CD40L-specific TN3-derived scaffolds for treatment and prevention of sicca syndrome

Abstract

Compositions and methods comprising a CD40L specific Tn3 scaffold are provided. Also provided are methods of using the same in the prevention and treatment of sicca syndrome.

Description

[0001] Cross-reference to related applications

[0002] This application claims priority to U.S. Application No. 63 / 492,715, filed March 28, 2023; U.S. Application No. 63 / 504,003, filed May 24, 2023; U.S. Application No. 63 / 584,134, filed September 20, 2023; and U.S. Application No. 63 / 624,959, filed January 25, 2024, each of which is incorporated herein by reference in its entirety for all purposes.

[0003] Reference to electronic sequence listing

[0004] The contents of the electronic sequence list (HOPA_067_04WO_SeqList_ST26.xml; size: 23,046 bytes; creation date: February 16, 2024) are incorporated herein by reference in their entirety. Technical Field

[0005] This disclosure relates to compositions comprising Tn3 scaffolds and methods of using these compositions in the treatment and prevention of Sjögren's syndrome. Background Technology

[0006] Sjögren's syndrome Severe dryness syndrome (SS) is a systemic autoimmune disease characterized by chronic lymphocytic inflammation of exocrine glands (primarily salivary and lacrimal glands), leading to loss of function manifested as excessive dryness. The subjective aspects of SS (including the patient's perception of dryness, musculoskeletal pain, and fatigue) can be debilitating and have been shown to have a substantial negative impact on quality of life (QoL). The main contributing factors to reduced QoL are dryness and fatigue. QoL is also affected by psychological and emotional challenges and impairment in social life, including dependence on relatives in daily life, difficulty at work, and difficulty in other tasks.

[0007] Currently, there are no approved immunomodulators or evidence-based treatment guidelines for treating the extraglandular manifestations of Sjögren's syndrome (SS). Therefore, new treatments for Sjögren's syndrome are needed. Attached Figure Description

[0008] Figure 1 An exemplary study flowchart is shown. Δ = Change; D = Days; Dazo = dazolibep; EoS = End of Study; EP = Endpoint; DASPRI = Sjögren's Syndrome Patient Reporting Index Diary (Diary for Assessing) Patient Reported Index); ESSDAI = EULAR Sjogren’s Syndrome Disease Activity Index; EULAR = European Alliance of Associations for Rheumatology; n = number of subjects in treatment group; PBO = placebo; q4wk = every 4 weeks; q12wk = every 12 weeks; wk = weeks. Note: Day 1 randomization stratification based on geographic location (North America and Europe vs. Japan vs. rest of the world), coexisting RA or SLE (yes vs. no), and screening ESSDAI score (<10 vs. >10).

[0009] Figure 2 An exemplary study flow diagram is shown. D = days; Dazo = dazolibep; EP = endpoint; ESSPRI = EULAR Sjogren’s Syndrome Patient Reported Index; EULAR = European Alliance of Associations for Rheumatology; n = number of subjects in treatment group; PBO = placebo; q4wk = every 4 weeks; q12wk = every 12 weeks; wk = weeks. Day 1 randomization stratification based on geographic location (North America and Europe vs. Japan vs. rest of the world) and screening ESSPRI score (<7.5 vs. >7.5).

[0010] Figure 3 An exemplary study flow diagram is shown. DAZ = dazolibep; ESSDAI = EULAR Sjogren’s Syndrome Disease Activity Index; EULAR = European League Against Rheumatism. Arrows indicate days of dazolibep or placebo administration.

[0011] Figure 4 An exemplary change from baseline in ESSDAI total score is shown. Change from baseline in ESSDAI total score is plotted as a function of time (days). The schedule of dazolibep and placebo administration is described in Figure 3

[0012] Figure 5 An exemplary change from baseline in ESSPRI total score is shown. Change from baseline in ESSPRI total score is plotted as a function of time (days). The schedule of dazolibep and placebo administration is described in Figure 3 ​Analyses were performed using mixed model repeated measures (MMRM); DAZ = daratumumab; ESSDAI = EULAR Sjogren's Syndrome Disease Activity Index; LS = least squares; MCID = minimal clinically important difference; SE = standard error.

[0013] Figures 6A-6C Example changes from baseline in 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 schedule of daratumumab and placebo administration is described in Figure 3

[0014] Figures 7A-7G Example baseline changes in blood biomarkers of B cell and T cell co-stimulation as a function of time (baseline to day 365) with daratumumab or placebo administration are shown: CXCL13 Figure 7A ; rheumatoid factor (RF; Figure 7B ); Ki67+post-switch memory B cells Figure 7C ; plasmablasts Figure 7D ; CD11cb+ B cells Figure 7E ; Ki67+T cells Figure 7F ; TfH cells Figure 7G . The schedule of daratumumab and placebo administration is described in Figure 3 . Data are presented as median fold change (FC) ± IQR from baseline. Black symbols represent placebo groups (subjects received placebo in Phase I and daratumumab in Phase II). Pink symbols represent daratumumab groups (subjects received daratumumab in Phase I and placebo in Phase II). Statistical significance of differences in FC from baseline values between treatment groups was assessed using the Mann-Whitney U test. Subjects were only included in the RF analysis if they were positive at baseline. *p < 0.05; **p < 0.01; ***p < 0.001; DAZ = daratumumab; FC = fold change; IQR = interquartile range; PBO = placebo; RF = rheumatoid factor.

[0015] Figure 8 Example biomarker heat maps showing median fold change (FC) from baseline to day 365 using biomarkers from Figures 7A-7G and ESSDAI total score are shown. DAZ = daratumumab; ESSDAI = EULAR Sjogren's Syndrome Disease Activity Index; PBO = placebo.

[0016] ​ Figure 9 An exemplary study flow diagram is shown. DAZ = darotenecept; ESSPRI = EULAR Sjogren’s Patient Reported Index; EULAR = European League Against Rheumatism. Arrows indicate days of darotenecept or placebo administration.

[0017] Figure 10 An exemplary change from baseline in ESSPRI total score is shown. Change from baseline in ESSPRI total score is plotted as a function of time (days). The schedule of darotenecept and placebo administration is described in Figure 9 . Analysis was performed using mixed model repeated measures (MMRM); DAZ = darotenecept; ESSDAI = EULAR Sjogren’s Disease Activity Index; LS = least squares; MCID = minimal clinically important difference; SE = standard error.

[0018] Figure 11A-11C An exemplary change from baseline in dryness ( Figure 11A ), fatigue ( Figure 11B ), and pain ( Figure 11C ) is shown. Change from baseline is plotted as a function of time (days). The schedule of darotenecept and placebo administration is described in Figure 9 . Data are plotted by study visit; analysis was performed using MMRM. **p < 0.01; BSL = baseline; DAZ = darotenecept; LS = least squares; PBO = placebo; SE = standard error.

[0019] Figure 12 An exemplary proportion of subjects achieving an ESSPRI response by darotenecept treatment up to Day 169 is shown compared to placebo. ESSPRI response rate is plotted as a function of days. ESSPRI response is defined as a decrease of > 1 point or 15% in ESSPRI score from baseline without premature study discontinuation and without rescue therapy. Data were analyzed using a logistic regression model. ***p < 0.001. CI = confidence interval. DAZ = darotenecept. ESSPRI = EULAR Sjogren’s Patient Reported Index. EULAR = European League Against Rheumatism.

[0020] Figure 13A An exemplary change from baseline in FACIT-Fatigue score ( Figure 13A ), OSDI ( Figure 13B ), and PGIS ( Figure 13C ) is shown. Change from baseline is plotted as a function of time (days). The schedule of darotenecept and placebo administration is described in Figure 9 . SUMMARY

[0021] Provided herein are methods of treating Sjogren's Syndrome (SS) in a subject in need thereof, the method comprising: administering a Tn3 scaffold, wherein the Tn3 scaffold comprises a CD40L-specific monomer subunit, wherein the CD40L-specific monomer subunit comprises seven beta strands designated A, B, C, D, E, F, and G, and six loop regions designated AB, BC, CD, DE, EF, and FG, wherein the AB loop comprises SEQ ID NO: 11, the BC loop comprises SEQ ID NO: 12, the CD loop comprises SEQ ID NO: 13, the DE loop comprises SEQ ID NO: 14, the EF loop comprises SEQ ID NO: 15, and the FG loop comprises SEQ ID NO: 16, wherein the Tn3 scaffold is administered at a dose of about 1500 mg once every 4 weeks, wherein the subject has a moderate to severe symptom status defined by an ESSPRI score > 5, has low systemic disease activity defined by an ESSDAI score < 5, and wherein after administration the subject has a reduced Sjogren's Syndrome Patient-Reported Index Assessment Diary (DASPRI) score. In aspects, the subject is administered at least 3 loading doses of 1500 mg each prior to the once every 4 weeks dosing. In aspects, the at least 3 loading doses are administered at week 0, week 2, and week 4.

[0022] Provided herein are methods of treating Sjogren's Syndrome (SS) in a subject in need thereof, the method comprising: administering a Tn3 scaffold, wherein the Tn3 scaffold comprises a CD40L-specific monomer subunit, wherein the CD40L-specific monomer subunit comprises seven beta strands designated A, B, C, D, E, F, and G, and six loop regions designated AB, BC, CD, DE, EF, and FG, wherein the AB loop comprises SEQ ID NO: 11, the BC loop comprises SEQ ID NO: 12, the CD loop comprises SEQ ID NO: 13, the DE loop comprises SEQ ID NO: 14, the EF loop comprises SEQ ID NO: 15, and the FG loop comprises SEQ ID NO: 16, wherein the Tn3 scaffold is administered at a dose of about 3000 mg once every 12 weeks, wherein the subject has a moderate to severe symptom status defined by an ESSPRI score > 5, has low systemic disease activity defined by an ESSDAI score < 5, and wherein after administration the subject has a reduced Sjogren's Syndrome Patient-Reported Index Assessment Diary (DASPRI) score. In aspects, the subject is administered at least 3 loading doses of 3000 mg each prior to the once every 12 weeks dosing. In aspects, the at least 3 loading doses are administered at week 0, week 4, and week 12.

[0023] In aspects, following administration of the Tn3 scaffold, salivary gland function of the subject is improved about 3 weeks, 1 month, 2 months, or 4 months after the administration. In aspects, salivary gland function is determined by complete stimulated saliva flow. In aspects, following the administration, the ESSPRI score is reduced. In aspects, the ESSPRI score is reduced by at least about 1.5, 2, 3, 4, or 5 points. In aspects, the DASPRI score is reduced 2 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months after the administration. In aspects, the DASPRI score is reduced by at least about 5, 10, 15, or 20 points. In aspects, administration of the Tn3 scaffold is effective to reduce the subject’s tender and swollen joint count baseline score after administration.

[0024] In aspects, administration of the Tn3 scaffold is effective to reduce the Short Form 36 (SF-36) Health Survey baseline score in the subject following administration. In aspects, administration of the Tn3 scaffold is effective to improve the baseline score in the subject, wherein the baseline scores are selected from the group consisting of: Functional Assessment of Chronic Illness Therapy Fatigue Scale (FACIT-Fatigue), PROMIS Fatigue Short Form 10a, Ocular Surface Disease Index (OSDI), EQ-5D-5L, and Patient Global Impression-Severity (PGIS). In aspects, administration of the Tn3 scaffold is effective to reduce baseline levels of inflammatory markers following administration, and wherein the markers are selected from the group consisting of: immunoglobulin, beta-2 microglobulin, C-reactive protein, and combinations thereof. In aspects, administration of the Tn3 scaffold is effective to reduce baseline levels of biomarkers, and wherein the biomarkers are selected from the group consisting of: plasma soluble CD40L, Ki67+CD27+ memory B cells, CD19, CD20, CD27, CD38, CD138, CD11c bright / high B cells, CD3, CD4, CD8, T follicular helper (Tfh) cells, serum CXCL13, rheumatoid factor, anti-SSA autoantibody, anti-Ro autoantibody, anti-SSB autoantibody, anti-La autoantibody, and combinations thereof. In aspects, administration of the Tn3 scaffold is effective to reduce baseline levels of disease symptoms, and wherein the disease symptoms are selected from the group consisting of: fatigue, dry mouth, dry eyes, dry vagina, pain, and combinations thereof. In aspects, to week 48 following the administration, the expression level of a gene associated with SS or the level of a protein encoded by the gene in a blood sample of the subject is reduced. In aspects, to week 48 following the administration, the level of B cells in a blood sample of the subject is reduced, the B cells are selected from the group consisting of: CD27+ memory B cells, marginal zone B cells, plasmablasts, plasma cells, and combinations thereof. In aspects, the subject is positive for anti-Ro autoantibody, rheumatoid factor (RF), or both anti-Ro autoantibody and RF. In aspects, the Tn3 scaffold is administered intravenously.

[0025] In the methods disclosed herein, the Tn3 scaffold comprises two CD40L-specific monomeric subunits linked in series. In aspects, the two CD40L-specific monomeric subunits each comprise SEQ ID NO: 3. In aspects, the CD40L-specific monomeric subunits are linked by a linker. In aspects, at least one CD40L-specific monomeric subunit is directly fused or conjugated to polyethylene glycol (PEG). In aspects, at least one CD40L-specific monomeric subunit is fused or conjugated to polyethylene glycol (PEG) via a linker. In aspects, the linker comprises a peptide linker. In aspects, the linker comprises SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, or SEQ ID NO: 10. In aspects, at least one CD40L-specific monomeric subunit is fused or conjugated to albumin. In aspects, the albumin is human serum albumin (HSA). In aspects, the HSA is a variant HSA comprising SEQ ID NO: 4. In aspects, the Tn3 scaffold comprises SEQ ID NO: 1.

[0026] In aspects, the subject of the disclosure has a co-existing autoimmune indication. In aspects, the co-existing autoimmune indication is rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), or both RA and SLE. In aspects, the co-existing autoimmune indication is rheumatoid arthritis. In aspects, the co-existing autoimmune indication is systemic lupus erythematosus. DETAILED DESCRIPTION

[0027] DEFINITIONS

[0028] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this subject matter belongs. All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety. In case of conflict between the disclosure of the specification (including the definitions) and the disclosure of the incorporated references, the specification (including the definitions) controls. Furthermore, the materials, methods, and examples described herein are illustrative only and are not intended to be limiting.

[0029] As used in this specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to “a compound” includes a mixture of compounds, and the like.

[0030] The term "about" or "approximately," when immediately preceding a numerical value, means a range (e.g., plus or minus 10% of the value). For example, "about 50" can mean 45 to 55, "about 25,000" can mean 22,500 to 27,500, etc., unless the context of the disclosure indicates otherwise or such interpretation is inconsistent with the definition of the term "about" provided herein. For example, in a list of numerical values such as "about 49, about 50, about 55,...", "about 50" means a range extending to less than half the interval between the values immediately before and after, e.g., greater than 49.5 to less than 52.5. Furthermore, the phrase "less than about" a certain value or "greater than about" a certain value shall be interpreted according to the definition of the term "about" provided herein. Similarly, when preceding a series of numerical values or a range of values (e.g., "about 10, 20, 30" or "about 10-30"), the term "about" refers to all values in the series or the range of values, respectively.

[0031] As used herein, the term "subject" refers to any subject for whom diagnosis, prognosis, or treatment is desired, e.g., a human or non-human mammal. The term "subject" can mean a human or non-human mammal affected by, likely to be affected by, or suspected of being affected by a disease. In aspects, the subject is a mammal. Mammals include primates (such as humans, monkeys, chimpanzees, and apes) and non-primate mammals (such as domesticated animals).

[0032] As used herein, the term "subject in need thereof includes a subject who can or will benefit from the methods described herein. Subjects in need of treatment include, but are not limited to, those already suffering from a condition or disorder, those prone to a condition or disorder, those suspected of having a condition or disorder, and those to be prevented, ameliorated, or reversed from a condition or disorder.

[0033] As used herein, "fused" refers to the recombinant joining of at least two polypeptides. As used herein, "conjugated" refers to the formation of a bond between two components through a chemical reaction. Typically, the two components conjugated to each other are chemically linked via a covalent bond.

[0034] As used herein, "treating" or "treat" describes the management and care of a subject for the purpose of combating the disease, condition, or disorder and includes the administration of a Tn3 scaffold used in the methods described herein to alleviate symptoms or complications of a disease, condition, or disorder, or to eliminate the disease, condition, or disorder. Thus, the terms "treat" or "treating" refer to treatments where the goal is to slow (lessen) or stop the progression of a disease (e.g., an autoimmune disease or disorder). Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilization (i.e., not worsening) of the state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (partial or total), whether

[0035] As used herein, “effective dose” describes the amount of a Tn3 scaffold used in the methods described herein to reduce or eliminate one or more symptoms of a disease, condition, or disorder.

