific monomer subunit, the CD40L-specific monomer subunit comprising seven β-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 comprising SEQ ID NO: 11, the BC loop comprising SEQ ID NO: 12, the CD loop comprising SEQ ID NO: 13, the DE loop comprising SEQ ID NO: 14, the EF loop comprising SEQ ID NO: 15, and the FG loop comprising SEQ ID NO: 16, wherein the subject is positive for anti-SSA / Ro antibody. 66. A method for treating Sjögren's syndrome (SS) in a subject requiring treatment for SS, comprising administering a Tn3 scaffold, the Tn3 scaffold comprising a CD40L-specific monomer subunit, the CD40L-specific monomer subunit comprising seven β-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 comprising SEQ ID NO: 11, the BC loop comprising SEQ ID NO: 12, the CD loop comprising SEQ ID NO: 13, the DE loop comprising SEQ ID NO: 14, the EF loop comprising SEQ ID NO: 15, and the FG loop comprising SEQ ID NO: 16, wherein the subject is positive for RF antibody. 67. The method according to any one of Embodiments 1 to 66, wherein the administration is effective in achieving a reduction of 5%, 10%, 15%, 20%, 40%, or 60% or more in the ESSPRI score compared to a subject that received a placebo, or compared to the baseline level of the subject. 68. The method according to any one of Embodiments 1 to 67, wherein the administration is effective in achieving a reduction of 5%, 10%, 15%, 20%, 40%, or 60% or more in the DASPRI score compared to a subject that was otherwise equivalent to a subject that received a placebo, or compared to the baseline level of the subject.

[0208] Embodiment Set 4 1. A Tn3 scaffold for use in the treatment of Sjögren's syndrome (SS), wherein the Tn3 scaffold comprises a CD40L-specific monomer subunit, which comprises seven β-strands designated A, B, C, D, E, F, and G, and six loop regions designated AB, BC, CD, DE, EF, and FG, with the AB loop comprising SEQ ID NO: 11, the BC loop comprising SEQ ID NO: 12, the CD loop comprising SEQ ID NO: 13, the DE loop comprising SEQ ID NO: 14, the EF loop comprising SEQ ID NO: 15, and the FG loop comprising SEQ ID NO: 16. The Tn3 scaffold containing the CD40L-specific monomer subunit is administered to subjects at a dose of approximately 1500 mg once every four weeks, and the subjects are members of five or more European Alliance of Rheumatism Associations (EUR). Tn3 scaffolds with moderate to severe systemic disease activity, as determined by the SS Disease Activity Index (ESSDAI) of Rheumatology (EULAR). 2. A Tn3 scaffold for use according to Embodiment 1, in which the subject has been administered at least three loading doses prior to one dose every four weeks. 3. A Tn3 scaffold for use according to Embodiment 2, wherein at least three load doses are applied in week 0, week 2, and week 4. 4. A Tn3 scaffold for use in the treatment of Sjögren's syndrome (SS), wherein the Tn3 scaffold comprises a CD40L-specific monomer subunit, the CD40L-specific monomer subunit comprising seven β-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 comprising SEQ ID NO: 11, the BC loop comprising SEQ ID NO: 12, the CD loop comprising SEQ ID NO: 13, the DE loop comprising SEQ ID NO: 14, the EF loop comprising SEQ ID NO: 15, and the FG loop comprising SEQ ID NO: 16. The Tn3 scaffold containing the CD40L-specific monomer subunit is administered to subjects at a dose of approximately 3000 mg once every 12 weeks, and the subjects are members of five or more European Alliance of Rheumatism Associations (European League for Rheumatism). Tn3 scaffolds with moderate to severe systemic disease activity, as determined by the SS Disease Activity Index (ESSDAI) of Rheumatology (EULAR). 5. A Tn3 scaffold for use according to Embodiment 4, in which the subject has been administered at least three loading doses prior to one dose every 12 weeks. 6. A Tn3 scaffold for use according to Embodiment 5, wherein at least three load doses are applied in week 0, week 4, and week 12. 7. A Tn3 scaffold for use in the treatment of Sjögren's syndrome (SS), wherein the Tn3 scaffold comprises a CD40L-specific monomer subunit, the CD40L-specific monomer subunit comprising seven β-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 comprising SEQ ID NO: 11, the BC loop comprising SEQ ID NO: 12, the CD loop comprising SEQ ID NO: 13, the DE loop comprising SEQ ID NO: 14, the EF loop comprising SEQ ID NO: 15, and the FG loop comprising SEQ ID NO: 16, and the Tn3 scaffold comprising the CD40L-specific monomer subunit is administered to the subject at a dose of approximately 1500 mg once every four weeks, the subject having a moderate to severe symptomatic state as defined by an ESSPRI score ≥ 5 and low systemic disease activity as defined by an ESSDAI score < 5. 8. A Tn3 scaffold for use according to Embodiment 7, in which the subject has been administered at least three loading doses prior to one dose every four weeks. 9. A Tn3 scaffold for use according to Embodiment 8, wherein at least three load doses are applied in week 0, week 2, and week 4. 10. A Tn3 scaffold for use in the treatment of Sjögren's syndrome (SS), wherein the Tn3 scaffold comprises a CD40L-specific monomer subunit, the CD40L-specific monomer subunit comprising seven β-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 comprising SEQ ID NO: 11, the BC loop comprising SEQ ID NO: 12, the CD loop comprising SEQ ID NO: 13, the DE loop comprising SEQ ID NO: 14, the EF loop comprising SEQ ID NO: 15, and the FG loop comprising SEQ ID NO: 16, and the Tn3 scaffold comprising the CD40L-specific monomer subunit is administered to the subject at a dose of approximately 3000 mg once every 12 weeks, the subject having a moderate to severe symptomatic state as defined by an ESSPRI score ≥ 5 and low systemic disease activity as defined by an ESSDAI score < 5. 11. A Tn3 scaffold for use according to Embodiment 10, in which the subject has been administered at least three loading doses prior to one dose every 12 weeks. 12. A Tn3 scaffold for use according to Embodiment 11, wherein at least three load doses are applied in week 0, week 4, and week 12. 13. A Tn3 scaffold for use according to any one of Embodiments 1 to 5, wherein the subject has an ESSDAI score of 5-7, 5-10, 5-13, or 10-13 prior to administration of the Tn3 scaffold. 14. A Tn3 scaffold for use according to any one of Embodiments 1-5, in which administration is effective in reducing ESSDAI. 15. A Tn3 scaffold for use according to Embodiment 14, wherein the ESSDAI score decreases by at least 1, 2, 3, 4, 5, 6, or 7 points. 16. A Tn3 scaffold for use according to Embodiment 15, wherein the ESSDAI score is reduced by at least 6 points. 17. A Tn3 scaffold for use according to any one of embodiments 13-16, wherein the ESSDAI score decreases by at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 1 year after administration of the initial loading dose, compared to the baseline ESSDAI score. 