[0036] The term “identity” when referring to a nucleic acid sequence or a protein sequence is used to denote similarity between two sequences. Unless otherwise indicated, the percent identity described herein is determined using the BLAST algorithm available at the web address blast.ncbi.nlm.nih.gov / Blast.cgi using default parameters.

[0037] Tn3 scaffold

[0038] Provided herein are compositions that bind CD40L. In aspects, the provided compositions comprise a CD40L antagonist. In aspects, provided herein are compositions comprising a Tn3 scaffold protein comprising a CD40L specific monomer subunit (e.g., “Tn3 scaffold”). In aspects, provided herein are compositions comprising a Tn3 scaffold comprising two CD40L specific monomer subunits. In aspects, the CD40L specific monomer subunit is also referred to as a CD40L specific Tn3 monomer. As used herein, the term “Tn3 scaffold” refers to a molecule comprising at least one Fnlll scaffold, wherein the A β chain comprises SEQ ID NO: 5, 23, or 24, the B β chain comprises SEQ ID NO: 6, the C β chain comprises SEQ ID NO: 17, the D β chain comprises SEQ ID NO: 18, the E β chain comprises SEQ ID NO: 19, the F β chain comprises SEQ ID NO: 20, and the G β chain comprises SEQ ID NO: 21.

[0039] In aspects, the provided compositions can comprise any Tn3 scaffold having an amino acid sequence as described in International Application No. PCT / US2012 / 059477 and PCT / US2019 / 052997, which are incorporated by reference herein in their entireties. In aspects, the provided compositions can comprise a Tn3 scaffold having an amino acid sequence as set forth in SEQ ID NO: 1 (referred to herein as dazolibep). Dazolibep can also be referred to as VIB4920, MEDI4920, or HZN-4920.

[0040] In aspects, the CD40L monomer subunit of the Tn3 scaffold comprises seven beta strands designated A, B, C, D, E, F, and G and six loop regions designated AB, BC, CD, DE, EF, and FG. In aspects, the Tn3 scaffold comprises a single CD40L specific monomer subunit. In aspects, the Tn3 scaffold comprises two CD40L specific monomer subunits. In aspects, the two CD40L specific monomer subunits are connected in series. In aspects, the two CD40L specific monomer subunits are connected by a linker. In aspects, the linker comprises a peptide linker, which can be a flexible peptide linker. In aspects, the peptide linker comprises a (GmX)n sequence, where X is serine (S), alanine (A), glycine (G), Leu (L), isoleucine (I), or valine (V); m and n are integer values; m is 1, 2, 3, or 4; and n is 1, 2, 3, 4, 5, 6, or 7.

[0041] In aspects, the Tn3 scaffold comprises a linker comprising a functional moiety. In aspects, the functional moiety is an immunoglobulin or fragment thereof. In aspects, the immunoglobulin or fragment thereof comprises an Fc domain. In aspects, the Fc domain is incapable of inducing at least one FcyR-mediated effector function (e.g., Fc deficient). In aspects, the at least one FcyR-mediated effector function is antibody-dependent cellular cytotoxicity (ADCC).

[0042] In aspects, the Tn3 scaffold comprises a CD40L specific monomer subunit comprising seven beta strands designated A, B, C, D, E, F, and G and six loop regions designated AB, BC, CD, DE, EF, and FG, wherein the AB loop comprises or consists of SEQ ID NO: 11, the BC loop comprises or consists of SEQ ID NO: 12, the CD loop comprises or consists of SEQ ID NO: 13, the DE loop comprises or consists of SEQ ID NO: 14, the EF loop comprises or consists of SEQ ID NO: 15, and the FG loop comprises or consists of SEQ ID NO: 16. In aspects, the Tn3 scaffold comprises or consists of SEQ ID NO: 1 (also known as VIB4920). In aspects, beta strand A comprises or consists of SEQ ID NO: 5, beta strand B comprises or consists of SEQ ID NO: 6, beta strand C comprises or consists of SEQ ID NO: 17, beta strand D comprises or consists of SEQ ID NO: 18, beta strand E comprises or consists of SEQ ID NO: 19, beta strand F comprises or consists of SEQ ID NO: 20, and beta strand G comprises or consists of SEQ ID NO: 21.

[0043] In aspects, the one or more CD40L-specific Tn3 monomers have a beta strand A comprising or consisting of IEV (SEQ ID NO: 5), RLDAPSQIEV (SEQ ID NO: 23), or SQIEV (SEQ ID NO: 24). In aspects, the Tn3 scaffold can comprise one or more CD40L-specific Tn3 monomers having the same or different beta strand A sequence. For example, a first CD40L-specific Tn3 monomer beta strand A can comprise or consist of IEV (SEQ ID NO: 5), and a second CD40L-specific Tn3 monomer beta strand A can comprise or consist of RLDAPSQIEV (SEQ ID NO: 23) or SQIEV (SEQ ID NO: 24).

[0044] The Tn3 scaffold may have the amino acid sequence shown in SEQ ID NO:1 and described above, or it may have one or more amino acid residue variations relative to the amino acid sequence shown in SEQ ID NO:1. For example, if the scaffold has amino acid sequence variations relative to those shown in SEQ ID NO:1, these variations may target one of the linkers. The Tn3 scaffold may comprise a Gly15 linker separating two CD40L-specific monomers and a Gly10 linker separating the CD40L-specific monomers from the HSA sequence. Two or one of these linkers may be altered and may be replaced by an amino acid sequence of (GmX)n, where X is serine (S), alanine (A), glycine (G), Leu (L), isoleucine (I), or valine (V); m and n are integer values; m is 1, 2, 3, or 4; and n is 1, 2, 3, 4, 5, 6, or 7. For example, one or both linkers can be modified to have an amino acid sequence containing one of 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 an amino acid sequence relative to the amino acid sequence provided as in SEQ ID NO:1, it is likely due to one or more variations in the HSA amino acid sequence fused with the two CD40L-specific monomers. HSAs fused with two CD40L-specific monomers can be altered relative to HSAs fused with two CD40L-specific Tn3 monomers, except for at least one amino acid substitution at a position selected from the group consisting of the following relative to position numbers in the full-length mature HSA: 407, 415, 463, 500, 506, 508, 509, 511, 512, 515, 516, 521, 523, 524, 526, 535, 550, 557, 573, 574, and 580; wherein the at least one amino acid substitution does not include the substitution of lysine (K) at position 573 with glutamic acid (E).

[0045] Exemplary sequences of Tn3 scaffolds are shown in Table 1. In aspects, a Tn3 scaffold has 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 to any one of SEQ ID NOs: 1-25 shown in Table 1. In aspects, any one of the sequences in Table 1 can be modified. In aspects, the modifications include one or more truncations, deletions, insertions, and combinations thereof. The modifications can occur at any residue and in any number of residues provided in Table 1. In aspects, the modifications can 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 aspects, the modifications can occur in up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, or 450 residues.

[0046] Table 1. Exemplary sequences of Tn3 scaffolds comprising CD40L-specific monomer subunits

[0047]

[0048]

[0049]

[0050]

[0051] If the Tn3 scaffold has amino acid sequence changes relative to those shown in SEQ ID NO: 1, the changes can be to the amino acid sequence of one or both of the CD40L-specific Tn3 monomers, so long as it does not adversely affect the in vivo efficacy of the scaffold, e.g., such that one or both of the CD40L-specific Tn3 monomers has an amino acid sequence change from the amino acid sequence shown in SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 22, and SEQ ID NO: 25. In aspects, the first one or two N-terminal amino acid residues (SQ) can be absent and / or replaced with alternative amino acid residues. In aspects, the Tn3 scaffold comprises a monomer subunit comprising SEQ ID NO: 22, SEQ ID NO: 25, or both SEQ ID NO: 22 and SEQ ID NO: 25.

[0052] In aspects, the Tn3 scaffold comprises at least one CD40L-specific monomeric subunit bound to a heterologous moiety. In aspects, such a heterologous moiety is selected from the group consisting of a protein, a peptide, a protein domain, a linker, a drug, a toxin, a cytotoxic agent, an imaging agent, a radionuclide, a radioactive compound, an organic polymer, an inorganic polymer, polyethylene glycol (PEG), biotin, albumin, a HSA FcRn binding moiety, an antibody or fragment thereof, a single chain antibody, a domain antibody, an albumin binding domain, an enzyme, a ligand, a receptor, a binding peptide, a non-FnIII scaffold, an epitope tag, a recombinant polypeptide polymer, a cytokine, and a combination of two or more of said moieties. In aspects, the heterologous moiety is albumin, and the albumin comprises human serum albumin. In aspects, the heterologous moiety is an antibody. In aspects, the antibody is selected from the group consisting of an Fc domain of an antibody, an antibody fragment, and a single chain antibody.

[0053] In aspects, the heterologous moiety is an antibody. In aspects, the antibody is selected from the group consisting of an Fc domain of an antibody, an antibody fragment, and a single chain antibody.

[0054] In aspects, the heterologous moiety is an imaging agent; for example, a radionuclide or biotin. In aspects, the heterologous moiety is a drug; for example, a cytotoxic agent or a radioactive compound.

[0055] In aspects, the heterologous moiety comprises PEG. In aspects, the Tn3 scaffold comprises at least one CD40L-specific monomeric subunit fused or conjugated to PEG, directly or via a linker. In aspects, both CD40L-specific monomeric subunits are fused, conjugated, or linked to PEG, directly or via a linker. In aspects, the Tn3 scaffold comprises at least one (e.g., two) CD40L-specific monomeric subunit fused or conjugated to PEG, directly or via a linker.

[0056] In aspects, the heterologous moiety comprises albumin. In aspects, the Tn3 scaffold comprises at least one CD40L-specific monomer subunit fused or conjugated to albumin, directly or via a linker. In aspects, the albumin is HSA. In aspects, the HSA is a variant HSA. In aspects, the amino acid sequence of the variant HSA is SEQ ID NO: 4. In aspects, the variant HSA has at least one improved property compared to native HSA or a native HSA fragment. In aspects, the amino acid sequence of the variant HSA is SEQ ID NO: 4, or has 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 aspects, the improved property is an altered plasma half-life compared to the plasma half-life of native HSA or a native HSA fragment. In aspects, the altered plasma half-life is a longer plasma half-life compared to the plasma half-life of native HSA or a native HSA fragment. In aspects, the altered plasma half-life is a shorter plasma half-life compared to the plasma half-life of native HSA or a native HSA fragment.

[0057] Dosing

[0058] In aspects, any composition comprising a Tn3 scaffold of the disclosure can be administered in any form. In aspects, the Tn3 scaffold is administered intravenously, subcutaneously, orally, intramuscularly, intrathecally, sublingually, rectally, vaginally, transdermally, systemically, topically, transdermally, or by inhalation. In aspects, the Tn3 scaffold is administered intravenously. In aspects, the Tn3 scaffold is administered by intravenous infusion.

[0059] The Tn3 scaffolds of the present disclosure can be administered at any dose. In aspects, the Tn3 scaffolds are administered at a dose of about and / or up to about: 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg, 2050 mg, 2100 mg, 2150 mg, 2200 mg, 2250 mg, 2300 mg, 2350 mg, 2400 mg, 2450 mg, 2500 mg, 2550 mg, 2600 mg, 2650 mg, 2700 mg, 2750 mg, 2800 mg, 2850 mg, 2900 mg, 2950 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, 4500 mg, 4550 mg, 4600 mg, 4650 mg, 4700 mg, 4750 mg, 4800 mg, 4850 mg, 4900 mg, 4950 mg, or about 5000 mg. Any of the foregoing doses can be an effective dose for a method (including treatment, reduction, or elimination).

[0060] In aspects, the Tn3 scaffold is administered at a dose of between about 800-5000 mg, 900-4900 mg, 1000-4800 mg, 1100-4700 mg, 1200-4600 mg, 1300-4500 mg, or 1500-3000 mg. In aspects, the Tn3 scaffold is administered at a dose selected from the group consisting of 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg, 2050 mg, 2100 mg, 2150 mg, 2200 mg, 2250 mg, 2300 mg, 2350 mg, 2400 mg, 2450 mg, 2500 mg, 2550 mg, 2600 mg, 2650 mg, 2700 mg, 2750 mg, 2800 mg, 2850 mg, 2900 mg, 2950 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 aspects, the Tn3 scaffold is administered at a dose of between about 1500 mg and 3000 mg. In aspects, the Tn3 scaffold is administered at a dose of 1500 mg or 3000 mg. In aspects, the Tn3 scaffold is administered at a dose of about 1500 mg. In aspects, the Tn3 scaffold is administered at a dose of about 3000 mg.

[0061] Frequency of administration

[0062] In aspects, the Tn3 scaffold of the present disclosure is administered on a schedule that provides optimal results. In aspects, the Tn3 scaffold is administered to a subject in need thereof about once a week, about twice a week, about once every two weeks, about once a month, about every four weeks, about every two months, about every 3 months, about every 12 weeks, about every fifteen weeks, about every sixteen weeks, about every four months, about every five months, about every six months, or every half year. Any number of administrations can be provided to a subject in need. In aspects, the Tn3 scaffold of the present disclosure is administered as a loading dose. A loading dose can also be referred to as an induction dose. In aspects, the Tn3 scaffold is administered as a maintenance dose.

[0063] Tn3 scaffolds of the present disclosure can be administered in about 1-10, 10-50, 50-75, 75-100, 100-200, or 200-300 total doses, or up to the life of the subject. In aspects, the Tn3 scaffold is administered in about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, or more doses. In aspects, the Tn3 scaffold is administered in at least about or at most about 2, 3, 4, or 5 total doses. In aspects, the Tn3 scaffold is administered in at least about or at most about 10, 11, 12, or 13 total doses.

[0064] In aspects, the effective dose is administered to the subject about every 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, 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, or up to the life of the subject after the start of treatment. In aspects, the subject receives the effective dose on day 1, day 15, day 29, day 57, day 85, day 113, day 141, day 169, day 197, day 225, day 253, day 281, and day 309 after the start of treatment. In aspects, the subject receives 1500 mg - 3000 mg of the Tn3 scaffold on day 1, day 15, day 29, day 57, day 85, day 113, day 141, day 169, day 197, day 225, day 253, day 281, and day 309 after the start of treatment.

[0065] In aspects, the subject is administered about 1500 mg - 3000 mg of the Tn3 scaffold every 2 weeks for about 3 administrations, and then every 4 weeks thereafter. In aspects, the subject is administered about 1500 mg of the Tn3 scaffold every 2 weeks for about 3 administrations, and then every 4 weeks thereafter. In aspects, the subject is administered about 3000 mg of the Tn3 scaffold at week 0, week 4, and week 12, and then every 12 weeks thereafter. In aspects, the subject is administered about 1500 mg of the Tn3 scaffold every 4 weeks. In aspects, the subject is administered about 3000 mg of the Tn3 scaffold every 12 weeks. In aspects, the subject is administered an initial dose of about 1500 mg - 3000 mg of the Tn3 scaffold of the disclosure every 2 weeks for at least 2, at least 3, or more administrations, and then every 4 weeks thereafter. In aspects, the subject is administered an initial dose of about 1500 mg of the Tn3 scaffold of the disclosure every 2 weeks for at least 2, at least 3, or more administrations, and then every 4 weeks thereafter. In aspects, the subject is administered an initial dose of about 3000 mg of the Tn3 scaffold of the disclosure every 2 weeks for at least 2, at least 3, or more administrations, and then every 12 weeks thereafter. In aspects, the subject is administered an initial dose of about 3000 mg of the Tn3 scaffold of the disclosure every 4 weeks for at least 2, at least 3, or more administrations, and then every 12 weeks thereafter. In aspects, a subject having SS with low systemic disease activity but with moderate to severe symptom status is treated. In aspects, a subject having SS with moderate systemic disease activity is treated. In aspects, a subject having SS with severe systemic disease activity is treated. In aspects, a subject having SS with moderate to severe systemic disease activity is treated. In aspects, a subject having SS with moderate or severe systemic disease activity as defined by an ESSDAI score of >5 is treated with the Tn3 scaffold. In aspects, a subject having SS with moderate to severe systemic disease activity as defined by an ESSDAI score of >5 is treated with the Tn3 scaffold. In aspects, a subject having SS with moderate or severe symptom activity as defined by an ESSPRI score of >5 and low systemic disease activity as defined by an ESSDAI score of <5 is treated with the Tn3 scaffold. In aspects, a subject having SS with moderate or severe systemic disease activity as defined by an ESSDAI score of >5 is treated with the Tn3 scaffold. In aspects, a subject having SS with moderate or severe symptom activity as defined by an ESSPRI score of >5 and low systemic disease activity as defined by an ESSDAI score of <5 is treated with the Tn3 scaffold.

[0066] The therapeutic or prophylactic methods of the disclosure comprise administering a Tn3 scaffold of the disclosure to a subject in need thereof. In aspects, the therapeutic methods comprise administering to a subject in need thereof an effective dose of a Tn3 scaffold every 2 weeks for about 3 doses, followed by administration of the Tn3 scaffold every 4 weeks thereafter. In aspects, the therapeutic methods comprise administering to a subject in need thereof an effective dose of a Tn3 scaffold at week 0, week 4, and week 12, followed by administration of the Tn3 scaffold every 12 weeks thereafter. In aspects, the therapeutic methods comprise administering to a subject in need thereof about 1400 mg to about 1600 mg of a Tn3 scaffold every 2 weeks for about 3 administrations, followed by administration of the Tn3 scaffold every 4 weeks thereafter. In aspects, the therapeutic methods comprise administering to a subject in need thereof about 2000 mg to about 4000 mg of a Tn3 scaffold at week 0, week 4, and week 12, followed by administration of the Tn3 scaffold every 12 weeks thereafter.

[0067] In aspects, the therapeutic methods comprise administering to a subject in need thereof about 1500 mg of a Tn3 scaffold every 2 weeks for 7 administrations. In aspects, the therapeutic methods comprise administering to a subject in need thereof about 1500 mg of a Tn3 scaffold every 4 weeks for 5 administrations. In aspects, the therapeutic methods comprise administering to a subject in need thereof about 1500 mg of a Tn3 scaffold every 2 weeks for about 3 administrations, followed by administration of the Tn3 scaffold every 4 weeks thereafter. In aspects, the therapeutic methods comprise administering to a subject in need thereof about 3000 mg of a Tn3 scaffold at week 0, week 4, and week 12, followed by administration of the Tn3 scaffold every 12 weeks thereafter. In aspects, the administration continues every 4 weeks thereafter for up to about 1 year, 2 years, 3 years, 4 years, or 5 years, or for the life of the subject. In aspects, any of the foregoing administrations can be off by about 1 day to about 4 days, about 3 days to about 7 days, or about 1 day to about 7 days. In aspects, any of the foregoing administrations can be off by about 1 day, 3 days, 4 days, or 7 days. In aspects, any of the foregoing administrations can be off by about 1 day. In aspects, any of the foregoing administrations can be off by about 3 days. In aspects, any of the foregoing administrations can be off by about 4 days. In aspects, any of the foregoing administrations can be off by about 7 days.

[0068] In aspects, the subject receives an effective dose of Tn3 Scaffold on day 1, day 15 (-3 days to +1 day), day 29 (±4 days), and day 57 (±7 days) after treatment initiation. In aspects, the subject in need thereof is administered 1500 mg Tn3 Scaffold on day 1, day 15 (-3 days to +1 day), day 29 (±4 days), and day 57 (±7 days) after treatment initiation, and then as needed every 4 weeks thereafter. In aspects, the subject in need thereof is administered 1500 mg Tn3 Scaffold on day 1, day 15 (±1 day), and day 29 (±3 days) after treatment initiation. In aspects, the subject in need thereof is administered 1500 mg Tn3 Scaffold on day 1 and day 57 (±7 days) after treatment initiation. In aspects, the subject in need thereof is administered 1500 mg Tn3 Scaffold on day 1, day 15 (±1 day), day 29 (±3 days), day 57 (±7 days), day 85 (±7 days), day 113 (±7 days), day 141 (±7 days) after treatment initiation. In aspects, the subject in need thereof is administered 1500 mg Tn3 Scaffold on day 169 (±7 days), day 197 (±7 days), day 225 (±7 days), day 253 (±7 days), and day 281 (±7 days) after treatment initiation. In aspects, the subject in need thereof is administered 3000 mg Tn3 Scaffold on day 1, day 15 (-3 days to +1 day), day 29 (±4 days), and day 57 (±7 days) after treatment initiation, and then as needed every 6 months thereafter. In aspects, the subject in need thereof is administered 3000 mg Tn3 Scaffold on day 1, day 15 (-3 days to +1 day), and day 29 (±4 days) after treatment initiation. In aspects, the subject in need thereof is administered 3000 mg Tn3 Scaffold on day 1 and day 57 (±7 days) after treatment initiation, and then as needed every 12 weeks thereafter.

[0069] In aspects, the subject in need thereof receives a dose of Tn3 Scaffold on day 1, day 15 (-3 days 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 aspects, the subject in need thereof receives an effective dose of 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).

[0070] In aspects, an effective dose of the Tn3 scaffold is administered to a subject in need thereof once every 2-4 weeks. In aspects, an effective dose of the Tn3 scaffold is administered to a subject in need thereof once every 2 weeks, 4 weeks, 6 weeks, 8 weeks, or 12 weeks. In aspects, a subject in need thereof is administered 1500 mg of the Tn3 scaffold once every 2 weeks for at least 3 doses; once every 4 weeks for at least 12 doses; once every 4 weeks for at least 13 doses; or a combination thereof. In aspects, a subject in need thereof is administered 3000 mg of the Tn3 scaffold once every 2 weeks for at least 3 doses; once every 4 weeks for at least 4 doses; once every 4 weeks for at least 5 doses; or a combination thereof. In aspects, 3000 mg of the Tn3 scaffold is administered every 3 months. In aspects, 3000 mg of the Tn3 scaffold is administered every 12 weeks.

[0071] In aspects, the Tn3 scaffold is administered at a dose of about 1500 mg once about every 2 weeks for at least 2 doses, and thereafter about once a month. In aspects, the Tn3 scaffold is administered at a dose of about 1500 mg once about every 2 weeks for at least 3 doses, and thereafter about once a month. In aspects, the Tn3 scaffold is administered at a dose of about 1500 mg once about every 2 weeks for at least 3 doses, and thereafter every 4 weeks. In aspects, the Tn3 scaffold is administered at a dose of about 1500 mg about once a month, about once every two months, or about once every three months. In aspects, the Tn3 scaffold is administered at a dose of about 3000 mg once about every 2 weeks for at least about 2 doses, and thereafter about once a month, every two months, or every three months, or a combination thereof. In aspects, the Tn3 scaffold is administered at a dose of about 3000 mg once about every 4 weeks for at least about 2 doses, and thereafter about once a month, every two months, or every three months, or a combination thereof. In aspects, the Tn3 scaffold is administered at a dose of about 3000 mg once about every 4 weeks for at least about 2 doses, and thereafter about every twelve weeks. In aspects, the Tn3 scaffold is administered at a dose of about 3000 mg about once a month, about once every two months, or about once every three months. In aspects, the Tn3 scaffold is administered for two or more doses. In aspects, a subject is administered 1500 mg of the Tn3 scaffold of the disclosure every 2 weeks. In aspects, a subject is administered 1500 mg of the Tn3 scaffold of the disclosure every 4 weeks. In aspects, a subject is administered 3000 mg of the Tn3 scaffold of the disclosure every 12 weeks.

[0072] In aspects, the methods of the present disclosure comprise administering a Tn3 scaffold at a dose of 3000 mg Tn3 scaffold every 12 weeks, wherein the dose of 3000 mg Tn3 scaffold is administered at weeks 0 and 4. In aspects, the methods of the present disclosure comprise administering a Tn3 scaffold at a dose of 1500 mg Tn3 scaffold every 4 weeks. In aspects, the methods of the present disclosure comprise administering a Tn3 scaffold comprising SEQ ID NO: 1 at a dose of 3000 mg Tn3 scaffold every 12 weeks, wherein the dose of 3000 mg Tn3 scaffold is administered at weeks 0 and 4. In aspects, the methods of the present disclosure comprise administering a Tn3 scaffold comprising SEQ ID NO: 1 at a dose of 1500 mg Tn3 scaffold every 2 weeks. In aspects, the methods of the present disclosure comprise administering a Tn3 scaffold comprising SEQ ID NO: 1 at a dose of 1500 mg Tn3 scaffold every 4 weeks. In aspects, the methods of the present disclosure comprise administering a Tn3 scaffold comprising SEQ ID NO: 1 at a dose of 1500 mg Tn3 scaffold every two weeks for 3 administrations, and then every 4 weeks thereafter. In aspects, the methods of the present disclosure comprise administering a Tn3 scaffold comprising SEQ ID NO: 1 at a dose of 3000 mg Tn3 scaffold every two weeks for 3 administrations, and then every 12 weeks thereafter.

[0073] In aspects, the methods of the present disclosure comprise administering a Tn3 scaffold at a dose of 3000 mg Tn3 scaffold every 12 weeks, wherein the dose of 3000 mg Tn3 scaffold is administered at weeks 0 and 4. In aspects, the methods of the present disclosure comprise administering a Tn3 scaffold at a dose of 1500 mg Tn3 scaffold every 4 weeks. In aspects, the methods of the present disclosure comprise administering a Tn3 scaffold comprising SEQ ID NO: 22 or SEQ ID NO: 25 at a dose of 3000 mg Tn3 scaffold every 12 weeks, wherein the dose of 3000 mg Tn3 scaffold is administered at weeks 0 and 4. In aspects, the methods of the present disclosure comprise administering a Tn3 scaffold comprising SEQ ID NO: 22 or SEQ ID NO: 25 at a dose of 1500 mg Tn3 scaffold every 2 weeks. In aspects, the methods of the present disclosure comprise administering a Tn3 scaffold comprising SEQ ID NO: 22 or SEQ ID NO: 25 at a dose of 1500 mg Tn3 scaffold every 4 weeks. In aspects, the methods of the present disclosure comprise administering a Tn3 scaffold comprising SEQ ID NO: 22 or SEQ ID NO: 25 at a dose of 1500 mg Tn3 scaffold every two weeks for 3 administrations, and then every 4 weeks thereafter. In aspects, the methods of the present disclosure comprise administering a Tn3 scaffold comprising SEQ ID NO: 22 or SEQ ID NO: 25 at a dose of 3000 mg Tn3 scaffold every two weeks for 3 administrations, and then every 12 weeks thereafter.

[0074] In aspects, the methods of the present disclosure comprise administering to a subject in need thereof a Tn3 scaffold at a dose of 3000 mg Tn3 scaffold every 12 weeks, wherein the dose is administered at weeks 0 and 4. In aspects, the methods of the present disclosure comprise administering to a subject in need thereof a Tn3 scaffold at a dose of 1500 mg Tn3 scaffold every 4 weeks. In aspects, the methods of the present disclosure comprise administering to a subject in need thereof a Tn3 scaffold comprising SEQ ID NO: 1 at a dose of 3000 mg Tn3 scaffold every 12 weeks, wherein the dose is administered at weeks 0 and 4. In aspects, the methods of the present disclosure comprise administering to a subject in need thereof a Tn3 scaffold comprising SEQ ID NO: 1 at a dose of 1500 mg Tn3 scaffold every 2 weeks. In aspects, the methods of the present disclosure comprise administering to a subject in need thereof a Tn3 scaffold comprising SEQ ID NO: 1 at a dose of 1500 mg Tn3 scaffold every 4 weeks. In aspects, the methods of the present disclosure comprise administering to a subject in need thereof a Tn3 scaffold comprising SEQ ID NO: 1 at a dose of 1500 mg Tn3 scaffold every two weeks for 3 administrations, and then every 4 weeks thereafter. In aspects, the methods of the present disclosure comprise administering to a subject in need thereof a Tn3 scaffold comprising SEQ ID NO: 1 at a dose of 1500 mg Tn3 scaffold every 2 weeks for 7 administrations. In aspects, the methods of the present disclosure comprise administering to a subject in need thereof a Tn3 scaffold comprising SEQ ID NO: 1 at a dose of 1500 mg Tn3 scaffold every 4 weeks for 5 administrations. In aspects, the methods of the present disclosure comprise administering to a subject in need thereof a Tn3 scaffold comprising SEQ ID NO: 1 at a dose of 3000 mg Tn3 scaffold every two weeks for 3 administrations, and then every 12 weeks thereafter.

[0075] In aspects, the methods of the present disclosure comprise administering to a subject in need thereof a Tn3 scaffold at a dose of 3000 mg Tn3 scaffold every 12 weeks, wherein the dose is administered at weeks 0 and 4. In aspects, the methods of the present disclosure comprise administering to a subject in need thereof a Tn3 scaffold at a dose of 1500 mg Tn3 scaffold every 2 weeks. In aspects, the methods of the present disclosure comprise administering to a subject in need thereof a Tn3 scaffold at a dose of 1500 mg Tn3 scaffold every 4 weeks. In aspects, the methods of the present disclosure comprise administering to a subject in need thereof a Tn3 scaffold comprising SEQ ID NO: 22 or SEQ ID NO: 25 at a dose of 3000 mg Tn3 scaffold every 12 weeks, wherein the dose is administered at weeks 0 and 4. In aspects, the methods of the present disclosure comprise administering to a subject in need thereof a Tn3 scaffold comprising SEQ ID NO: 22 or SEQ ID NO: 25 at a dose of 1500 mg Tn3 scaffold every 2 weeks. In aspects, the methods of the present disclosure comprise administering to a subject in need thereof a Tn3 scaffold comprising SEQ ID NO: 22 or SEQ ID NO: 25 at a dose of 1500 mg Tn3 scaffold every 4 weeks. In aspects, the methods of the present disclosure comprise administering to a subject in need thereof a Tn3 scaffold comprising SEQ ID NO: 22 or SEQ ID NO: 25 at a dose of 1500 mg Tn3 scaffold every 2 weeks for 7 administrations. In aspects, the methods of the present disclosure comprise administering to a subject in need thereof a Tn3 scaffold comprising SEQ ID NO: 22 or SEQ ID NO: 25 at a dose of 1500 mg Tn3 scaffold every 4 weeks for 5 administrations. In aspects, the methods of the present disclosure comprise administering to a subject in need thereof a Tn3 scaffold comprising SEQ ID NO: 22 or SEQ ID NO: 25 at a dose of 1500 mg Tn3 scaffold every two weeks for 3 administrations, and thereafter every 4 weeks. In aspects, the methods of the present disclosure comprise administering to a subject in need thereof a Tn3 scaffold comprising SEQ ID NO: 22 or SEQ ID NO: 25 at a dose of 3000 mg Tn3 scaffold every two weeks for 3 administrations, and thereafter every 12 weeks.

[0076] In aspects, the Tn3 scaffold is administered at a dose of about 1500 mg. In aspects, the Tn3 scaffold is administered at a dose of about 3000 mg. In aspects, the Tn3 scaffold is administered at a dose of about 1500 mg every 2 weeks. In aspects, the Tn3 scaffold is administered at a dose of about 1500 mg every 4 weeks. In aspects, the Tn3 scaffold is administered at a dose of about 1500 mg once every 2 weeks for at least 2 or more doses. In aspects, the Tn3 scaffold is administered at a dose of about 1500 mg twice every 2 weeks for at least 2 or more doses. In aspects, the Tn3 scaffold is administered at a dose of about 1500 mg once every 4 weeks for at least 2 or more doses. In aspects, the Tn3 scaffold is administered at a dose of about 1500 mg twice every 4 weeks for at least 2 or more doses. In aspects, the Tn3 scaffold is administered at a dose of about 1500 mg twice every 4 weeks thereafter. In aspects, the Tn3 scaffold is administered at a dose of about 1500 mg every 2 weeks for 3 doses, and thereafter every 4 weeks. In aspects, the Tn3 scaffold is administered at a dose of about 1500 mg every 2 weeks for 2 doses, and thereafter every 4 weeks. In aspects, the Tn3 scaffold is administered at a dose of about 3000 mg every 2 weeks. In aspects, the Tn3 scaffold is administered at a dose of about 3000 mg every 4 weeks. In aspects, the Tn3 scaffold is administered at a dose of about 3000 mg twice every 2 weeks for at least 2 or more doses. In aspects, the Tn3 scaffold is administered at a dose of about 3000 mg twice every 4 weeks for at least 2 or more doses. In aspects, the Tn3 scaffold is administered at a dose of about 3000 mg twice every 12 weeks for at least 2 or more doses. In aspects, the Tn3 scaffold is administered at a dose of about 3000 mg twice every 12 weeks thereafter. In aspects, the Tn3 scaffold is administered at a dose of about 3000 mg every 2 weeks for 3 doses, and thereafter every 12 weeks. In aspects, the Tn3 scaffold is administered at a dose of about 3000 mg every 4 weeks for at least 2 doses, and thereafter every 12 weeks.