18. A Tn3 scaffold for use according to Embodiment 17, wherein the ESSDAI score decreases by 11 months after administration of the initial loading dose. 19. A Tn3 scaffold for use according to any one of Embodiments 7 to 12, wherein the subject has a total salivary flow rate at stimulation of more than 0.1 mL / min at baseline. 20. A Tn3 scaffold for use according to Embodiment 19, wherein the ESSPRI score decreases by at least approximately 1.5, 2, 3, 4, or 5 points after the loading dose administration at week 0. 21. A Tn3 scaffold for use according to any one of embodiments 7-12, wherein the DASPRI score decreases after administration. 22. A Tn3 scaffold for use according to Embodiment 21, wherein the DASPRI score decreases by at least approximately 5, 10, 15, or 20 points after the loading dose administration in week 0. 23. A Tn3 scaffold for use according to any one of Embodiments 1 to 22, wherein administration of the Tn3 scaffold is effective in reducing the baseline score of tenderness and swollen joints in the subject after administration. 24. A Tn3 scaffold for use according to any one of Embodiments 1 to 23, wherein administration of the Tn3 scaffold is effective in reducing the baseline score of the subject in the Short Form 36 (SF-36) Health Survey after administration. 25. A Tn3 scaffold for use according to any one of Embodiments 1 to 22, wherein administration of the Tn3 scaffold is effective in improving the baseline score of the subject, the baseline score being selected from the group consisting of the Functional Assessment of Chronic Disease Treatment - Fatigue (FACIT-fatigue), PROMIS Fatigue Short Form 10a, Ocular Surface Disease Index (OSDI), EQ-5D-5L, and Patient's General Impression of Severity (PGIS). 24. A Tn3 scaffold for use according to any one of embodiments 1 to 23, wherein administration of the Tn3 scaffold is effective to reduce the baseline level of an inflammatory marker, and the marker is selected from the group consisting of immunoglobulins, β-2 microglobulin, C-reactive protein, and combinations thereof. 25. A Tn3 scaffold for use according to any one of embodiments 1 to 24, wherein administration of the Tn3 scaffold is effective to reduce the baseline level of a biomarker, and the biomarker is selected from the group consisting of plasma soluble CD40L, Ki67+CD27+ memory B cells, plasmablasts, CD11c high expression / high (bright / high) B cells, CD3, CD4, CD8, Tfh cells, serum CXCL13, rheumatoid factor, anti-SSA autoantibody (i.e., anti-Ro autoantibody), anti-SSB autoantibody (i.e., anti-La autoantibody), and combinations thereof. 26. A Tn3 scaffold for use according to any one of embodiments 1 to 25, wherein administration of the Tn3 scaffold is effective to reduce the baseline level of a disease symptom, and the disease symptom is selected from the group consisting of fatigue, dry mouth, dry eyes, vaginal dryness, pain, and combinations thereof. 27. A Tn3 scaffold for use according to any one of embodiments 1 to 26, wherein the expression level of a gene associated with SS in a blood sample of a subject decreases by 48 weeks after administration. 28. A Tn3 scaffold for use according to any one of embodiments 1 to 27, wherein the level of B cells selected from the group consisting of CD27+ memory B cells, marginal zone B cells, plasmablasts, plasma cells, and combinations thereof decreases in a blood sample of a subject by 48 weeks after administration. 29. A Tn3 scaffold for use according to any one of embodiments 1 to 28, wherein the Tn3 scaffold is administered intravenously. 30. A Tn3 scaffold for use according to any one of embodiments 1 to 29, wherein the Tn3 scaffold comprises two CD40L-specific monomeric subunits linked in tandem. 31. The Tn3 scaffold according to Embodiment 30, wherein two CD40L-specific monomer subunits each include Sequence ID No. 3. 32. A Tn3 scaffold for use according to any one of embodiments 30-31, wherein CD40L-specific monomer subunits are linked by a linker. 33. A Tn3 scaffold for use according to any one of embodiments 30 to 32, wherein at least one CD40L-specific monomer subunit is directly fused to or conjugated to polyethylene glycol (PEG). 34. A Tn3 scaffold for use according to any one of embodiments 30 to 33, wherein at least one CD40L-specific monomer subunit is fused to or conjugated to polyethylene glycol (PEG) via a linker. 35. A Tn3 scaffold for use according to Embodiment 34, wherein the linker comprises a peptide linker. 36. A Tn3 scaffold for use according to Embodiment 35, wherein the linker includes SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, or SEQ ID NO: 10. 37. A Tn3 scaffold for use according to any one of embodiments 30 to 36, wherein at least one CD40L-specific monomer subunit is fused to or conjugated with albumin. 38. A Tn3 scaffold for use according to Embodiment 37, wherein the albumin is human serum albumin (HSA). 39. A Tn3 scaffold for use according to Embodiment 38, wherein the HSA is a variant HSA containing SEQ ID NO: 4. 40. A Tn3 scaffold for use according to any one of embodiments 1 to 39, wherein the Tn3 scaffold includes Sequence ID No. 1.