[0077] Methods

[0078] In aspects herein, the methods are directed to treating, reducing, or eliminating an autoimmune disease or disorder. In aspects, the methods comprise administering a Tn3 scaffold of the disclosure. In aspects, the Tn3 scaffold is used to treat SS. In aspects, the Tn3 scaffold is administered to a subject in need thereof using any of the dosing schedules disclosed herein to treat SS. In aspects, the Tn3 scaffold is administered about once every 2 weeks for at least 2 doses at a dose of about 1500 mg, and thereafter about once a month. In aspects, the Tn3 scaffold is administered about once every 2 weeks for at least 3 doses at a dose of about 1500 mg, and thereafter about once a month or once every 4 weeks. In aspects, the Tn3 scaffold is administered about once a month, about once every two months, or about once every three months at a dose of about 1500 mg. In aspects, the Tn3 scaffold is administered about once a month, about once every two months, or about once every three months at a dose of about 3000 mg. In aspects, the Tn3 scaffold is administered about once every 2 weeks for at least 3 doses at a dose of about 3000 mg, and thereafter about once every 3 months. In aspects, the Tn3 scaffold is administered about once every 4 weeks for at least 2 doses at a dose of about 3000 mg, and thereafter about once every 3 months. In aspects, the Tn3 scaffold is administered about once every 4 weeks for at least 2 doses at a dose of about 3000 mg, and thereafter about once every 12 weeks. In aspects, the Tn3 scaffold is administered at a dose of about 3000 mg, followed by an additional administration at 4 weeks and 12 weeks, and thereafter about once every 3 months or once every 12 weeks. In aspects, the Tn3 scaffold is administered for two or more doses.

[0079] In aspects, the methods comprise treating a subject having SS. In aspects, the methods comprise treating a subject having SS with a European League Against Rheumatism (EULAR) Sjogren’s Syndrome Disease Activity Index (ESSDAI) of about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 20, about 25, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 110, or about 120 or greater. In aspects, the methods comprise treating a subject having SS with a European League Against Rheumatism (EULAR) Sjogren’s Syndrome Patient Reported Index (ESSPRI) score of about 1, about 2, about 4, about 5, about 6, about 7, about 8, about 9, or about 10.

[0080] In aspects, the method comprises treating a subject in need thereof. In aspects, the method comprises treating a subject having SS. In aspects, the method comprises treating a subject having SS with low systemic disease activity. In aspects, the method comprises treating a subject having SS with low systemic disease activity but with moderate to severe symptom status. In aspects, the method comprises treating a subject having SS with moderate systemic disease activity. In aspects, the method comprises treating a subject having SS with severe systemic disease activity. In aspects, the method comprises treating a subject having SS with moderate to severe systemic disease activity. In aspects, the method comprises treating a subject having SS with moderate to severe systemic disease activity by administering a Tn3 scaffold at any dose in any schedule disclosed herein. In aspects, the method comprises treating a subject having SS and coexisting rheumatoid arthritis (RA). In aspects, the method comprises treating a subject having SS and coexisting systemic lupus erythematosus (SLE). In aspects, moderate to severe systemic disease activity can be defined by EULAR Sjogren’s Syndrome Patient Reported Index (ESSPRI) > 5. In aspects, moderate to severe systemic disease activity can be defined by EULAR Sjogren’s Syndrome Disease Activity Index (ESSDAI) > 5. In aspects, low systemic disease activity can be defined by ESSDAI < 5. In aspects, the method comprises treating a subject having SS with low subjective symptoms by administering a Tn3 scaffold. In aspects, the method comprises treating a subject having SS with moderate to severe subjective symptoms by administering a Tn3 scaffold. In aspects, the subject can have moderate to severe symptom activity as defined by ESSPRI score > 5 but low systemic disease activity as defined by ESSDAI score < 5. In aspects, moderate to severe systemic disease activity can be defined by ESSDAI score > 5. In aspects, the method comprises treating a subject having severe SS. In aspects, the method comprises treating a subject having SS with ESSDAI exceeding 14. In aspects, the method comprises treating a subject having SS with ESSDAI > 14. In aspects, the method comprises treating a subject having SS with ESSDAI of 14 to about 20, 14 to about 30, 14 to about 40, 14 to about 50, 14 to about 60, 15 to about 40, about 20 to about 70, about 30 to about 80, about 40 to about 90, about 50 to about 100, about 60 to about 110, about 70 to about 120, or about 80 to about 123. In aspects, the Tn3 scaffold is administered at a dose of 1500 mg. In aspects, the Tn3 scaffold is administered at a dose of 3000 mg.

[0081] In all respects, the method of treating subjects in need includes administering an effective dose of Tn3 stents. In all respects, administration is effective in reducing disease or condition compared to: a) the disease or condition of subjects who lack administration and are otherwise equivalent; or b) baseline measurements of the disease or condition of subjects in need. In all respects, administration is effective as assessed by the Sjögren's Syndrome Patient-Reported Index Assessment Diary (DASPRI). In all respects, subjects receiving Tn3 stents show a reduction in DASPRI scores of at least or at most about 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 all respects, as assessed by the Sjögren's Syndrome Response Assessment Tool (… The administration is effective in reducing the ESSPRI score of the subject in need as compared to the baseline level of the subject. In aspects, the ESSPRI score of the subject administered the Tn3 scaffold is reduced by at least about or at most about 1-fold, 5-fold, 10-fold, 25-fold, 50-fold, 75-fold, 100-fold, 150-fold, or 250-fold as compared to the baseline level of the subject. In aspects, the ESSPRI score of the subject administered the Tn3 scaffold is reduced by at least about or at most about 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 as compared to the baseline level of the subject. In aspects, the ESSPRI score of the subject administered the Tn3 scaffold is reduced by at least about or at most about 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 about 100% as compared to the baseline level of the subject. The administration is effective in reducing the ESSDAI score of the subject in need as compared to the baseline level of the subject. In aspects, the ESSDAI score of the subject administered the Tn3 scaffold is reduced by at least about or at most about 1-fold, 5-fold, 10-fold, 25-fold, 50-fold, 75-fold, 100-fold, 150-fold, or 250-fold as compared to the baseline level of the subject. In aspects, the ESSDAI score of the subject administered the Tn3 scaffold is reduced by at least about or at most about 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 as compared to the baseline level of the subject. In aspects, the ESSDAI score of the subject administered the Tn3 scaffold is reduced by at least about or at most about 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 about 100% as compared to the baseline level of the subject.

[0082] In aspects, the Tn3 scaffold of the present disclosure increases the response rate in an area selected from the group consisting of constitutional, lymphadenopathic, glandular, joint, skin, lung, kidney, muscle, peripheral nervous system, central nervous system, hematologic, and biologic areas as compared to a subject administered a control. In aspects, the response rate is increased by at least about 5%, 10%, 15%, 20%, 30%, 40%, or 50% as compared to a subject administered a control. In aspects, the response rate of a subject administered the Tn3 scaffold of the present disclosure is increased in the constitutional area as compared to the response of a subject administered a control. In aspects, the response rate of a subject administered the Tn3 scaffold of the present disclosure is increased in the lymphadenopathic area as compared to the response of a subject administered a control. In aspects, the response rate of a subject administered the Tn3 scaffold of the present disclosure is increased in the glandular area as compared to the response of a subject administered a control. In aspects, the response rate of a subject administered the Tn3 scaffold of the present disclosure is increased in the joint area as compared to the response of a subject administered a control. In aspects, the response rate of a subject administered the Tn3 scaffold of the present disclosure is increased in the skin area as compared to the response of a subject administered a control.

[0083] In aspects, the Tn3 scaffold is administered via intravenous administration at a dose of about 1500 mg. In aspects, the Tn3 scaffold is administered via intravenous administration at a dose of about 3000 mg. In aspects, the Tn3 scaffold is administered via intravenous administration at a dose of about 1500 mg once every 2 weeks. In aspects, the Tn3 scaffold is administered via intravenous administration at a dose of about 1500 mg once every 4 weeks. In aspects, the Tn3 scaffold is thereafter administered via intravenous administration at a dose of about 1500 mg twice every 4 weeks. In aspects, the Tn3 scaffold is administered via intravenous administration at a dose of about 1500 mg every 2 weeks for 3 doses, and thereafter every 4 weeks. In aspects, the Tn3 scaffold is administered at a dose of about 1500 mg at weeks 0, 2, and 4, and thereafter every 4 weeks (Q4W). In aspects, the Tn3 scaffold is administered via intravenous administration at a dose of about 1500 mg at weeks 0, 2, and 4, and thereafter once every 4 weeks (Q4W). In aspects, the Tn3 scaffold is administered at a dose of about 1500 mg every 2 weeks for 7 doses. In aspects, the Tn3 scaffold is administered via intravenous administration at a dose of about 1500 mg every 2 weeks for 7 doses. In aspects, the Tn3 scaffold is administered at a dose of about 1500 mg every 4 weeks for 5 doses. In aspects, the Tn3 scaffold is administered via intravenous administration at a dose of about 1500 mg every 4 weeks for 5 doses. In aspects, the Tn3 scaffold is thereafter administered via intravenous administration at a dose of about 3000 mg twice every 12 weeks. In aspects, the Tn3 scaffold is administered via intravenous administration at a dose of about 3000 mg every 2 weeks for 3 doses, and thereafter every 12 weeks. In aspects, the Tn3 scaffold is administered via intravenous administration at a dose of about 3000 mg every 2 weeks for at least 2 doses, and thereafter every 12 weeks. In aspects, the Tn3 scaffold is administered via intravenous administration at a dose of about 3000 mg every 4 weeks for at least 2 doses, and thereafter every 12 weeks.

[0084] In aspects, the methods of the present disclosure comprise administering to a subject in need thereof a Tn3 scaffold via intravenous administration at a dose of 3000 mg Tn3 scaffold every 12 weeks, wherein the dose is administered at week 0 and week 4. In aspects, the methods of the present disclosure comprise administering to a subject in need thereof a Tn3 scaffold via intravenous administration at a dose of 1500 mg Tn3 scaffold every 4 weeks, wherein the dose is administered at week 0 and week 2. In aspects, the methods of the present disclosure comprise administering to a subject in need thereof a Tn3 scaffold comprising SEQ ID NO: 22 or SEQ ID NO: 25 via intravenous administration at a dose of 3000 mg Tn3 scaffold every 12 weeks, wherein the dose is administered at week 0 and week 4. In aspects, the methods of the present disclosure comprise administering to a subject in need thereof a Tn3 scaffold comprising SEQ ID NO: 22 or SEQ ID NO: 25 via intravenous administration at a dose of 1500 mg Tn3 scaffold every 4 weeks. In aspects, the methods of the present disclosure comprise administering to a subject in need thereof a Tn3 scaffold comprising SEQ ID NO: 22 or SEQ ID NO: 25 via intravenous administration at a dose of 1500 mg Tn3 scaffold every two weeks for 3 administrations, and then every 4 weeks thereafter. In aspects, the methods of the present disclosure comprise administering to a subject in need thereof a Tn3 scaffold comprising SEQ ID NO: 22 or SEQ ID NO: 25 via intravenous administration at a dose of 3000 mg Tn3 scaffold every two weeks for 3 administrations, and then every 12 weeks thereafter.

[0085] In aspects, compositions comprising Tn3 scaffolds are formulated for administration. In aspects, the Tn3 scaffold is formulated at a concentration of at least about or at most 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, 80 mg / mL, 85 mg / mL, 90 mg / mL, 95 mg / mL, 100 mg / mL, 105 mg / mL, 110 mg / mL, 115 mg / mL, 120 mg / mL, 125 mg / mL, 130 mg / mL, 135 mg / mL, 140 mg / mL, 145 mg / mL, 150 mg / mL, 155 mg / mL, 160 mg / mL, 165 mg / mL, 170 mg / mL, 175 mg / mL, 180 mg / mL, 185 mg / mL, 190 mg / mL, 195 mg / mL, 200 mg / mL, 205 mg / mL, 210 mg / mL, 215 mg / mL, 220 mg / mL, 225 mg / mL, 230 mg / mL, 235 mg / mL, 240 mg / mL, 245 mg / mL, 250 mg / mL, 255 mg / mL, 260 mg / mL, 265 mg / mL, 270 mg / mL, 275 mg / mL, 280 mg / mL, 285 mg / mL, 290 mg / mL, 295 mg / mL, 300 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 about 400 mg / mL. In aspects, a Tn3 scaffold effective dose can be formulated at a concentration of about 100 mg / mL.

[0086] In aspects, administration of the Tn3 scaffold is effective to eliminate a disease in a subject in need thereof. In aspects, administration of the Tn3 scaffold is effective to reduce a disease in a subject in need thereof. In some cases, administration of the Tn3 scaffold is effective to eliminate or reduce a disease in a subject in need thereof 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 for the life of the subject. In aspects, administration of the Tn3 scaffold is effective to eliminate a disease in a subject in need thereof 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 aspects, administration of the Tn3 scaffold is effective to eliminate or reduce a disease in a subject in need thereof 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 aspects, administration of the Tn3 scaffold is effective to eliminate or reduce a disease in a subject in need thereof 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 aspects, administration of the Tn3 scaffold is effective to eliminate or reduce a disease for the life of a subject in need thereof.

[0087] In aspects, a Tn3 scaffold is administered to a subject in need thereof. In aspects, a Tn3 scaffold is administered to a subject in need thereof as a first line therapy. In aspects, prior to administration of a Tn3 scaffold of the disclosure, the subject has not been administered one or more prior therapies and / or concomitant therapies for treating SS. In aspects, prior to administration of a Tn3 scaffold, a subject in need thereof has been administered one or more prior therapies and / or concomitant therapies for treating SS. In aspects, the prior therapies and / or concomitant therapies include drugs and / or vaccines (e.g., over-the-counter [OTC] or prescription drugs, recreational drugs, vitamins, and / or herbal supplements). Exemplary prior therapies and / or concomitant therapies are described below.

[0088] Biological B-cell depleting therapies

[0089] In aspects, the subject was previously treated with a biological B cell depleting therapy (e.g., rituximab, ocrelizumab, inebilizumab, ofatumumab, belimumab, or ianalumab, or a combination thereof). In aspects, the subject was previously treated with a biological B cell depleting therapy more than about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or about 12 months prior to screening. In aspects, the subject was previously treated with a biological B cell depleting therapy more than about 3 months prior to screening. In aspects, the subject was previously treated with a biological B cell depleting therapy more than about 12 months prior to screening. In aspects, the subject was previously treated with belimumab more than about 3 months prior to screening. In aspects, the subject was previously treated with rituximab, ocrelizumab, inebilizumab, ofatumumab, or ianalumab, or a combination thereof more than about 12 months prior to screening.

[0090] Corticosteroid

[0091] In aspects, the subject was previously treated with a corticosteroid. In aspects, the subject is concomitantly treated with a corticosteroid. In aspects, the corticosteroid is a glucocorticoid. In aspects, the subject was previously treated with an injectable corticosteroid (e.g., intra-articular [IA] or intramuscular [IM]) or oral dose of prednisone (or equivalent) at a dose > 10 mg / day. In aspects, the subject was previously treated with an injectable corticosteroid (e.g., intra-articular [IA] or intramuscular [IM]) or oral dose (e.g., prednisone or equivalent) at a dose > 10 mg / day more than 6 weeks prior to screening. In aspects, the subject was previously treated with a systemic corticosteroid for 2 or more weeks more than 6 months prior to screening. In aspects, the subject is concomitantly treated with an oral corticosteroid (e.g., prednisone or equivalent) at a dose of < 10 mg / day, wherein the dose is stable for at least 2 or more weeks prior to screening. In aspects, the subject is concomitantly treated with an inhaled corticosteroid, intranasal corticosteroid, or topical corticosteroid at a stable dose. In aspects, the subject is not treated with a corticosteroid.

[0092] In aspects, the subject has or was previously treated with a corticosteroid (e.g., at a dose of < 10 mg / day) prior to administration. In aspects, the subject is treated with 1500 mg or 3000 mg of the Tn3 scaffold of the disclosure.

[0093] In aspects, the subject is not administered a corticosteroid prior to administration if the subject has an ESSDAI score > 5 and an ESSPRI score < 5. In aspects, the subject is treated with 1500 mg or 3000 mg of the Tn3 scaffold of the disclosure.

[0094] Antimalarial drug

[0095] In aspects, the subject is treated with an antimalarial drug (e.g., chloroquine, hydroxychloroquine, quinacrine, etc.) concomitantly. In aspects, the subject was previously treated with an antimalarial drug. In aspects, the subject is treated with an antimalarial drug concomitantly and treated with the antimalarial drug more than 8 weeks prior to screening. In aspects, the subject is treated with an antimalarial drug concomitantly and maintained on a stable dose of the antimalarial drug more than 8 weeks prior to screening.

[0096] Immunomodulator

[0097] In aspects, the subject was previously treated with an immunomodulator. In aspects, the subject is treated with an immunomodulator concomitantly. In aspects, the immunomodulator is also a disease modifying antirheumatic drug (DMARD) (e.g., methotrexate, sulfasalazine, leflunomide, hydroxychloroquine, plaquenil, cevimeline, pilocarpine, cyclosporine, cyclosporine, etanercept, baricitinib, tofacitinib, upadacitinib, infliximab, adalimumab, certolizumab, and golimumab, and combinations thereof). In aspects, the subject was previously treated with a DMARD. In aspects, the subject was previously treated with a DMARD 4 weeks or more prior to screening. In aspects, the subject was previously treated with cevimeline, pilocarpine, and / or cyclosporine 2 weeks or more prior to screening. In aspects, the subject is treated with cevimeline, pilocarpine, and / or cyclosporine concomitantly and the dose is stable 2 weeks or more prior to screening.