[0209] Embodiment Set 5 1. A method for treating Sjögren's syndrome (SS) in a subject requiring treatment for SS, comprising administering a Tn3 scaffold, the Tn3 scaffold comprising a CD40L-specific monomer subunit, the CD40L-specific monomer subunit comprising seven β-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 comprising SEQ ID NO: 11, the BC loop comprising SEQ ID NO: 12, the CD loop comprising SEQ ID NO: 13, the DE loop comprising SEQ ID NO: 14, the EF loop comprising SEQ ID NO: 15, and the FG loop comprising SEQ ID NO: 16, the Tn3 scaffold being administered once every four weeks at a dose of approximately 1500 mg, the subject having moderate to severe systemic disease activity as determined by the European Alliance of Associations for Rheumatology (EULAR) SS Disease Activity Index (ESSDAI) of five or more subjects. 2. The method according to Embodiment 1, wherein the subject has been administered at least three loading doses of 1500 mg each, prior to one dose every four weeks. 3. The method according to Embodiment 2, wherein at least three loading doses are administered in week 0, week 2, and week 4. 4. A method for treating Sjögren's syndrome (SS) in a subject requiring treatment for SS, comprising administering a Tn3 scaffold, the Tn3 scaffold comprising a CD40L-specific monomer subunit, the CD40L-specific monomer subunit comprising seven β-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 comprising SEQ ID NO: 11, the BC loop comprising SEQ ID NO: 12, the CD loop comprising SEQ ID NO: 13, the DE loop comprising SEQ ID NO: 14, the EF loop comprising SEQ ID NO: 15, and the FG loop comprising SEQ ID NO: 16, the Tn3 scaffold being administered once every 12 weeks at a dose of approximately 3000 mg, the subject having moderate to severe systemic disease activity as determined by the European Alliance of Associations for Rheumatology (EULAR) SS Disease Activity Index (ESSDAI) of 5 or more. 5. The method according to Embodiment 4, wherein the subject was administered at least three loading doses of 3000 mg each, prior to one dose every 12 weeks. 6. The method according to Embodiment 5, wherein at least three loading doses are administered in week 0, week 4, and week 12. 7. A method for treating Sjögren's syndrome (SS) in subjects requiring treatment for SS is provided herein, comprising administering a Tn3 scaffold, wherein the Tn3 scaffold comprises a CD40L-specific monomer subunit, the CD40L-specific monomer subunit comprising seven β-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, the Tn3 scaffold is administered once every four weeks at a dose of approximately 1500 mg, the subjects having a moderate to severe symptomatic state as defined by an ESSPRI score ≥ 5 and low systemic disease activity as defined by an ESSDAI score < 5, and the subjects experience a decrease in the Sjögren's Syndrome Patient Reported Index Assessment Diary (DASPRI) score after administration. 8. The method according to Embodiment 1, wherein the subject was administered at least three loading doses of 1500 mg each, prior to seven administrations every four weeks. 9. The method according to Embodiment 8, wherein at least three loading doses are administered in week 0, week 2, and week 4. 10. A method for treating Sjögren's syndrome (SS) in a subject requiring treatment for SS, comprising administering a Tn3 scaffold, the Tn3 scaffold comprising a CD40L-specific monomer subunit, the CD40L-specific monomer subunit comprising seven β-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 comprising SEQ ID NO: 11, the BC loop comprising SEQ ID NO: 12, the CD loop comprising SEQ ID NO: 13, the DE loop comprising SEQ ID NO: 14, the EF loop comprising SEQ ID NO: 15, and the FG loop comprising SEQ ID NO: 16, the Tn3 scaffold being administered once every 12 weeks at a dose of approximately 3000 mg, the subject having a moderate to severe symptomatic state as defined by an ESSPRI score ≥ 5 and low systemic disease activity as defined by an ESSDAI score < 5, and the subject experiencing a decrease in the Sjögren's Syndrome Patient Reported Index Assessment Diary (DASPRI) score after administration. 11. The method according to Embodiment 10, wherein the subject was administered at least three loading doses of 3000 mg each, prior to one dose every 12 weeks. 12. The method according to Embodiment 11, wherein at least three loading doses are administered in week 0, week 4, and week 12. 13. The method according to any one of Embodiments 1 to 5, wherein the subject has an ESSDAI score of 5-7, 5-10, 5-13, or 10-13 before administration of the Tn3 scaffold. 14. The method according to any one of Embodiments 1 to 6, wherein the administration is effective in reducing the ESSDAI score. 15. The method according to Embodiment 14, wherein the ESSDAI score is reduced by at least about 1, 2, 3, 4, 5, 6, or 7 points. 16. The method according to Embodiment 15, wherein the ESSDAI score is reduced by at least about 6 points. 17. The method according to any one of Embodiments 15 to 16, wherein the ESSDAI score decreases compared to the baseline ESSDAI score by at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 1 year after administration of the initial loading dose. 18. The method according to Embodiment 17, wherein the ESSDAI score decreases by 11 months after administration of the initial loading dose. 19. The method according to any one of Embodiments 7 to 18, wherein the salivary gland function of the target is improved after administration of the Tn3 scaffold, or within approximately 3 weeks, 1 month, 2 months, or 4 months after administration. 20. The method according to Embodiment 19, wherein salivary gland function is determined by the total salivary flow rate at stimulation. 21. The method according to any one of Embodiments 9 to 20, wherein the ESSPRI score decreases by at least about 1.5, 2, 3, 4, or 5 points after administration of a loading dose. 22. The method according to any one of Embodiments 7 to 21, wherein the DASPRI score decreases to 2 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months after administration. 23. The method according to Embodiment 22, wherein the DASPRI score decreases by at least about 5, 10, 15, or 20 points after administration of a loading dose. 24. The method according to any one of Embodiments 1 to 23, wherein administration of the Tn3 scaffold is effective in reducing the baseline score of tenderness and swollen joints in the subject after administration. 25. The method according to any one of Embodiments 1 to 24, wherein administration of the Tn3 scaffold is effective in reducing the baseline score of the subject on the Short Form 36 (SF-36) Health Survey after administration. 26. A method according to any one of Embodiments 1 to 25, wherein administration of a Tn3 scaffold is effective in improving the baseline score of the subject, the baseline score being selected from the group consisting of the Functional Assessment of Chronic Disease Treatment - Fatigue (FACIT-fatigue), PROMIS Fatigue Short Form 10a, Ocular Surface Disease Index (OSDI), EQ-5D-5L, and Patient's General Impression of Severity (PGIS). 27. A method according to any one of Embodiments 1 to 26, wherein administration of a Tn3 scaffold is effective in reducing baseline levels of inflammatory markers after administration, the markers being selected from the group consisting of immunoglobulins, β-2 microglobulins, C-reactive proteins, and combinations thereof. 28. A method according to any one of Embodiments 1 to 27, wherein administration of a Tn3 scaffold is effective in reducing baseline levels of a biomarker, the biomarker being selected from the group consisting of plasma-soluble CD40L, Ki67+CD27+ memory B cells, CD19, CD20, CD27, CD38, CD138, CD11c high-expression / high (bright / high) B cells, CD3, CD4, CD8, Tfh cells, serum CXCL13, rheumatoid factor, anti-SSA autoantibody (i.e., anti-Ro autoantibody), anti-SSB autoantibody (i.e., anti-La autoantibody), and combinations thereof. 29. A method according to any one of Embodiments 1 to 28, wherein administration of a Tn3 scaffold is effective in reducing the baseline level of disease symptoms, the disease symptoms being selected from the group consisting of fatigue, dry mouth, dry eyes, dry vagina, pain, and combinations thereof. 30. The method according to any one of Embodiments 1 to 29, wherein the expression level of a gene related to SS, or the level of the protein encoded by that gene, in the target blood sample decreases by 48 weeks after administration. 31. A method according to any one of Embodiments 1 to 30, wherein the level of B cells selected from the group consisting of CD27+ memory B cells, marginal zone B cells, plasmablasts, plasma cells, and combinations thereof decreases in the blood sample of the subject by 48 weeks after administration. 32. The method according to any one of Embodiments 1 to 31, wherein the subject is positive for anti-Ro autoantibody, rheumatoid factor (RF), or both anti-Ro autoantibody and RF. 33. The method according to any one of embodiments 1 to 32, wherein the Tn3 scaffold is administered intravenously. 34. The method according to any one of embodiments 1 to 33, wherein the Tn3 scaffold comprises two CD40L-specific monomer subunits linked in tandem. 35. The method according to Embodiment 34, wherein each of the two CD40L-specific monomer subunits comprises Sequence ID No. 3. 36. The method according to any one of embodiments 34 to 35, wherein the CD40L-specific monomer subunits are linked by a linker. 37. The method according to any one of Embodiments 1 to 36, wherein at least 34 CD40L-specific monomer subunits are directly fused to or conjugated to polyethylene glycol (PEG). 38. The method according to any one of embodiments 34 to 37, wherein at least one CD40L-specific monomer subunit is fused to or conjugated to polyethylene glycol (PEG) via a linker. 39. The method according to Embodiment 38, wherein the linker comprises a peptide linker. 40. The method according to Embodiment 39, wherein the linker includes SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, or SEQ ID NO: 10. 41. The method according to any one of embodiments 34 to 40, wherein at least one CD40L-specific monomer subunit is fused to or conjugated to albumin. 42. The method according to Embodiment 41, wherein the albumin is human serum albumin (HSA). 43. The method according to Embodiment 42, wherein the HSA is a mutant HSA containing Sequence ID No. 4. 44. The method according to any one of Embodiments 1 to 42, wherein the Tn3 scaffold includes Sequence ID No. 1.

[0210] Embodiment Set 6 1. Use of a Tn3 scaffold for the preparation of a pharmacopoeia for the treatment of Sjögren's syndrome (SS) in subjects requiring treatment of SS, wherein the pharmacopoeia is formulated to be administered at a dose of 1500 mg once every four weeks, the Tn3 scaffold comprising a CD40L-specific monomer subunit, the CD40L-specific monomer subunit comprising seven β-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 comprising SEQ ID NO: 11, the BC loop comprising SEQ ID NO: 12, the CD loop comprising SEQ ID NO: 13, the DE loop comprising SEQ ID NO: 14, the EF loop comprising SEQ ID NO: 15, and the FG loop comprising SEQ ID NO: 16, the subject having moderate to severe systemic disease activity as determined by the European Alliance of Associations for Rheumatology (EULAR) SS Disease Activity Index (ESSDAI) of five or more subjects. 2. The use described in Embodiment 1, wherein the subject has been administered at least three loading doses of 1500 mg each, prior to one dose every four weeks. 3. The use according to Embodiment 2, wherein at least three loading doses are administered in week 0, week 2, and week 4. 4. Use of a Tn3 scaffold for the preparation of a pharmacopoeia for the treatment of Sjögren's syndrome (SS) in subjects requiring treatment of SS, wherein the pharmacopoeia is formulated to be administered at a dose of 3000 mg once every 12 weeks, the Tn3 scaffold comprising a CD40L-specific monomer subunit, the CD40L-specific monomer subunit comprising seven β-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 comprising SEQ ID NO: 11, the BC loop comprising SEQ ID NO: 12, the CD loop comprising SEQ ID NO: 13, the DE loop comprising SEQ ID NO: 14, the EF loop comprising SEQ ID NO: 15, and the FG loop comprising SEQ ID NO: 16, the subject having moderate to severe systemic disease activity as determined by the European Alliance of Associations for Rheumatology (EULAR) SS Disease Activity Index (ESSDAI) of 5 or more subjects. 5. The use described in Embodiment 4, wherein the subject has been administered at least three loading doses of 3000 mg each, prior to one dose every 12 weeks. 6. The use according to Embodiment 5, wherein at least three loading doses are administered in week 0, week 4, and week 12. 7. Use of a Tn3 scaffold for the preparation of a pharmacopoeia for the treatment of Sjögren's syndrome (SS) in subjects requiring treatment of SS, wherein the pharmacopoeia is formulated to be administered at a dose of 1500 mg once every four weeks, the Tn3 scaffold comprising a CD40L-specific monomer subunit, the CD40L-specific monomer subunit comprising seven β-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 comprising SEQ ID NO: 11, the BC loop comprising SEQ ID NO: 12, the CD loop comprising SEQ ID NO: 13, the DE loop comprising SEQ ID NO: 14, the EF loop comprising SEQ ID NO: 15, and the FG loop comprising SEQ ID NO: 16, the subject having a moderate to severe symptomatic state as defined by an ESSPRI score ≥ 5 and low systemic disease activity as defined by an ESSDAI score < 5, and the subject experiencing a decrease in the Sjögren's Syndrome Patient Reported Index Assessment Diary (DASPRI) score after administration. 8. The use according to Embodiment 7, wherein the subject has been administered at least three loading doses of 1500 mg each, prior to one dose every four weeks. 9. The use according to Embodiment 8, wherein at least three loading doses are administered in week 0, week 2, and week 4. 10. Use of a Tn3 scaffold for the preparation of a pharmacopoeia for the treatment of Sjögren's syndrome (SS) in subjects requiring treatment of SS, wherein the pharmacopoeia is formulated to be administered once every 12 weeks at a dose of 3000 mg, the Tn3 scaffold comprising a CD40L-specific monomer subunit, the CD40L-specific monomer subunit comprising seven β-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 comprising SEQ ID NO: 11, the BC loop comprising SEQ ID NO: 12, the CD loop comprising SEQ ID NO: 13, the DE loop comprising SEQ ID NO: 14, the EF loop comprising SEQ ID NO: 15, and the FG loop comprising SEQ ID NO: 16, the subject having a moderate to severe symptomatic state as defined by an ESSPRI score ≥ 5 and low systemic disease activity as defined by an ESSDAI score < 5, and the subject experiencing a decrease in the Sjögren's Syndrome Patient Reported Index Assessment Diary (DASPRI) score after administration. 11. The use according to Embodiment 1, wherein the subject has been administered at least three loading doses of 3000 mg each, prior to 10 doses administered every 12 weeks. 12. The use according to Embodiment 11, wherein at least three loading doses are administered in week 0, week 4, and week 12. 13. Use according to any one of Embodiments 1 to 5, wherein the subject has an ESSDAI score of 5-7, 5-10, 5-13, or 10-13 prior to administration of the Tn3 scaffold. 14. Use according to any one of Embodiments 1 to 6, wherein the administration is effective in reducing the ESSDAI score. 15. The use according to Embodiment 14, wherein the ESSDAI score decreases by at least about 1, 2, 3, 4, 5, 6, or 7 points. 16. The use according to Embodiment 15, wherein the ESSDAI score decreases by at least about 6 points. 17. Use of any one of Embodiments 15-16, wherein the ESSDAI score decreases compared to the baseline ESSDAI score by at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 1 year after administration of the initial loading dose. 18. The use according to Embodiment 17, wherein the ESSDAI score decreases by 11 months after administration of the initial loading dose. 19. Use according to any one of Embodiments 7 to 18, wherein the salivary gland function of the target is improved after administration of the Tn3 scaffold, or within approximately 3 weeks, 1 month, 2 months, or 4 months after administration. 20. The use according to Embodiment 19, wherein salivary gland function is determined by the total salivary flow rate at stimulation. 21. The use according to any one of Embodiments 9 to 20, wherein the ESSPRI score decreases by at least approximately 1.5, 2, 3, 4, or 5 points after administration of a loading dose. 22. Use according to any one of Embodiments 7 to 21, wherein the DASPRI score decreases to 2 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months after administration. 23. The use according to Embodiment 22, wherein the DASPRI score decreases by at least about 5, 10, 15, or 20 points after administration of a loading dose. 24. The use according to any one of Embodiments 1 to 23, wherein the administration of the Tn3 scaffold is effective in reducing the baseline score of tenderness and swollen joints in the subject after administration. 25. The use according to any one of Embodiments 1 to 24, wherein administration of the Tn3 scaffold is effective in reducing the baseline score of the subject on the Short Form 36 (SF-36) Health Survey after administration. 26. A method of use according to any one of Embodiments 1 to 25, wherein administration of the Tn3 scaffold is effective in improving the baseline score of the subject, the baseline score being selected from the group consisting of the Functional Assessment of Chronic Disease Treatment - Fatigue (FACIT-fatigue), PROMIS Fatigue Short Form 10a, Ocular Surface Disease Index (OSDI), EQ-5D-5L, and Patient's General Impression of Severity (PGIS). 27. Use according to any one of Embodiments 1 to 26, wherein administration of the Tn3 scaffold is effective in reducing baseline levels of inflammatory markers after administration, and the markers are selected from the group consisting of immunoglobulins, β-2 microglobulins, C-reactive proteins, and combinations thereof. 28. Use according to any one of Embodiments 1 to 27, wherein administration of the Tn3 scaffold is effective in reducing baseline levels of a biomarker, and the biomarker is selected from the group consisting of plasma-soluble CD40L, Ki67+CD27+ memory B cells, CD19, CD20, CD27, CD38, CD138, CD11c high-expression / high (bright / high) B cells, CD3, CD4, CD8, Tfh cells, serum CXCL13, rheumatoid factor, anti-SSA autoantibody (i.e., anti-Ro autoantibody), anti-SSB autoantibody (i.e., anti-La autoantibody), and combinations thereof. 29. Use according to any one of Embodiments 1 to 28, wherein administration of the Tn3 scaffold is effective in reducing the baseline level of disease symptoms, the disease symptoms being selected from the group consisting of fatigue, dry mouth, dry eyes, dry vagina, pain, and combinations thereof. 30. The use according to any one of Embodiments 1 to 29, wherein the expression level of SS-related genes or the level of proteins encoded by those genes in the target blood sample decreases by 48 weeks after administration. 31. Use according to any one of Embodiments 1 to 30, wherein the level of B cells selected from the group consisting of CD27+ memory B cells, marginal zone B cells, plasmablasts, plasma cells, and combinations thereof decreases in the blood sample of the subject by 48 weeks after administration. 32. Use according to any one of Embodiments 1 to 31, wherein the subject is positive for anti-Ro autoantibody, rheumatoid factor (RF), or both anti-Ro autoantibody and RF. 33. Use according to any one of embodiments 1 to 32, wherein the Tn3 scaffold is administered intravenously. 34. Use according to any one of Embodiments 1 to 33, wherein the Tn3 scaffold includes two CD40L-specific monomer subunits linked in tandem. 35. The use according to Embodiment 34, wherein each of the two CD40L-specific monomer subunits comprises Sequence ID No. 3. 36. The use according to any one of embodiments 34 to 35, wherein the CD40L-specific monomer subunit is linked by a linker. 37. The use according to any one of Embodiments 1 to 36, wherein at least 34 CD40L-specific monomer subunits are directly fused to or conjugated to polyethylene glycol (PEG). 38. The use according to any one of embodiments 34 to 37, wherein at least one CD40L-specific monomer subunit is fused to or conjugated to polyethylene glycol (PEG) via a linker. 39. The use according to Embodiment 38, wherein the linker comprises a peptide linker. 40. The use according to Embodiment 39, wherein the linker includes SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, or SEQ ID NO: 10. 41. The use according to any one of embodiments 34 to 40, wherein at least one CD40L-specific monomer subunit is fused to or conjugated to albumin. 42. The use according to Embodiment 41, wherein the albumin is human serum albumin (HSA). 43. The use according to Embodiment 42, wherein the HSA is a mutant HSA containing Sequence ID No. 4. 44. Use according to any one of Embodiments 1 to 42, wherein the Tn3 scaffold includes Sequence ID 1. [Examples]