[0098] NSAID

[0099] In aspects, the subject was previously treated with a non-steroidal anti-inflammatory drug (NSAID). In aspects, the subject is concomitantly treated with an NSAID. Exemplary NSAIDs can include, but are not limited to, aspirin, ibuprofen, naproxen, and nabumetone. In aspects, the subject is treated with an NSAID, and the NSAID has a stable dose for at least 2 weeks or more prior to screening. In aspects, the subject is treated with an NSAID, and the NSAID is not administered for the first time for at least 2 weeks or more prior to screening.

[0100] Cholinergic agonist

[0101] In aspects, the subject was previously treated with a cholinergic agonist. In aspects, the subject is concomitantly treated with a cholinergic agonist. Exemplary cholinergic agonists include, but are not limited to, cevimeline and pilocarpine.

[0102] In aspects, the one or more prior therapy and / or concomitant therapy is administered more than about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 20 weeks, about 25 weeks, about 30 weeks, about 35 weeks, about 40 weeks, about 45 weeks, or about 52 weeks or more prior to administration of the Tn3 scaffold. In aspects, the one or more prior therapy or concomitant therapy is administered more than about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, or about 12 months or more prior to administration of the Tn3 scaffold.

[0103] The dosage and dosing regimen of the Tn3 scaffold disclosed herein can be such that any therapeutic effect achieved from administration of the Tn3 scaffold to treat any autoimmune disease or disorder can be considered to be “sustained.” A “sustained” effect of the Tn3 scaffold in treating an autoimmune disease or disorder is the maintenance of a therapeutic effect achieved by the Tn3 scaffold (despite no longer administering the Tn3 scaffold) 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 about at least 5 years after the last dose of the course of Tn3 scaffold administration. In aspects, lower frequency dosing of any of the compositions provided herein can be advantageous. Exemplary advantages of lower frequent dosing include, but are not limited to, a reduction in the frequency of side effects associated with administration of the composition, a reduction in treatment-related toxicities, an improvement in the quality of life of the subject being treated, and the like.

[0104] Evaluation

[0105] In aspects, a subject is evaluated. In aspects, a subject is evaluated as part of a treatment. In aspects, a subject having a confirmed or possible autoimmune disease or condition (e.g., SS) is evaluated as part of a treatment. The evaluation can be performed at any point prior to, during, or after administration of the Tn3 scaffold. In aspects, the evaluation is performed prior to the start of administration. In aspects, the evaluation is performed concurrently with administration. In aspects, the evaluation is performed after the end of administration.

[0106] Any of the evaluations cited below can be performed at any time. In aspects, the subject is evaluated on a minute-by-minute, hourly, daily, weekly, monthly, or yearly basis. In aspects, the evaluation is completed twice daily, every two weeks, every two months, or every half year. In aspects, the evaluation is from day -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, 112, 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, days after the administration of the first dose of the anti-CD93 antibody.Day 143, Day 144, Day 145, Day 146, Day 147, Day 148, Day 149, Day 150, Day 151, Day 152, Day 153, Day 154, Day 155, Day 156, Day 157, Day 158, Day 159, Day 160, Day 161, Day 162, Day 163, Day 164, Day 165, Day 166, Day 167, Day 168, Day 169, Day 170, Day 171, Day 172, Day 173, Day 174, Day 175, Day 176, Day 177, Day 178, Day 179, Day 180, Day 181, Day 182, Day 183, Day 184, Day 185, Day 186, Day 187, Day 188, Day 189, Day 190, Day 191, Day 192, Day 193, Day 194, Day 195, Day 196, Day 197, Day 198, Day 199, Day 200, Day 201, Day 202, Day 203, Day 204, Day 205, Day 206, Day 207, Day 208, Day 209, Day 210, Day 211, Day 212, Day 213, Day 214, Day 215, Day 216, Day 217, Day 218, Day 219, Day 220, Day 221, Day 222, Day 223, Day 224, Day 225, Day 226, Day 227, Day 228, Day 229, Day 230, Day 231, Day 232, Day 233, Day 234, Day 235, Day 236, Day 237, Day 238, Day 239, Day 240, Day 241, Day 242, Day 243, Day 244, Day 245, Day 246, Day 247, Day 248, Day 249, Day 250, Day 251, Day 252, Day 253, Day 254, Day 255, Day 256, Day 257, Day 258, Day 259, Day 260, Day 261, Day 262, Day 263, Day 264, Day 265, Day 266, Day 267, Day 268, Day 269, Day 270, Day 271, Day 272, Day 273, Day 274, Day 275, Day 276, Day 277, Day 278, Day 279, Day 280, Day 281, Day 282, Day 283, Day 284, Day 285, Day 286, Day 287, Day 288, Day 289, Day 290, Day 291, Day 292, Day 293, Day 294, Day 295, Day 296, Day 297, Day 298, Day 299, Day 300, Day 301, Day 302, Day 303, Day 304, Day 305, Day 306, Day 307, Day 308,on days 309, 310, 311, 312, 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, 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, 392, or up to about day 393 ± 7 days (after treatment).

[0107] In aspects, treating SS can be characterized by a reduction in clinical symptoms of the disease or disorder, or a reduction in inflammation, or a reduction in a biomarker of the disease or disorder, 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%, relative to the level prior to treatment with the Tn3 stent. The reduction in any of these symptoms, or inflammation, or biomarker can be a reduction of at least about 10%, 15%, 20%, 25%, about 30%, about 40%, about 50%, about 60%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, or up to about 100%, relative to the level prior to the start of treatment with the Tn3 stent. The reduction can be such that the SS is characterized as being in remission.

[0108] In aspects, the subject is evaluated and a baseline measurement of the disease is determined. In aspects, the subject is evaluated and a baseline measurement of the disease is determined at any point prior to, during, or after administration of the Tn3 scaffold. In aspects, the subject is evaluated and a baseline measurement of the disease is determined prior to administration of the Tn3 scaffold. In aspects, the subject is evaluated and a baseline measurement of the disease is determined concurrently with administration of the Tn3 scaffold. In aspects, the subject is evaluated and a baseline measurement of the disease is determined after administration of the Tn3 scaffold.

[0109] In aspects, the baseline measurement of the disease is elevated or reduced in response to administration of the present disclosure or lack thereof. In aspects, the baseline measurement of the disease can be elevated and indicative of effective treatment of the disease or condition. In aspects, the baseline measurement of the disease can be reduced and indicative of effective treatment of the disease or condition. In aspects, the baseline measurement of the disease is elevated or reduced after administration of the Tn3 scaffold. In aspects, the baseline measurement of the disease can be elevated after administration of the Tn3 scaffold and is indicative of effective treatment of the disease or condition. In aspects, the baseline measurement of the disease can be reduced after administration of the Tn3 scaffold and is indicative of effective treatment of the disease or condition.

[0110] In aspects, the baseline measurement of the disease is compared to a measurement of the disease in the subject after administration of the Tn3 scaffold. In aspects, the measurement of the disease in the subject administered the Tn3 scaffold is elevated compared to the baseline measurement of the disease measured prior to administration of the Tn3 scaffold. In aspects, the measurement of the disease in the subject administered the Tn3 scaffold is reduced compared to the baseline measurement of the disease measured prior to administration of the Tn3 scaffold. In aspects, the measurement of the disease in the subject administered the Tn3 scaffold is elevated compared to the baseline measurement of the disease measured prior to administration of the Tn3 scaffold and is indicative of effective treatment. In aspects, the measurement of the disease in the subject administered the Tn3 scaffold is reduced compared to the baseline measurement of the disease measured prior to administration of the Tn3 scaffold and is indicative of effective treatment.

[0111] In aspects, the assessment comprises determining efficacy of treatment. Efficacy can be determined by any assessment of the disclosure. In aspects, effectiveness in preventing, reducing, or eliminating an autoimmune disease or disorder (e.g., SS) is determined by detecting a change in European League Against Rheumatism (EULAR) Sjogren’s Syndrome Disease Activity Index (ESSDAI) score. In aspects, the ESSDAI is reduced by about 1 point, about 2 points, about 3 points, about 4 points, about 5 points, about 6 points, about 7 points, about 8 points, about 9 points, about 10 points, or more relative to baseline. In aspects, effectiveness in preventing, reducing, or eliminating an autoimmune disease or disorder (e.g., SS) is determined by detecting a change in EULAR Sjogren’s Syndrome Patient Reported Index (ESSPRI) score. In aspects, the ESSPRI is reduced by about 1 point (ESSPRI[l]), about 1.5 points (ESSPRI[l.5]), about 2 points (ESSPRI[2]), about 3 points (ESSPRI[3]), about 4 points (ESSPRI[4]), about 5 points (ESSPRI[5]), about 6 points (ESSPRI[6]), about 7 points (ESSPRI[7]), about 8 points (ESSPRI[8]), about 9 points (ESSPRI[9]), about 10 points (ESSPRI

[10] ), or more relative to baseline. In aspects, effectiveness in preventing, reducing, or eliminating an autoimmune disease or disorder is determined by evaluating: pharmacokinetic parameters of the Tn3 scaffold for treating a subject in need thereof; baseline changes in blood levels of IgM, rheumatoid factor (RF), sCD40L, CXCL13 of the subject; presence of anti-drug antibodies (ADA); and combinations thereof. In aspects, effectiveness in preventing, reducing, or eliminating an autoimmune disease or disorder is determined by evaluating levels of plasma immunoglobulins (IgM, IgG, and IgA), beta-2 microglobulin, high-sensitivity CRP, serum C3, C4, free light chains, cryoglobulins, and serum anti-SSA (e.g., anti-Ro), anti-SSB (e.g., anti-La), and IgG of the subject. In aspects, effectiveness in preventing, reducing, or eliminating an autoimmune disease or disorder is determined by evaluating one or more rheumatoid factors (RF). RFs are antibodies to the Fc portion of immunoglobulin G with various isotypes and affinities. The most common rheumatoid factor is IgM RF, but other immunoglobulin types, including IgG and IgA, can be found.

[0112] In aspects, effectiveness in preventing, reducing, or eliminating an autoimmune disease or disorder is determined by evaluating a subject’s population of white blood cells (e.g., B lymphocytes). Subject B cells can be present in peripheral blood. In aspects, subject B cells are present in salivary glands. In aspects, a subject of the disclosure exhibits perturbed 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+ subset. In aspects, a subject of the disclosure includes an increase in the number of naive non-switched peripheral memory B cells (CD19+, CD27-, IgD+), with a decrease in the number of peripheral memory B cells (CD19+, CD27+, IgD-). In aspects, a subject of the disclosure includes an increase in the frequency of transitional B cells and mature naive B cells expressing polyreactive antibodies in peripheral blood. The compositions and methods herein are effective in addressing any of the B cell level perturbations described herein. For example, a subject treated with a composition of the disclosure (e.g., a Tn3 scaffold) can exhibit an increase in the frequency and / or absolute number of peripheral CD27+ memory B cells following administration of a composition of the disclosure. In aspects, a subject administered a composition of the disclosure exhibits an increase in the CD27+ IgM+ subset as compared to the subject’s baseline level. In aspects, a subject of the disclosure exhibits a decrease in the number of naive non-switched peripheral memory B cells (CD19+, CD27-, IgD+), with an increase in the number of peripheral memory B cells (CD19+, CD27+, IgD-) as compared to baseline.

[0113] In aspects, effectiveness in preventing, reducing, or eliminating an autoimmune disease or disorder is determined by evaluating a subject’s population of CD27+ memory B cells, marginal zone B cells, plasmablasts, plasma cells, and combinations thereof. In aspects, effectiveness in preventing, reducing, or eliminating an autoimmune disease or disorder is determined by evaluating a subject’s population of B cells (e.g., Ki67+ post-switch memory B cells, Ki67+ / CD27+ memory B cells, CD27br / CD38br / IgD- plasmablasts, CD11c high In aspects, effectiveness in preventing, reducing, or eliminating an autoimmune disease or disorder is determined by evaluating a subject’s TfH cell level. In aspects, a subject’s TfH cell level is evaluated by evaluating the percentage of positive CXCR5+ and / or ICOS+ cells. In aspects, a subject’s TfH cell level is evaluated by evaluating the percentage of positive CXCR5+ and / or ICOS+ cells of identified CD4+ and / or CD3+ cells.

[0114] In aspects, the subject of the disclosure exhibits perturbation of B cells within exocrine gland infiltrates. For example, the perturbation can include one or more of the following: presence of germinal center-like structures, increased frequency of IgG plasma cells compared to a healthy subject, autoreactive B cells and / or plasma cells, increased levels of B cell-associated cytokines and chemokines (e.g., IL-6, IL-21, BAFF, APRIL, CXCL12, CXCL13) compared to a healthy subject, presence of clonal B cell populations and / or autobody-producing plasma cells, and any combination thereof. In aspects, the subject administered the composition of the disclosure exhibits a decrease in the level of a B cell-associated cytokine or chemokine selected from the group consisting of: IL-6, IL-21, BAFF, APRIL, CXCL12, CXCL13, and any combination thereof. In aspects, the decrease is at least about or at most about 5%, 10%, 20%, 40%, 60%, 80%, 100%, or 150%. In aspects, evaluating the level of one or more parameters (e.g., B cells) includes quantifying the number of the one or more parameters in a sample of the subject.

[0115] Evaluation for inclusion

[0116] In aspects, the subject in need is evaluated prior to initiation of treatment.

[0117] In aspects, the subject in need can be a male or female. In aspects, the subject in need is an adult subject. In aspects, the subject in need can be at least about 18 years of age. In aspects, the subject is 18-100 years of age.

[0118] In aspects, the subject in need is diagnosed with SS. In aspects, the subject in need is diagnosed with SS according to the American College of Rheumatology (ACR) criteria. In aspects, the subject in need is diagnosed with SS according to the 2016 American College of Rheumatology (ACR) criteria. In aspects, the subject in need has an ESSPRI score of >5. In aspects, the subject in need has an ESSDAI score of <5. In aspects, the subject in need has an ESSDAI score of >5. In aspects, the subject in need is positive for anti-SSA (e.g., anti-Ro) autoantibodies. In aspects, the subject in need is positive for rheumatoid factor (RF). In aspects, the subject in need is positive for both anti-SSA (e.g., anti-Ro) autoantibodies and RF. In aspects, the subject in need is diagnosed with rheumatoid arthritis (RA). In aspects, the subject in need is diagnosed with systemic lupus erythematosus (SLE). In aspects, the subject in need has SS and coexisting RA. In aspects, the subject in need has SS and coexisting SLE. The assessment for inclusion in the present disclosure can be performed up to about 0 days (after treatment initiation) from about -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.

[0119] ESSPRI

[0120] In aspects, the assessment can include an ESSPRI evaluation. In aspects, the ESSPRI evaluation is a self-evaluation (Seror et al., 2011). In aspects, the ESSPRI evaluation uses a 0 to 10 numerical analog scale (ranging from 0 [no symptoms] to 10 [maximum severity imaginable]) for the assessment of each of the 3 domains: dryness, fatigue, and pain (joint and / or muscle pain). ESSPRI fatigue has been shown to be a major predictor of poor quality of life (QoL) and pain in SS subjects. In aspects, the ESSPRI dryness domain has been shown to correlate with sleep quality, presence and degree of anxiety and depression (Gandia et al., 2014), and overall QoL (Schmalz et al., 2020). In aspects, the subject in need has an ESSPRI score of >5, which can be considered a cutoff score for an “unsatisfactory symptom state” (Seror et al., 2016).

[0121] The weights for the domains can be the same, and the average of the scores for the 3 domains represents the final score. In each question, the recall period can be stated as “past 2 weeks.” In aspects, the subject has an ESSPRI score of about 1 to about 100 prior to administration of the compositions of the disclosure. In aspects, the subject has an ESSPRI score of about 1-10, 5-15, 10-20, 15-25, 20-30, 25-35, 30-40, 35-45, 40-50, 45-55, 50-60, 55-65, 60-70, 65-75, 70-80, 75-85, 80-90, 85-95, 90-100, or about 95-100 prior to administration of the compositions of the disclosure. In aspects, the subject has an ESSPRI score of about 5-6, 5-7, 6-8, 6-9, or about 5-10 prior to administration of the compositions of the disclosure.

[0122] ESSPRI [1.5] refers to a reduction in ESSPRI score of at least 1.5 points from baseline.