[0211] Example 1 - Phase 3 randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of dazodalibep in participants with moderate to severe systemic disease activity of Sjögren's syndrome. Disclosed herein is a phase 3 randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of dazodalibep in participants with moderate to severe systemic disease activity of Sjögren's syndrome (SS).

[0212] Objectives and evaluation criteria: The research objectives and evaluation items are shown in Table 2.

[0213] [Table 2-1]

[0214] [Table 2-2]

[0215] [Table 2-3]

[0216] [Table 2-4]

[0217] Test design This study is a phase 3, randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of dazodalibep in participants aged 18 years or older diagnosed with moderate to severe Sjögren's syndrome (SS), defined as a EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) score of 5 or higher. The study design is shown in Figure 1.

[0218] Participants will undergo a screening period of up to 28 days (see Table 3), followed by randomization and treatment until their 44th week visit. Approximately 510 participants will be randomized to receive either dazodarivep dose 1, dazodarivep dose 2, or placebo (1:1:1): • Dazodalibep dosage 1: 1500 mg intravenously (IV) (weeks 0, 2, and 4), then once every 4 weeks (Q4W) (total 13 doses: 13 doses of dazodalibep) (n=170) • Dazodalibep dosage 2: 3000 mg IV (weeks 0, 4, and 12), then once every 12 weeks (Q12W) (total 13 doses: 5 doses of dazodalibep; 8 doses of placebo) (n=170) • Placebo (Total 13 doses: 13 placebo doses) (n=170)

[0219] Participants will receive randomized treatment (dazodalibep or placebo) until week 44. The primary endpoint visit will take place at week 48. At the week 44 visit, eligible participants may provide written informed consent to screening for an open-label extension (OLE) trial to receive an open-label dose of dazodalibep. Participants who are not eligible for or do not wish to enroll in the OLE extension will make a final trial visit at week 56, after their last dose of the investigational drug (IP). The expected total participation period for each individual in this study, including screening, is a maximum of 420 days.

[0220] Eligible participants interested in participating in OLE will complete their participation in this Phase 3 trial at a visit at week 48, after completing all visit-based evaluations. These week 48 visit values ​​will serve as the baseline (day 1) for the OLE trial, and open-label dazodalibep dose 1 will be administered at or around the time of the final visit of this Phase 3 trial, week 48. All participants, including those enrolled in OLE, will not be informed of their Phase 3 treatment assignment until the Phase 3 trial is completed.

[0221] The primary objective of this study is to evaluate the effect of dazodalibep on systemic symptoms of SS in participants with moderate to severe systemic disease activity. This will be assessed by evaluating the change from baseline in the ESSDAI score at week 48.

[0222] [Table 3-1]

[0223] [Table 3-2]

[0224] Test group Selection Criteria To participate in this exam, an individual must meet all of the following criteria: 1. Adults, 18 years of age or older at the time of informed consent. 2. Diagnosed with SS based on meeting the 2016 American College of Rheumatology (ACR) / EULAR classification criteria. 3. The ESSDAI score is ≥ 5 at the time of screening. 4. Positive for either anti-Ro autoantibodies or rheumatoid factor (RF), or both, at the time of screening. 5. Sexually active, fertile women with unsterilized male partners must use highly effective contraception from the time they sign the Informed Consent Form (ICF) and agree to continue using such preventative measures until the end of the study; they must consult with their physician regarding discontinuing contraception after this point. Highly effective contraception includes: a. Combined hormonal contraceptives (containing estrogen and progestogen) that suppress ovulation: i. Oral ii. Inside the vagina iii. Transdermal iv. Injectable drugs b. Progestogen monotherapy with ovulation suppression: i. Oral ii. Injectable drugs iii. Embedded type c. Intrauterine devices d. Intrauterine hormone-releasing system e. Bilateral fallopian tube obstruction f. A partner with azoospermia (due to vasectomy or other medical reasons) i. Azoospermia is a very effective method of contraception if the partner is the sole sexual partner of a woman of childbearing age and it is confirmed that he does not have sperm. Otherwise, additional, very effective methods of contraception should be used. The spermatogenesis cycle is approximately 90 days. g.Abstinence i. Abstinence is considered a highly effective method only if it is a preferred normal lifestyle for the participant and the participant agrees to refrain from heterosexual intercourse from screening until the end of the study follow-up. Regular abstinence, rhythmic abstinence, and withdrawal methods are not acceptable as methods of contraception. It is necessary to recommend that female partners (of childbearing potential) of male study participants must use highly effective methods of contraception other than barrier methods. 1. A woman of childbearing potential is defined as a woman who has not undergone sterilization (sterilization includes bilateral tubal ligation, bilateral oophorectomy, or hysterectomy) or who is not postmenopausal (defined as the absence of menstruation for 12 months without other medical cause). 2. A partner who has undergone vasectomy is an extremely effective birth control method; however, the partner must be the sole sexual partner of the female trial participant who is capable of becoming pregnant, and the partner who has undergone vasectomy must have received a medical evaluation of the success of the surgery. 6. Male participants who have sexual activity with a female partner who may become pregnant and who have not been sterilized must use spermicide-containing male condoms and refrain from providing fresh, unwashed semen from day 1 until the end of the study. Because condoms can break or leak, the male's female partner must also be advised of the benefits of using a highly effective method of contraception. 7. Participants received the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) vaccine at least two weeks prior to screening, in accordance with any current local government guidelines. The first or subsequent doses of the COVID-19 vaccine under investigation are permitted, unless administered during the screening period or within one week after dose 1. If the vaccine is administered during this period, screening must be postponed to complete the vaccination schedule. 8. All of the following tuberculosis (TB) diagnostic criteria are met: a. Except for latent TB with documented evidence of appropriate treatment being completed locally, there is no history of latent or active TB prior to screening. b. There are no signs or symptoms suggestive of active TB based on medical history or physical examination. c. You have not had close contact with a person with active TB in recent times (within 12 weeks of screening) (close contact is defined as 4 hours or more per week, living in the same household, or living in a house frequently visited by a person with active TB). d. Negative interferon-gamma release assay (IGRA) test result for TB at screening, unless previously treated in accordance with inclusion criterion 8(a). Subjects with inconclusive test results may be retested, but if the retest is also inconclusive, the subject will be excluded. e. Chest X-ray images (obtained during the screening period or at any point within 12 weeks prior to screening) show no evidence of current active TB or other infection, or of any clinically significant abnormalities (except those attributable to SS) suggesting a history of TB, malignancy, or active disease.