[0123] In aspects, the compositions of the disclosure are effective to reduce ESSPRI score. In aspects, 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 aspects, 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 aspects, the ESSPRI score is reduced by about 0.6-5, 0.6-10, 1-10, 1-5, 2-10, or 5-10 points. In aspects, the ESSPRI score is reduced compared to an otherwise comparable method, wherein the subject of the otherwise comparable method is not administered a Tn3 scaffold, for example, the reduction can be about 10%, 15%, 20%, 25%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or up to 100% compared to the ESSPRI score of the otherwise comparable method, wherein the subject of the otherwise comparable method is not administered a Tn3 scaffold. In aspects, the ESSPRI score is reduced compared to an otherwise comparable method, wherein the subject of the otherwise comparable method is not administered a Tn3 scaffold, for example, the reduction can be about 10%, 15%, 20%, 25%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or up to 100% compared to baseline.

[0124] In aspects, the ESSPRI score is assessed at about -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, 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 treatment initiation) has begun. In aspects, the ESSPRI score is assessed at about 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, 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 about day 337 (±7 days) (after treatment initiation). The ESSPRI score can be assessed at any time before, during, or after treatment with a Tn3 scaffold of the disclosure, as described herein.

[0125] Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue Short Form 10a Survey

[0126] In aspects, the assessment includes the PROMIS Fatigue 10a survey. The PROMIS Fatigue 10a survey can assess a range of self-reported symptoms, from mild subjective tiredness to overwhelming, debilitating, and persistent exhaustion. In aspects, fatigue is divided into fatigue experience (frequency, duration, and intensity) and the impact of fatigue on physical, psychological, and social activities. In aspects, the PROMIS Fatigue 10a survey assesses symptoms over the past week. In aspects, the PROMIS Fatigue 10a survey can include an assessment of a subject in need thereof administered a Tn3 stent of the disclosure compared to baseline. In aspects, the subject’s self-reported symptoms are improved compared to a method otherwise comparable, wherein the subject of the method otherwise comparable is not administered a Tn3 stent of the disclosure.

[0127] In aspects, the PROMIS Fatigue 10a survey of a Tn3 stent of the disclosure can be assessed at about -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, 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 treatment initiation). In aspects, the PROMIS Fatigue is assessed at any time before, during, or after treatment with a Tn3 stent of the disclosure.

[0128] 5-level EQ-ED (EQ-5D-5L)

[0129] In aspects, the assessment can include an EQ-5D-5L survey. The EQ-5D-5L survey is provided to the subject to capture information covering five dimensions of their health status: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. The EQ-5D-5L survey has five response levels: no problem (1), slight problem (2), moderate problem (3), severe problem (4), complete inability / extreme problem. The subject indicates their health status by selecting the most appropriate response level for each of the five dimensions. In aspects, the EQ-5D-5L survey assesses symptoms over the past week. In aspects, the EQ-5D-5L survey can include assessing a subject in need thereof administered a Tn3 stent of the disclosure compared to baseline. In aspects, the subject’s self-reported symptoms are improved compared to a method otherwise comparable, wherein the subject of the method otherwise comparable is not administered a Tn3 stent of the disclosure.

[0130] In aspects, the EQ-5D-5L survey of a Tn3 stent of the disclosure can be assessed at about -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, 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 treatment initiation). In aspects, the EQ-5D-5L is assessed at any time before, during, or after treatment with a Tn3 stent of the disclosure.

[0131] 36-Item Short Form Survey (SF-36)

[0132] In aspects, the assessment can include SF-36. SF-36 is a 36-item general health status assessment that can capture information about 8 domains of health: Physical Functioning, Role Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role Emotional, and Mental Health. SF-36 provides a score for each domain as well as 2 psychometrically-based summary scores: the Physical Component Summary (PCS) and the Mental Component Summary (MCS). The recall period for the acute version is one week (i.e., “last week”). SF-36 is a widely used, validated, professional quality of life score that covers multiple domains and is sensitive to change (Hemingway et al., 1997). SF-36 PCS is derived from multiple physical domains and has been shown to be validated and responsive in related autoimmune diseases (Kosinski et al., 1999; Devilliers et al., 2015). SF-36 PCS scores can capture improvements in physical and mental functioning globally, as these scores are based on assessments of several symptoms close to those experienced by subjects with SS, such as pain and mental and physical health (Sjogren’s Syndrome Foundation (SSF) 2021).

[0133] In aspects, the SF-36 survey can include assessing a subject in need thereof administered with a Tn3 stent compared to baseline. In aspects, the subject’s functional health and well-being is improved compared to a method otherwise comparable, wherein the subject of the method otherwise comparable is not administered a Tn3 stent.

[0134] ​In aspects, SF-36 for Tn3 scaffolds of the disclosure can be assessed at about -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, 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 treatment initiation) in aspects, SF-36 for Tn3 scaffolds of the disclosure can be assessed at about 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 about day 337 (±7 days) (after treatment initiation). In aspects, SF-36 is assessed at any time before, during, or after treatment with a Tn3 scaffold of the disclosure.

[0135] Dry site improvement project

[0136] The assessments of the present disclosure can include a dry site improvement project. A dry site improvement project is a series of assessments of problems with dry sites. In aspects, the problems are completed during a screening and ask the subject to rank the dry sites that are most important to improve (1 = most important site to improve, 4 = least important site to improve). Follow-up questions include asking the subject to select the site that improved the most (if any) at 2 different time points: week 24 (question 2) and week 48 (question 3). Additional time points are contemplated 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 treatment initiation. In aspects, dry site improvement is assessed at any time before, during, or after treatment with a Tn3 scaffold of the present disclosure.

[0137] In aspects, treatment with a composition of the present disclosure is effective to reduce dryness as determined by a dry site improvement measure. In aspects, a subject treated with a composition of the present disclosure experiences a reduction in dryness at one or more sites identified as dry prior to treatment. Dryness can be self-identified or identified by a professional medical practitioner. In aspects, a reduction in dryness is determined by self-identification, and includes at least about or at most about 1 event, 2 events, 3 events, 4 events, or 5 events of self-identification.

[0138] Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue

[0139] In aspects, the assessment can include a FACIT-Fatigue assessment. The FACIT-Fatigue is a 13-item questionnaire completed by the subject to assess the impact of fatigue. The recall period for the FACIT-Fatigue is 7 days. Responses range from 0 (not at all) to 4 (very much). In aspects, the FACIT-Fatigue score for a question is about 0, 1, 2, 3, or up to about 4. In aspects, the FACIT-Fatigue score for a question is about 0 to about 4 or about 1 to about 4. To calculate the total score, the items for negative statements are reversed by subtracting the response from “4.” The final score is the sum of the responses, and ranges from 0 to 52. In aspects, the FACIT-Fatigue total score is about 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 about 52. A higher score indicates a better quality of life. In aspects, the FACIT-Fatigue assessment can include assessing a subject in need thereof administered a Tn3 scaffold as compared to baseline. In aspects, the subject has an increased FACIT-Fatigue score as compared to a subject in an otherwise comparable method, wherein the subject in the otherwise comparable method is not administered a Tn3 scaffold.

[0140] In aspects, the treatment with the compositions of the disclosure is effective to reduce the FACIT-Fatigue score. In aspects, 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 aspects, 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 aspects, the FACIT-Fatigue score is reduced by about 1-5, 2-10, 5-10, 5-20, 10-20, 25-45, or 20-30 points.

[0141] In aspects, FACIT-Fatigue assessments of the Tn3 scaffolds of the present disclosure can be assessed at about -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, 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 treatment initiation). In aspects, FACIT-Fatigue assessments of the Tn3 scaffolds of the present disclosure can be assessed at about 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 about day 337 (±7 days) (after treatment initiation). In aspects, FACIT-Fatigue is assessed at any time before, during, or after treatment with the Tn3 scaffolds of the present disclosure.

[0142] Visual analog scale (VAS) for ocular, oral, and / or vaginal dryness

[0143] In aspects, the assessment can include a VAS of ocular, oral, and / or vaginal dryness. The VAS Oral / Eye / Vagina consists of 3 instruments that use a continuous 100 mm VAS (0 mm = best, 100 mm = worst) to assess changes in the severity of oral, ocular, and vaginal dryness throughout the study. Subjects are asked to place a line perpendicular to the VAS line at a point that represents the intensity of the symptoms over the past 2 weeks. The VAS Oral is rated to the question “How dry does your mouth feel most of the time?” (completely not dry: 0 mm; as dry as the desert: 100 mm). The VAS Eye is rated to the question “How dry do your eyes feel most of the time?” (completely not dry: 0 mm; very dry: 100 mm). The VAS Vagina asks the respondent (as appropriate) to rate symptoms of vaginal dryness (no symptoms: 0 mm; worst possible symptoms: 100 mm). In aspects, the VAS Oral / Eye / Vagina survey scores from about 0 to about 100, from about 1 to about 100, from about 10 to about 100, or from about 0 to about 90. In aspects, the VAS Eye / Oral / Vagina survey scores from 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, 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, up to about 100. In aspects, the VAS Oral / Eye / Vagina assessment can include assessing a subject in need thereof administered a Tn3 stent as compared to baseline. In aspects, the subject’s VAS Oral / Eye / Vagina score is reduced as compared to a subject in an otherwise comparable method wherein the subject in the otherwise comparable method is not administered a Tn3 stent. In aspects, the baseline (VAS) Oral / Eye / Vagina score is reduced by about 3%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or up to about 100% as compared to the subject’s VAS Oral / Eye / Vagina score prior to administration of the Tn3 stent.

[0144] In aspects, the VAS oral / ocular / vaginal score is effectively reduced by treatment with the compositions of the present disclosure. In aspects, 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 aspects, 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 aspects, the VAS oral / ocular / vaginal score is reduced by about 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 about 90-100 points.

[0145] In aspects, the VAS oral / ocular / vaginal evaluation of the Tn3 scaffold of the present disclosure can be assessed at about -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, 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 treatment initiation). In aspects, the VAS oral / ocular / vaginal evaluation of the Tn3 scaffold of the present disclosure can be assessed at about 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 about day 337 (±7 days) (after treatment initiation). In aspects, the VAS oral / ocular / vaginal dryness is assessed at any time before, during, or after treatment with the Tn3 scaffold of the present disclosure.

[0146] Patient Global Impression - Severity (PGIS)

[0147] In aspects, the assessment can include a PGIS survey. PGIS is a single item questionnaire designed to capture the subject’s perception of the severity of overall SS symptoms (e.g., pain, fatigue, and / or dryness) in the past 7 days on a 5-point categorical response scale (1 = none, 2 = mild, 3 = moderate, 4 = severe, or 5 = extreme). In aspects, the PGIS score can include an assessment of a subject in need thereof administered a Tn3 stent compared to baseline. In aspects, the subject’s PGIS score is reduced compared to a method otherwise comparable, wherein the subject of the method otherwise comparable is not administered a Tn3 stent. The reduction can be about 1, 2, 3, 4, or up to about 5 points. In aspects, the subject receives 3 symptom specific PGIS items (e.g., pain, fatigue, and / or dryness) as well as an overall symptom PGIS. The overall symptom PGIS can include additional symptoms other than pain, fatigue, and / or dryness.

[0148] In aspects, treatment with the compositions of the disclosure is effective to reduce the PGIS score. In aspects, the PGIS score is reduced by at least about 1, 2, 3, 4, or 5 points. In aspects, the PGIS score is reduced by up to about 1, 2, 3, 4, or 5 points. In aspects, the PGIS score is reduced by about 1-5, 2-5, 1-4, or 3-5 points.

[0149] In aspects, the PGIS survey can be assessed at about -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, 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 treatment initiation) has begun. In aspects, the PGIS survey can be assessed at about 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, 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 about day 337 (±7 days) (after treatment initiation) has begun. In aspects, the PGIS is assessed at any time before, during, or after treatment with a Tn3 scaffold of the disclosure.

[0150] Patient Global Impression-Change (PGIC)

[0151] In aspects, the assessment can include a PGIC survey. PGIC is a single-item questionnaire designed to capture the subject’s perception of change in their SS symptoms (e.g., pain, fatigue, and / or dryness) from the start of treatment. Change in severity is captured using a 5-point scale (1 = much better, 2 = a little better, 3 = no change, 4 = a little worse or 5 = much worse). In aspects, the PGIC score can include an assessment of a subject in need of administration of a Tn3 scaffold as compared to baseline. In aspects, the subject’s PGIC score is reduced as compared to a method otherwise comparable, wherein the subject of the method otherwise comparable is not administered a Tn3 scaffold. The reduction can be about 1, 2, 3, 4, or up to about 5 points. In aspects, the subject receives 3 symptom-specific PGIC items (pain, fatigue, and / or dryness) as well as an overall symptom PGIC.

[0152] In aspects, treatment with the compositions of the disclosure is effective to reduce the PGIC score. In aspects, the PGIC score is reduced by at least about 1, 2, 3, 4, or 5 points. In aspects, the PGIC score is reduced by up to about 1, 2, 3, 4, or 5 points. In aspects, the PGIC score is reduced by about 1-5, 2-5, 1-4, or 3-5 points.

[0153] In aspects, the PGIC survey can be assessed at about -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, 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 treatment initiation) after treatment initiation. In aspects, the PGIC survey can be assessed at about day 15 (±3 days 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), or about day 337 (±7 days) (after treatment initiation). In aspects, the PGIC is assessed at any time before, during, or after treatment with a Tn3 stent of the disclosure.

[0154] Unstimulated Salivary Flow

[0155] Assessments of the disclosure can include an unstimulated salivary flow assay. Unstimulated salivary flow assessments can be performed prior to stimulated salivary flow collection, but other time periods are also contemplated. Subjects receiving standard of care for xerostomia at the time of screening can discontinue use of pilocarpine and / or cevimeline for at least about 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, or 15 hours, and / or discontinue use of artificial saliva for at least about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, or 10 hours, prior to saliva collection. Participants should avoid eating or drinking water for at least about 30 minutes, 60 minutes, 90 minutes, 120 minutes, or 175 minutes prior to saliva collection.

[0156] For unstimulated salivary flow collection, the subject avoids swallowing or talking throughout the collection time, except for a single swallow immediately prior to the start of the collection timing. In aspects, the total duration of the procedure is about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 minutes during which the subject accumulates saliva in the oral cavity for a period of 60 seconds, after which it is emptied into a pre-weighed container. This is repeated for a total of about 1, 2, 3, 4, 5, 6, 7, or 8 times during the test. The weight of the container needs to be recorded at the beginning and at the end of the procedure.

[0157] In aspects, the subject treated with the compositions of the disclosure experiences an increase in salivary flow as determined by the unstimulated salivary flow assay. In aspects, the subject exhibits an increased salivary flow, wherein the weight of the subject’s container is increased compared to the weight of the container at baseline. In aspects, the weight is increased by at least about or at most about 5%, 10%, 20%, 30%, 40%, 50%, 75%, 100%, 120%, 150%, or up to about 200%.

[0158] Female Sexual Function Index (FSFI)

[0159] In all aspects, the assessment may include the FSFI survey. The FSFI survey is designed to define female sexual function in clinical and non-clinical samples through research on female sexual function to establish clear endpoints and outcomes (Rosen et al., 2000). The FSFI is a 19-item self-reported and validated questionnaire that assesses function in the following areas over the past 4 weeks: libido, arousal, lubrication, orgasm, satisfaction, and pain. Each item is rated on a scale from 0 (no sexual activity) or 1 (maximum dysfunction) to 5 (no sexual dysfunction). The final score is calculated as follows: to standardize each area based on the number of items, the sum of the scores for each area is first multiplied by the area factor ratio (libido 0.6; arousal 0.3; lubrication 0.3; orgasm 0.4; satisfaction 0.4; and pain 0.4), and then the area scores are summed to produce the final score. In all aspects, the FSFI survey scores are approximately 0 to 36, approximately 1 to 36, approximately 2 to 36, approximately 0 to 30, approximately 1 to 30, or approximately 2 to 30. In all aspects, the FSFI survey score ranged 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 to up to approximately 36. This questionnaire can be completed by female participants. In all aspects, the FSFI score can include an assessment of participants requiring Tn3 stent placement compared to baseline. In all aspects, participants with increased FSFI scores compared to otherwise comparable methods, where participants using otherwise comparable methods did not receive Tn3 stent placement.

[0160] In all respects, treatment with the compositions disclosed herein effectively increases the FSFI survey score. In all respects, the FSFI score increases by at least about 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 to up to about 36 points. In all respects, the PGIC score increases by 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 to up to about 36. In each category, the FSFI score increases by approximately 1-36, 1-30, 1-20, 1-10, 5-10, 15-25, 20-36, or 25-36 points.

[0161] In aspects, the FSFI survey can be assessed at about -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, 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 treatment initiation) after treatment initiation. In aspects, the FSFI survey can be assessed at about 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 about day 337 (±7 days) (after treatment initiation). In aspects, the FSFI is assessed at any time before, during, or after treatment with a Tn3 scaffold of the disclosure.