[0225] Exclusion criteria If an individual meets any of the following criteria, that individual is not eligible for this exam: 1. Individuals with a history of definitive deep vein thrombosis, pulmonary embolism, or arterial thromboembolism within two years of screening. 2. A history or presence of polymyositis or dermatomyositis with complications, or systemic sclerosis. 3. Active malignant tumor or history of malignant tumor within the past five years, except in the following cases: a. A treated cervical carcinoma in situ that appears to have been successfully cured more than 12 months prior to screening; or b. Later basal cell carcinoma of the skin, which appears to have undergone curative treatment. 4. Individuals who are pregnant or breastfeeding during the study, or who are planning to become pregnant. 5. Individuals who have tested positive for hepatitis B or human immunodeficiency virus (HIV) infection, or who have received treatment for it. A positive test for hepatitis B infection at the time of screening is defined as follows: (1) positive for hepatitis B surface antigen; or (2) positive for hepatitis B core antibody. Individuals who have tested positive for hepatitis C or who have a history of treatment for hepatitis C are excluded unless there is a record of a sustained viral response to antiviral drugs approved for the treatment of hepatitis C (defined as a state in which hepatitis C RNA viral levels are undetectable for at least 24 weeks after the end of treatment). Patients with advanced fibrosis or cirrhosis due to hepatitis C should not be enrolled. 6. Individuals who test positive for SARS-CoV-2 on the day of randomization, or who have symptoms suggestive of SARS-CoV-2 at the time of randomization, or who have been significantly exposed to COVID-19 within 10 days prior to randomization. Individuals with COVID-19 or who have been exposed to COVID-19 may have their randomization delayed by 10 days and be randomized after recovery. Otherwise, rescreening will be required. 7. Individuals who have the following: a. A history of two or more episodes of herpes zoster and / or opportunistic infections in the past 12 months (see Table 4), unless there has been an unusually severe non-invasive herpes simplex, oral candidiasis, vaginal candidiasis, or cutaneous fungal infection at any site within the past 12 months. b. Active infection requiring systemic treatment at the time of screening or before randomization, or a history of three or more infections requiring IV antibiotics within 12 months prior to screening. 8. Individuals with a history of severe allergies or reactions to any component of the IP formulation or to any other biological therapy. 9. Any individual having any severe cardiovascular, respiratory, endocrine, gastrointestinal, hematological, neurological, psychiatric, or systemic disorder or any other medical condition that, in the opinion of the principal investigator, could put the individual at risk of unacceptable complications or interfere with the assessment of intrapreventive hazard (IP). 10. Individuals who are unable or unwilling to comply with the requirements of the protocol (e.g., due to active drug or alcohol abuse or other reasons). 11. Individuals who have received a live (attenuated) vaccine within four weeks prior to randomization, or who are scheduled to receive a live vaccine during participation in the study. While vaccination with non-live vaccines is permitted during the study period (see inclusion criterion 7 for COVID-19 vaccines), for subjects scheduled to receive a vaccine within one month of their first dose, consideration should be given to completing vaccination before the start of administration. 12. The last administration of an experimental or investigational biological agent or oral medication (other than those listed in Exclusion Criterion 16) was within six months of the screening. 13. Individuals who have previously received any biological B-cell depletion therapy (e.g., rituximab, ocrelizumab, inebilizumab, ofatumumab, or ianarumab) within 12 months prior to randomization, or other B-cell targeted therapy (e.g., belimumab) within 3 months prior to screening. 14. Treatment with injectable corticosteroids (including intra-articular [IA] or intramuscular [IM]) or oral prednisone or equivalent at doses exceeding 10 mg / day within 6 weeks prior to randomization. For underlying conditions such as SS, rheumatoid arthritis (RA), or systemic lupus erythematosus (SLE), concomitant treatment with oral corticosteroids of 10 mg / day or less of prednisone or equivalent is permitted, provided that this dose is stable from at least 2 weeks prior to screening until randomization (day 1) and is expected to remain stable throughout the duration of treatment. Inhaled, intranasal, or topical corticosteroids are permitted if dose stabilization is expected during the study. 15. Individuals who have been treated with systemic corticosteroids for a total of more than two weeks within the six months prior to screening for indications other than SS, RA, and SLE. 16. Use of the following drug therapies: a. Antimalarial drugs (e.g., chloroquine, hydroxychloroquine, quinacrine) if initiated within 8 weeks prior to screening or if the dosage has been changed. b. Mycophenolate mofetil (MTX) if the dose exceeds 25 mg / week, or if there has been any change or initiation of a new dose within 4 weeks prior to screening. c. If the dose exceeds 150 mg / day, or if there has been any dose change or initiation of a new dose within 4 weeks prior to screening, azathioprine. d. Leflunomide if the dose exceeds 20 mg / day, or if there has been any change or initiation of a new dose within 4 weeks prior to screening. e. If the dose exceeds 2g / day, mycophenolate mofetil (MMF) may be used if there has been any change or initiation of a new dose within 4 weeks prior to screening. f. Any other disease-modifying antirheumatic drug (DMARD), immunosuppressant, or antiproliferative agent whose final dose was taken within the following timeframe: i. Four weeks prior to screening; or ii. Drug-specific half-life elimination period (if longer than 4 weeks). g. Any drug therapy that, in the opinion of the principal investigator, could interfere with the evaluation of IP or the interpretation of the study results. h. Increased dose or initiation of cyclosporine eye drops (Restasis®) or Lifitegrast eye drops (Xiidra®) within two weeks prior to screening. i. If the patient is taking the above medications, no adjustments are permitted during the screening period, and the medication is expected to remain stable throughout the entire study period. 17. Individuals who have previously received treatment with an anti-CD40L compound at any point prior to screening. 18. Individuals who have had any of the following blood tests at the time of screening: a. Aspartate aminotransferase (AST) > 2 × upper limit of normal (ULN) b. Alanine aminotransferase (ALT) > 2 × ULN c. Total bilirubin (TBL) > 2 × ULN (unless Gilbert's syndrome is recorded in the medical history) d. Hemoglobin <75 g / L e. Neutrophil <0.8×10 9 / L f. Lymphocytes < 0.8 × 10⁻⁶ 9 / L g. Platelets <100×10 9 / L h. International normalized ratio (INR) of prothrombin time > 1.3 × ULN

[0226] [Table 4-1]

[0227] [Table 4-2]

[0228] Lifestyle considerations Meat and dietary restrictions: There are no dietary or fasting restrictions during the examination period.

[0229] Activities: There are no restrictions on activities during this exam.

[0230] Criteria for temporarily delaying randomization Individuals with COVID-19 or those exposed to COVID-19 may have their randomization delayed by 10 days and be randomized after recovery. Otherwise, rescreening may be required (see Exclusion Criterion 11).

[0231] Trial interventions and combination therapies Investigational drug to be administered IP management is carried out by a blinded administrator. IP preparation is carried out by an uninvolved, open-label pharmacist / IP administrator or site staff member. Prepared IP must be sealed in a bag before being provided to the blinded administrator.

[0232] Table 5 includes descriptions of the IP used in this study, its formulation, unit dose intensity, dose level, route of administration, use, procurement, and packaging.

[0233] [Table 5]

[0234] Blinding Participants were randomly assigned to the test group in a 1:1:1 ratio (see Table 6).

[0235] [Table 6]

[0236] Continued access to IP after the exam Participants will receive randomized treatment (dazodalibep or placebo) until week 44. The primary endpoint visit will take place at week 48. At the week 44 visit, eligible participants may be screened for an OLE trial to receive open-label dazodalibep, which will commence after this trial is completed at week 48.

[0237] Table 7 shows the schedule for trial evaluations during the treatment period.

[0238] Previous treatme...

Claims

1. A method for treating a subject in need of treatment for Sjögren's syndrome (SS), comprising administering a Tn3 scaffold, wherein the Tn3 scaffold comprises a CD40L-specific monomer subunit, the CD40L-specific monomer subunit comprising seven β-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. The Tn3 scaffold is administered once every four weeks at a dose of approximately 1500 mg. The subject has a moderate to severe symptomatic state as defined by an ESSPRI score ≥ 5 and low systemic disease activity as defined by an ESSDAI score < 5, and the method is such that the Sjögren's Syndrome Patient Reporting Index (DASPRI) score decreases in the subject after administration.

2. The method according to claim 1, wherein, prior to the administration once every four weeks, the subject was administered at least three loading doses of 1500 mg each.

3. The method according to claim 2, wherein the aforementioned at least three loading doses are administered in week 0, week 2, and week 4.

4. A method for treating a subject in need of treatment for Sjögren's syndrome (SS), comprising administering a Tn3 scaffold, wherein the Tn3 scaffold comprises a CD40L-specific monomer subunit, the CD40L-specific monomer subunit comprising seven β-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. The Tn3 scaffold is administered once every 12 weeks at a dose of approximately 3000 mg. The subject has a moderate to severe symptomatic state as defined by an ESSPRI score ≥ 5 and low systemic disease activity as defined by an ESSDAI score < 5, and the method is such that the Sjögren's Syndrome Patient Reporting Index (DASPRI) score decreases in the subject after administration.

5. The method according to claim 4, wherein, prior to the administration once every 12 weeks, the subject was administered at least three loading doses of 3,000 mg each.

6. The method according to claim 5, wherein the aforementioned three loading doses are administered in week 0, week 4, and week 12.

7. The method according to any one of claims 1 to 6, wherein the salivary gland function of the subject is improved after administration of the Tn3 scaffold, or within approximately 3 weeks, 1 month, 2 months, or 4 months after administration.

8. The method according to claim 7, wherein salivary gland function is determined by the total salivary flow rate at stimulation.

9. The method according to any one of claims 1 to 8, wherein the ESSPRI score decreases after administration.

10. The method according to claim 9, wherein the ESSPRI score is reduced by at least about 1.5, 2, 3, 4, or 5 points.

11. The method according to any one of claims 1 to 10, wherein the DASPRI score decreases by 2 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months after administration.

12. The method according to claim 11, wherein the DASPRI score is reduced by at least about 5, 10, 15, or 20 points.

13. The method according to any one of claims 1 to 12, wherein the administration of the Tn3 scaffold is effective in reducing the baseline score of tenderness and number of swollen joints in the subject after the administration.

14. The method according to any one of claims 1 to 13, wherein the administration of the Tn3 scaffold is effective in reducing the baseline score of the subject's short-form 36 (SF-36) health survey after the administration.

15. The method according to any one of claims 1 to 14, wherein the administration of the Tn3 scaffold is effective in improving the baseline score of the subject, and the baseline score is selected from the group consisting of the functional assessment of chronic disease treatment - fatigue (FACIT-fatigue), PROMIS fatigue short form 10a, ocular surface disease index (OSDI), EQ-5D-5L, and patient's general impression of severity (PGIS).

16. The method according to any one of claims 1 to 15, wherein the administration of the Tn3 scaffold is effective in reducing baseline levels of inflammatory markers after the administration, and the markers are selected from the group consisting of immunoglobulins, β-2 microglobulins, C-reactive proteins, and combinations thereof.

17. The method according to any one of claims 1 to 16, wherein the administration of the Tn3 scaffold is effective in reducing the baseline level of the biomarker, and the biomarker is selected from the group consisting of plasma soluble CD40L, Ki67+CD27+ memory B cells, CD19, CD20, CD27, CD38, CD138, CD11c high-expression / high (bright / high) B cells, CD3, CD4, CD8, follicular helper T (Tfh) cells, serum CXCL13, rheumatoid factor, anti-SSA autoantibody, anti-Ro autoantibody, anti-SSB autoantibody, anti-La autoantibody, and combinations thereof.

18. The method according to any one of claims 1 to 17, wherein the administration of the Tn3 scaffold is effective in reducing the baseline level of disease symptoms, the disease symptoms being selected from the group consisting of fatigue, dry mouth, dry eyes, dry vagina, pain, and combinations thereof.

19. The method according to any one of claims 1 to 18, wherein the expression level of a gene related to SS, or the level of the protein encoded by the gene, in the target blood sample decreases by 48 weeks after administration.

20. The method according to any one of claims 1 to 19, wherein the level of B cells selected from the group consisting of CD27+ memory B cells, marginal zone B cells, plasmablasts, plasma cells, and combinations thereof decreases in the target blood sample by 48 weeks after administration.

21. The method according to any one of claims 1 to 20, wherein the subject is positive for anti-Ro autoantibodies, rheumatoid factor (RF), or both anti-Ro autoantibodies and RF.

22. The method according to any one of claims 1 to 21, wherein the Tn3 scaffold is administered intravenously.

23. The method according to any one of claims 1 to 22, wherein the Tn3 scaffold comprises two CD40L-specific monomer subunits linked in tandem.

24. The method according to claim 23, wherein each of the two CD40L-specific monomer subunits includes SEQ ID NO:

3.

25. The method according to any one of claims 23 to 24, wherein the CD40L-specific monomer subunits are linked by a linker.

26. The method according to any one of claims 23 to 25, wherein at least one CD40L-specific monomer subunit is directly fused to or conjugated to polyethylene glycol (PEG).

27. The method according to any one of claims 23 to 26, wherein at least one CD40L-specific monomer subunit is fused to or conjugated to polyethylene glycol (PEG) via a linker.

28. The method according to claim 27, wherein the linker includes a peptide linker.

29. The method according to claim 28, wherein the linker includes sequence number 7, sequence number 8, sequence number 9, or sequence number 10.

30. The method according to any one of claims 23 to 29, wherein at least one CD40L-specific monomer subunit is fused to or conjugated to albumin.

31. The method according to claim 30, wherein the albumin is human serum albumin (HSA).

32. The method according to claim 31, wherein the HSA is a mutant HSA containing Sequence ID No.

4.

33. The method according to any one of claims 1 to 32, wherein the Tn3 scaffolding includes sequence number 1.

34. The method according to any one of claims 1 to 33, wherein the subject has coexisting autoimmune indicators.

35. The method according to claim 34, wherein the coexisting autoimmune indicator is rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), or both RA and SLE.

36. The method according to claim 34, wherein the coexisting autoimmune indicator is rheumatoid arthritis.

37. The method according to claim 34, wherein the coexisting autoimmune indicator is systemic lupus erythematosus.

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