[0162] ESSDAI

[0163] The assessments of the disclosure can include an ESSDAI evaluation. In aspects, the ESSDAI evaluation includes a physical examination. ESSDAI is a systemic disease activity index that includes organ-specific definitions of disease activity (Seror et al., 2010). ESSDAI grades disease activity in 12 domains (cutaneous, respiratory, renal, articular, muscular, peripheral nervous system, central nervous system, hematologic, glandular, constitutional, lymphadenopathy, and biological). The weight of each domain is modeled by multiple regression, using the Physician’s Global Assessment of Activity as the gold standard.

[0164] Each domain is assigned a weight of 1 (biological domain) to 6 (muscle domain), and each domain has 3 or 4 levels of activity, ranging from 0 (no activity) to 3 or 4 (severe activity).

[0165] The theoretical range of ESSDAI values is 0 to 123, and the final score is calculated as follows: 1) Final score = sum of all 12 domain scores; 2) Domain score = level of activity x domain weight.

[0166] Low activity status is defined as ESSDAI < 5, moderate activity is defined as 5 < ESSDAI < 13, and severe activity is defined as ESSDAI > 14 (Seror et al., 2016). ESSDAI can be an appropriate primary endpoint as it is a validated and widely used measure of systemic disease activity in SS (Seror et al., 2015). It was found to have good construct validity and reliable scoring; moreover, the systemic score demonstrated good sensitivity to changes in subjects with improvement in disease activity. ESSDAI[3] can refer to a 3-point reduction in ESSDAI score from baseline in a subject in need thereof previously administered a Tn3 stent of the present disclosure. ESSDAI[4] can refer to a 4-point reduction in ESSDAI score from baseline in a subject in need thereof previously administered a Tn3 stent of the present disclosure. ESSDAI[5] can refer to a 5-point reduction in ESSDAI score from baseline in a subject in need thereof previously administered a Tn3 stent of the present disclosure. ESSDAI[6] can refer to a 6-point reduction in ESSDAI score from baseline in a subject in need thereof previously administered a Tn3 stent of the present disclosure.

[0167] In aspects, the ESSDAI score is about 0 to about 123, about 1 to about 123, about 2 to about 123, about 10 to about 120, or about 5 to about 120. In aspects, the ESSDAI score is about 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, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, or up to about 123. In aspects, the subject has an ESSDAI score of about 5-7, 5-10, 5-13, or 10-13 prior to treatment with the compositions of the disclosure.

[0168] In aspects, treatment with the compositions of the disclosure is effective to reduce the ESSDAI score. In aspects, 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 aspects, 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 aspects, the ESSDAI score is reduced by about 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.

[0169] In aspects, the compositions of the disclosure are effective to reduce ESSDAI score. In aspects, the ESSDAI score is reduced by at least about or at most 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%, 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 aspects, the ESSDAI score is reduced by about 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 about 90%-100%.

[0170] In aspects, the ESSDAI assessment can be evaluated at about -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, 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 treatment initiation) in aspects, the ESSDAI assessment can be evaluated at about 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, 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 about day 337 (±7 days) (after treatment initiation). In aspects, the ESSDAI is assessed at any time before, during, or after treatment with a Tn3 scaffold of the disclosure.

[0171] Clinical EULAR Sjogren's Syndrome Disease Activity Index (ClinESSDAI)

[0172] In aspects, the assessment can comprise a ClinESSDAI evaluation. The ClinESSDAI is a validated ESSDAI-based index of SS disease activity that excludes the biology domain and assigns different weights to each domain. The ClinESSDAI was developed to reduce the possible association between B-cell biomarkers measured by the ESSDAI biology domain and clinical activity measures (Seror et al., 2016). The theoretical range of values for the ClinESSDAI is 0 to 135. Similar to the ESSDAI, low activity is defined as <5, moderate activity is defined as 5 < ClinESSDAI < 13, and high activity is defined as >14 (Seror et al., 2016). The ClinESSDAI has been validated and shown to be well correlated with the ESSDAI, and is considered a useful tool to detect changes not dependent on drug biological effects (Seror et al., 2016; Dumusc et al., 2018; Quartuccio et al., 2017).

[0173] In aspects, the ClinESSDAI score is about 0 to 135, about 1 to about 135, about 2 to about 135, about 10 to about 130, or about 5 to about 130. In aspects, the ClinESSDAI score is about 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, 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 about 135. In aspects, the ClinESSDAI score can include an assessment of a subject in need of administration of a Tn3 scaffold as compared to baseline. In aspects, the subject has a reduced ClinESSDAI score as compared to a subject in an otherwise comparable method, wherein the subject in the otherwise comparable method is not administered a Tn3 scaffold.

[0174] In aspects, the composition of the disclosure is effective to reduce the ClinESSDAI score. In aspects, the ClinESSDAI score is reduced 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, 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, 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 aspects, the ClinESSDAI score is reduced by 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, 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, 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 aspects, the ClinESSDAI score is reduced by about 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.

[0175] In aspects, the ClinESSDAI assessment can be performed about -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, 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 treatment initiation) from the subject. In aspects, the ClinESSDAI can be performed about 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, 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 about day 337 (±7 days) (after treatment initiation) from the subject. In aspects, the ClinESSDAI is assessed at any time before, during, or after treatment with a Tn3 scaffold of the disclosure.

[0176] 28 Joint Assessments (TJC and SJC)

[0177] In aspects, the assessment can include a 28 joint assessment. In aspects, the 28 joint assessment includes a tender joint count (TJC). In aspects, the 28 joint count includes a swollen joint count (SJC). In aspects, the 28 joint count includes both TJC and SJC. The 28 joint assessment will assess for tenderness and swelling in the following joints: left and right shoulder, elbow, wrist, 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 extremity, and left and right knee joints of the lower extremity. Each of the 28 joints can be evaluated for synovitis. At the start of the 28 joint count (before assessing for tenderness and swelling), the subject can be asked if they have experienced or are experiencing pain in any of the 28 joints. In aspects, the 28 joint assessment is scored from about 0 to about 28. In aspects, the 28 joint assessment is scored from about 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, up to about 28. In aspects, the 28 joint assessment can include assessing a subject in need thereof administered a Tn3 scaffold compared to baseline. In aspects, the subject has a decreased 28 joint assessment score compared to a subject in an otherwise comparable method, wherein the subject in the otherwise comparable method is not administered a Tn3 scaffold.

[0178] In aspects, treatment with the compositions of the disclosure is effective to decrease the 28 joint assessment score. In aspects, the 28 joint assessment score is decreased 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 aspects, the 28 joint assessment score is decreased by 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, or 28 points. In aspects, the 28 joint assessment score is decreased by about 1-28, 1-5, 2-10, 5-10, 1-20, 5-20, 10-15, 10-20, 15-25, or 20-28 points.

[0179] In aspects, the 28 joint assessment can be performed at about -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, 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 treatment initiation) in aspects, the 28 joint assessment can be performed at about 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 about day 337 (±7 days) (after treatment initiation). In aspects, the 28 joint count is assessed at any time before, during, or after treatment with a Tn3 scaffold of the disclosure.

[0180] Stimulated salivary flow

[0181] In aspects, the assessment can include a stimulated salivary flow measurement. In aspects, the complete stimulated salivary flow is measured to objectively assess changes in salivary gland function during treatment with a Tn3 scaffold of the disclosure. Subjects receiving standard of care for dry mouth at the time of screening can discontinue use of pilocarpine or cevimeline for at least 12 hours and discontinue use of artificial saliva for at least 3 hours prior to saliva collection. The subject can be prohibited from eating or drinking water for at least 90 minutes prior to saliva collection. Saliva can be collected simultaneously in all visits.

[0182] For complete stimulated salivary flow rate measurements, a roll of approximately 5 x 5 cm square parafilm is given to the subject to chew like gum at a rate of approximately 60 times / minute. The subject should sit upright, eyes open, and head slightly tilted forward, and begin chewing the parafilm for 60 seconds, at which time all collected saliva should be spat into a separate (unpre- weighed) falcon tube, leaving the parafilm in the mouth. This first collection allows the subject to become accustomed to the procedure. Three rounds of saliva collection are performed in a pre-weighed falcon tube, each round after 20 seconds of chewing. The rounds are consecutive, but the timer should be stopped during saliva collection and restarted immediately upon saliva deposition in the pre-weighed falcon tube, for a total stimulation time of 60 seconds. If the 60 second collection is not feasible due to the subject’s inability to do so, the total collection time should be recorded. The total stimulated saliva collected is assessed by subtracting the weight of the test tube before collection from the final weight of the test tube. In aspects, the change in stimulated salivary flow relative to baseline is determined.

[0183] In aspects, stimulated salivary flow measurements can be assessed at about -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, 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 treatment initiation). In aspects, stimulated salivary flow measurements can be assessed at about day 1, day 85 (±7 days), day 169 (±7 days), day 253 (±7 days), or about day 337 (±7 days) (after treatment initiation). In aspects, salivary flow is assessed at any time before, during, or after treatment with a Tn3 stent of the disclosure.

[0184] European Quality of Life 5-Dimension 5-Level version (EQ-5D-5L)

[0185] The assessment of the present disclosure can be EQ-5D-5L. The 5-level version of the EQ-5D (EQ-5D-5L) is a generic PRO instrument to measure health status. It consists of a descriptive system and an EQ visual analogue scale (EQ VAS). The EQ-5D-5L descriptive system includes 5 health dimensions: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. For each dimension, the patient selects one of 5 severity levels: no problems, mild problems, moderate problems, severe problems, and extreme problems. The EQ VAS records the patient’s self-rated health on a vertical visual analogue scale from 0 to 100, where the endpoints are labeled as worst imaginable health and best imaginable health, respectively.

[0186] In aspects, after treatment with the compositions of the present disclosure, the subject reports an increase in health level as determined by EQ-5D-5L. In aspects, the health is increased by at least about or at most about 5, 10, 20, 30, 40, 50, 60, 70, 80, or 90 points compared to the baseline level prior to treatment. In aspects, the EQ-5D-5L test is performed at any time prior to, during, or after treatment with the Tn3 scaffold of the present disclosure.

[0187] Schirmer test

[0188] The assessment of the present disclosure can be a Schirmer test. In aspects, the Schirmer test is performed without local anesthesia. The Schirmer test measures lacrimal gland function. It measures tear flow using a calibrated, non-toxic filter paper strip. One end of the filter paper strip is placed in the lower eyelid. Both eyes need to be measured simultaneously. After placement, the participant is asked to gently close their eyes for 5 minutes, at which time the filter paper strips are removed from the eyelids and the degree of wetness of each filter paper strip is recorded.

[0189] In aspects, after treatment with the compositions of the present disclosure, an increase in wetness is detected compared to the level of wetness or baseline level prior to treatment. In aspects, the wetness is increased by at least about or at most about 5%, 10%, 20%, 30%, 40%, or 50% compared to baseline. In aspects, the Schirmer test is performed at any time prior to, during, or after treatment with the Tn3 scaffold of the present disclosure.

[0190] Physician’s Global Impression of Severity (MDGIS)

[0191] In aspects, the assessment can include an MDGIS questionnaire. MDGIS represents an assessment of the severity of SS disease and is a 5-point categorical response scale (1 = none, 2 = mild, 3 = moderate, 4 = severe, or 5 = extreme). In aspects, the MDGIS score can range from about 0 to about 5 or about 1 to about 5. In aspects, the MDGIS score can be about 1, 2, 3, 4, or up to about 5. In aspects, the MDGIS score can be about 0, 1, 2, 3, or up to about 4. In aspects, the MDGIS score can include an assessment of a subject in need of administration of a Tn3 stent as compared to baseline. In aspects, the subject has a reduced MDGIS score as compared to a subject in an otherwise comparable method, wherein the subject in the otherwise comparable method is not administered a Tn3 stent.

[0192] In aspects, treatment with the compositions of the disclosure is effective to reduce the MDGIS score. In aspects, the MDGIS score is reduced by at least about 1, 2, 3, 4, or 5 points. In aspects, the MDGIS score is reduced by up to about 1, 2, 3, 4, or 5 points. In aspects, the MDGIS score is reduced by about 1-5, 2-5, 1-4, or 3-5 points.

[0193] In aspects, the MDGIS investigation can be performed about -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, 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 treatment initiation) after treatment initiation. In aspects, the MDGIS investigation can be performed about 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 about day 337 (±7 days) (after treatment initiation). In aspects, the MDGIS is assessed at any time before, during, or after treatment with a Tn3 scaffold of the disclosure.

[0194] electrocardiogram (ECG)

[0195] In aspects, the assessment can include an ECG. A single 12-lead ECG can be performed with the subject in a supine position. If the electrocardiogram measurement is performed after venotomy, it can be delayed by at least 10 minutes. Each ECG can include ventricular heart rate and intervals (PR, QRS, QT, RR).

[0196] In aspects, ECG evaluation can be assessed at about -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, 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 treatment initiation). In aspects, ECG evaluation can be assessed at about day 1, day 169 (±7 days), or about day 337 (±7 days) (after treatment initiation). In aspects, ECGs are assessed at any time before, during, or after treatment with a Tn3 stent of the disclosure.

[0197] Clinical safety laboratory tests

[0198] In aspects, the assessment can include clinical safety laboratory tests. Blood and urine samples can be collected for laboratory safety testing using clinically acceptable methods and devices. Abnormal laboratory results related to potential illnesses can not be considered clinically significant.

[0199] All laboratory tests with values considered to be clinically significantly abnormal during the study period or within the protocol follow-up period after the last dose of Tn3 stent can be repeated until the values return to normal or baseline or are no longer considered clinically significant. Additional testing can be performed at any time during the study.

[0200] In aspects, the clinical safety laboratory tests can include hematology, clinical chemistry, urine tests (urinalysis), pregnancy tests, and other screening tests. Exemplary hematology parameters can include, but are not limited to, platelet count, red blood cell (RBC) count, RBC indices (mean corpuscular volume [MCV] and mean corpuscular hemoglobin [MCH]), white blood cell [WBC] count with differential (e.g., neutrophils, lymphocytes, monocytes, eosinophils, and / or basophils), hemoglobin, hematocrit, and immunoglobulins (IgG, IgM, and IgA). Exemplary clinical chemistry parameters can 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 glutamyl transpeptidase, albumin, total protein, creatine kinase, calculated estimated glomerular filtration rate (eGFR), uric acid, total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides. Exemplary urine test parameters include, but are 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 can include, but are not limited to, serum beta human chorionic gonadotropin (beta-hCG) pregnancy test and urine pregnancy test. Other screening test parameters can include, but are not limited to, follicle-stimulating hormone, serology (e.g., hepatitis B virus [HBV], HCV, human immunodeficiency virus-1 [HIV-1], HIV-2), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rapid test, tuberculosis (TB) test (e.g., interferon gamma release assay [IGRA]), and coagulation panel (e.g., prothrombin time, international normalized ratio [INR], partial thromboplastin time [PTT]). In aspects, the clinical safety laboratory tests can include assessments of a subject in need thereof administered a Tn3 stent as compared to baseline. In aspects, the subject’s clinical safety laboratory tests are reduced as compared to a method otherwise comparable, wherein the subject of the method otherwise comparable is not administered a Tn3 stent. In aspects, the subject’s clinical safety laboratory tests are increased as compared to a method otherwise comparable, wherein the subject of the method otherwise comparable is not administered a Tn3 stent.

[0201] In aspects, clinical safety laboratory tests can be assessed about -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, 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 treatment initiation) have begun. In aspects, clinical safety laboratory tests can be assessed about 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, day 0, day 1, day 15 (day -3 to 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), day 337 (±7 days), or about day 393 (±7 days) (after treatment initiation). In aspects, clinical tests are performed at any time before, during, or after treatment with a Tn3 scaffold of the disclosure.

[0202] Immunogenicity

[0203] In aspects, the assessment can include determining the level of immunogenicity, if any, of the anti-Tn3 scaffolds of the present disclosure. Immunogenicity includes determining whether there are anti-drug antibodies (ADA) against the Tn3 scaffold. The presence of an ADA can be evaluated using plasma samples from subjects administered the Tn3 scaffold. Plasma samples for ADAs against the Tn3 scaffolds of the present disclosure can be taken prior to IP administration according to a visit and assessed using a validated immunoassay. In aspects, no ADA is detected after administration of the Tn3 scaffold. In aspects, the level of ADA is reduced compared to an otherwise comparable method, where the subjects of the otherwise comparable method are not administered the Tn3 scaffold, for example, the reduction can be about 10%, 15%, 20%, 25%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or up to 100% compared to the level of ADA of the otherwise comparable method, where the subjects of the otherwise comparable method are not administered the Tn3 scaffold.

[0204] Antibodies against the Tn3 scaffolds of the present disclosure can be evaluated in plasma samples collected from all subjects. Additionally, plasma samples should also be collected from subjects who discontinue administration of the Tn3 scaffold or who withdraw from the study at the last visit.

[0205] Plasma samples can be screened for antibodies that bind to the Tn3 scaffolds of the present disclosure, and titers of confirmed positive samples can be reported. Additional analyses can be performed to verify the stability of the antibodies to the Tn3 scaffolds of the present disclosure and / or further characterize the immunogenicity of the Tn3 scaffolds of the present disclosure.

[0206] Detection and characterization of antibodies against the Tn3 scaffolds of the present disclosure can be performed using validated assay methods. Antibodies can be further characterized and / or evaluated for their ability to neutralize the activity of one or more study interventions. Samples can be stored for up to at least 15 years after the last study visit of the last subject to enable further analysis of the immune response to the Tn3 scaffolds of the present disclosure. The number and percentage of subjects with an ADA and the titer of the ADA can be summarized by visit and treatment group.

[0207] In aspects, immunogenicity assessment can be performed at about -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, 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 treatment initiation). In aspects, immunogenicity assessment can be performed at about day 1, day 15 (-3 days 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 about day 393 (±7 days) (after treatment initiation). In aspects, immunogenicity or lack thereof is assessed at any time before, during, or after treatment with a Tn3 scaffold of the disclosure.

[0208] Ultrasound imaging

[0209] In aspects, assessment can include ultrasound imaging. In aspects, ultrasound imaging can be imaging of one or more joints. In aspects, ultrasound imaging can be imaging of one or more salivary glands.

[0210] Salivary gland ultrasound imaging

[0211] Ultrasound measurements can be performed on parotid and submandibular glands. Subjects with significant glandular disease can be selected for participation. The above glands can be assessed in longitudinal and transverse planes with the subject in supine position. After image capture and quality assessment, images will be scored and data summed. The echotexture of each gland on B-mode images can be scored on a 5-point scale (0 to 4) as previously described (Gazeau et al., 2018). Grading criteria are as follows: Grade 0: normal homogenous gland; Grade 1: small hypoechoic area with hyperechoic band; Grade 2: multiple <2 mm hypoechoic areas; Grade 3: multiple 2 to 6 mm hypoechoic areas; Grade 4: multiple >6 mm hypoechoic areas.

[0212] At each time point of assessment, 4 scores can be collected, one for each parotid gland, and one for each submandibular gland. The salivary gland ultrasound score for each assessment will be the sum of these grades.

[0213] Joint ultrasound imaging

[0214] Small peripheral joints can be evaluated by ultrasound. Subjects with possible joint involvement can be selected. A modified German 7 joint US scoring system (Backhaus et al., 2009) can be used. After image capture and quality assessment, images are transmitted for scoring and data summation.

[0215] Grey-scale (GS) ultrasound can be performed on the following clinically important hand and foot joints: wrist joint (dorsal, volar and ulnar planes), second and third MCP (MCP2 and MCP3, volar plane) and PIP (PIP2 and PIP3, volar plane) joints, and second and fifth metatarsophalangeal (MTP2 and MTP5, dorsal plane) joints. In GS, each joint and each plane can be semi-quantitatively scored on a 0 to 3 scale for synovitis as follows: Grade 0 = no synovitis; Grade 1 = mild synovitis (small hypoechoic / anechoic line below joint capsule); Grade 2 = moderate synovitis (joint capsule parallel to joint elevation), and; Grade 3 = severe synovitis (joint capsule maximally distended). The total synovitis GS score will be the sum of each joint or plane, scored 0-27. In aspects, the total synovitis GS score is about 0 to about 27 or about 1 to about 27. In aspects, the total synovitis GS score will be about 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 about 27.

[0216] Energy Doppler ultrasound will be performed on the following clinically important hand and foot joints: wrist joint (dorsal, volar, and ulnar planes), second and third MCP (MCP2 and MCP3, volar and dorsal planes) and PIP (PIP2 and PIP3, volar and dorsal planes) joints, and second and fifth metatarsophalangeal (MTP2 and MTP5, dorsal plane only) joints. The synovitis using energy Doppler will be scored on a scale of 0 to 3 as follows: Grade 0 = no IA color signal; Grade 1 = mild synovitis (up to 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 is less than 50% of the IA space), and; Grade 3 = severe synovitis (color is greater than 50% of the IA space). The synovitis GS total score will be the sum of each joint or plane, scored 0-39. In aspects, the GS total score is about 0 to about 39 or about 1 to about 39. In aspects, the GS total score is about 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, up to about 39.

[0217] The synovitis total score will be the sum of the GS and energy Doppler scores, ranging from 0-66. In aspects, the synovitis total score is about 0 to about 66 or about 1 to about 66. In aspects, the synovitis total score is about 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, up to about 66.

[0218] In aspects, the synovitis score of the present disclosure can include an assessment of a subject in need of a Tn3 scaffold as compared to baseline. In aspects, the synovitis score of the present disclosure is reduced as compared to a method otherwise comparable, wherein the subject of the method otherwise comparable is not administered a Tn3 scaffold.

[0219] In aspects, the composition of the disclosure is effective to reduce synovitis score. In aspects, 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 aspects, 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 aspects, the synovitis score is reduced by about 1-5, 2-10, 5-10, 5-20, 10-20, 20-30, 30-40, 40-50, 50-60, or 55-66 points.

[0220] In aspects, the ultrasound imaging assessment can be performed about -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, 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 treatment initiation). In aspects, the ultrasound imaging assessment can be performed about day 1, day 197 (±7 days), or about day 337 (±7 days) (after treatment initiation). In aspects, imaging is completed at any time before, during, or after treatment with the Tn3 stent of the disclosure.

[0221] Transcriptomics

[0222] In aspects, the assessment can include evaluating transcriptomics. In aspects, RNA testing is performed. In aspects, RNA testing is performed to measure expression levels of genes associated with disease activity, specific cell types (e.g., plasma cell gene signature), T follicular helper gene signature, and signaling (e.g., CD40L / CD40 pathway).

[0223] In aspects, blood RNA measurements are used to measure the expression levels of genes associated with disease activity, specific cell types (e.g., plasma cell gene signature), T follicular helper gene signature, and signaling, including the CD40L / CD40 pathway. In aspects, blood samples will be collected using the PAXgene Blood RNA system in order to collect, transport, and store blood in a closed tube and stabilize intracellular RNA, and subsequently isolate and purify intracellular RNA from whole blood for microarray analysis and quantitative polymerase chain reaction.

[0224] In aspects, the expression levels of genes associated with disease activity by RNA analysis can be reduced by at least about 10%, 15%, 20%, 25%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or up to 100% compared to a method that is otherwise comparable except that the subject is not administered a Tn3 scaffold.

[0225] In aspects, the transcriptomic evaluation can be assessed at about -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, 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 treatment initiation). In aspects, the transcriptomic evaluation can be assessed at about day 1, day 15 (-3 days to +1 day), day 29 (±4 days), day 85 (±7 days), day 169 (±7 days), or about day 337 (±7 days) (after treatment initiation). In aspects, the transcriptomics is performed at any time before, during, or after treatment with a Tn3 scaffold of the disclosure.

[0226] Genetic analysis

[0227] In all respects, the assessments provided herein may include evaluating genetics through DNA or RNA testing. DNA testing is performed in all respects. RNA testing is performed in all respects. DNA testing may be performed in all respects to measure pharmacogenomics (single nucleotide polymorphism [SNP]) profiles of CD40 and other genes involved in the CD40 / CD40L axis. DNA is collected in all respects for epigenetic analysis of immune-related genes, such as DNA methylation. The assessment includes determining the sequences of genes associated with disease activity through whole blood DNA analysis.

[0228] In all respects, whole blood can be collected and used to evaluate gene sequences before, during, and after treatment with any of the compositions provided herein. Quantitative methods can be used to analyze whole blood to identify treatment-regulated gene sequences. Samples can be used to examine gene sequences and their changes over time, as assessed by NGS, Sanger sequencing, or PCR.

[0229] In all aspects, genetic analysis and evaluation can be performed at 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. Evaluations should be performed at weeks 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, or at least approximately 56 weeks (after treatment initiation). In all respects, genetic evaluations should be performed at any time before, during, or after treatment with the Tn3 stent disclosed herein.

[0230] Pharmacokinetics

[0231] In aspects, the methods provided herein can include determining the concentration of the Tn3 scaffold in a subject in need thereof after administration. In aspects, the methods include pharmacokinetic assessments. In aspects, the sample is a blood sample, or a plasma sample, or a combination of both. In aspects, suitable assays to measure pharmacokinetics can include electrochemiluminescence (ECL) assays, bead-based assays, cell-based assays, and combinations thereof. In aspects, the sample can comprise plasma, and the Tn3 scaffold concentration in the plasma is assessed by measuring the following: maximum observed concentration (C max ), area under the concentration-time curve (AUC), clearance (CL), and terminal elimination half-life (t 1 / 2 ).

[0232] Samples will be used to evaluate the PK of the Tn3 scaffolds of the disclosure. The samples collected for analysis of Tn3 scaffold plasma concentrations of the disclosure can also be used to evaluate safety or efficacy during or after the study.

[0233] In aspects, the pharmacokinetic assessments can be performed at about -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, 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 treatment initiation). In aspects, the immunogenicity assessments can be performed at about day 1, day 85 (±7 days), day 169 (±7 days), day 253 (±7 days), day 337 (±7 days), or about day 393 (±7 days) (after treatment initiation). In aspects, the pharmacokinetics are assessed at any time before, during, or after treatment with the Tn3 scaffolds of the disclosure.

[0234] Pharmacodynamics

[0235] In aspects, the assessment can include evaluation of pharmacodynamics (PD). In aspects, the assessment can be performed over a period of time. Whole blood, plasma, urine, saliva, and serum samples can be collected to evaluate the PD of the Tn3 scaffolds of the present disclosure. In aspects, the samples can be assessed by validated assays, including but not limited to flow cytometry.

[0236] Samples can be collected to assess the level of biomarkers, including but not limited to immunoglobulins (IgM, IgG, and IgA), sCD40L, CXCL13, beta-2 microglobulin, high-sensitivity CRP, serum C3, C4, free light chains, peripheral blood mononuclear cells (PBMCs), anti-SSA, anti-SSB, cryoglobulins, and serum and urine immunofixation. In aspects, the immunoglobulin is a plasma immunoglobulin. In aspects, the biomarker is a cellular biomarker, such as a cellular biomarker expressed by a subset of B cells or T cells. Exemplary subsets of B cells and T cells include, but are not limited to, proliferation of plasmablasts (e.g., a CD27br / CD38br / IgD subset of CD19+ cells), precursor memory B cells (e.g., a CDllcbrsubset of CD19+ cells), T follicular helper (Tfh) cells (e.g., a CXCR5+ / ICOS+ subset of CD3+ / CD4+ cells), proliferation of post- transition memory B cells (e.g., a Ki67+ subset of CD27br / IgD- / CD19+ cells), and / or proliferation of total T cells (e.g., a Ki67+ subset of CD3+ cells). In aspects, the assessment includes determining the level of one or more of CD19, CD20, CD27, CD38, and CD138.

[0237] In aspects, the level of a biomarker in a subject in need is increased following administration of a Tn3 scaffold of the disclosure. In aspects, the level of a biomarker in a subject in need is decreased following administration of a Tn3 scaffold of the disclosure. In aspects, a decrease in a biomarker can be detected compared to an otherwise comparable method, wherein the subject of the otherwise comparable method is not administered a Tn3 scaffold. In aspects, an elimination of a biomarker can be detected compared to an otherwise comparable method, wherein the subject of the otherwise comparable method is not administered a Tn3 scaffold compared to the otherwise comparable method lacking administration of a Tn3 scaffold. In aspects, a decrease in a biomarker comprises at least about or at most about 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 55-fold, 60-fold, 65-fold, 70-fold, 75-fold, 80-fold, 85-fold, 90-fold, 95-fold, 100-fold, 105-fold, 110-fold, 115-fold, 120-fold, 125-fold, 130-fold, 135-fold, 140-fold, 145-fold, 150-fold, 155-fold, 160-fold, 165-fold, 170-fold, 175-fold, 180-fold, 185-fold, 19-fold, 195-fold, 200-fold, 210-fold, 220-fold, 230-fold, 240-fold, 250-fold, 260-fold, 270-fold, 280-fold, 290-fold, or up to about 300-fold decrease compared to the otherwise comparable method lacking administration. In aspects, the therapeutic efficacy of a Tn3 scaffold on a biomarker can be assessed over time using a suitable immunoassay. In aspects, the effect of a Tn3 scaffold is assessed over time using a qualified immunoassay.

[0238] The disclosure provides Tn3 scaffold-containing compositions that alter the CD40 / CD40L pathway in a subject. The disclosure provides Tn3 scaffold-containing compositions effective to reduce or deplete soluble CD40L (sCD40L) in a subject. Because the Tn3 scaffold binds to and depletes a biomarker, a decrease or elimination of the biomarker can be used as a measure of therapeutic efficacy. In aspects, sCD40L is a measure of target engagement. In aspects, a suitable assay to assess sCD40L levels can include flow cytometry, histology, immunohistochemistry, blood analysis, microscopic examination, PCR, ELISA, and combinations thereof.

[0239] The present disclosure provides Tn3 scaffold-containing compositions effective to reduce, eliminate, or inhibit a primary leukocyte population (e.g., B lymphocytes), anti-SSA (Ro), anti-SSB (La), anti-nuclear antibodies, rheumatoid factor (RF), and combinations thereof. Suitable assays to evaluate a primary leukocyte population, anti-SSA (Ro), anti-SSB (La), anti-nuclear antibodies, and rheumatoid factor (RF) can include flow cytometry, histology, immunohistochemistry, blood analysis, microscopic examination, PCR, ELISA, and combinations thereof.

[0240] In aspects, the Tn3 scaffolds of the present disclosure can achieve at least about 10%, 15%, 20%, 25%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or up to about 100% reduction in CD40L compared to a method that is otherwise comparable except that the subject of the otherwise comparable method is not administered the Tn3 scaffold. The reduction in the primary leukocyte population can persist for an extended period of time. In aspects, the depletion of CD40L primary leukocyte population, anti-SSA (Ro), anti-SSB (La), anti-nuclear antibodies, and rheumatoid factor (RF), or combinations thereof, can persist 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 aspects, the depletion of CD40L primary leukocyte population, anti-SSA (Ro), anti-SSB (La), anti-nuclear antibodies, and rheumatoid factor (RF), or combinations thereof, can persist for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, or at least 10 weeks. In aspects, the depletion of CD40L primary leukocyte population, anti-SSA (Ro), anti-SSB (La), anti-nuclear antibodies, and rheumatoid factor (RF), or combinations thereof, can persist for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, or at least 12 months.

[0241] In aspects, pharmacodynamic assessments can be assessed at about -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, 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 treatment initiation) have been initiated. In aspects, pharmacodynamic assessments can be assessed at about 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, day 0, day 1, day 15 (day -3 to 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 about day 337 (±7 days) (after treatment initiation). In aspects, pharmacodynamics are assessed at any time before, during, or after treatment with a Tn3 scaffold of the disclosure.

[0242] Inflammatory markers

[0243] In aspects, the assessment includes determining the level of an inflammatory marker. Exemplary inflammatory markers include, but are not limited to: immunoglobulins (IgM, IgG, IgA), beta-2 microglobulin, C-reactive protein (CRP), CXCL13, serum C3, C4, and free light chains, cryoglobulins, and serum and urine immunofixation, and combinations thereof. In aspects, whole blood, plasma, serum, and urine are collected to assess the inflammatory markers. In aspects, changes from baseline are determined. In aspects, changes in the level of inflammatory markers (immunoglobulins, beta-2 microglobulin, CRP, CXCL13, serum C3, C4, and free light chains) relative to baseline are determined. In aspects, suitable assays to assess the level of inflammation include: ELISA, high sensitivity (hs)-CRP test, CRP test, Luminex, and combinations thereof. In aspects, administration of the Tn3 scaffold of the disclosure is effective to reduce the level of an inflammatory biomarker in a subject by at least about or at most about 20%, 30%, 40%, 45%, 50%, 60%, 75%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or up to 100% as compared to the level of the self-antibody in a method otherwise comparable, wherein the subject in the method otherwise comparable is not administered the Tn3 scaffold. In aspects, administration of the Tn3 scaffold of the disclosure is effective to reduce the level of an inflammatory biomarker in a subject by at least about or at most about 3-5%, 5-10%, 10-20%, or 5-25% as compared to the baseline level prior to administration.

[0244] In aspects, inflammatory marker assessment can be performed at about -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, 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 treatment initiation). In aspects, inflammatory marker assessment can be performed at about day 1, day 15 (-3 days 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), or about day 337 (±7 days) (after treatment initiation). In aspects, markers are assessed at any time before, during, or after treatment with a Tn3 scaffold of the disclosure.

[0245] American College of Rheumatology / European League Against Rheumatism (ACR / EULAR)

[0246] In aspects, the assessment comprises the ACR / EULAR classification. In aspects, the assessment comprises the 2016 ACR / EULAR classification. In aspects, the assessment comprises the 2016 ACR / EULAR classification for primary Sjogren’s syndrome. In aspects, the classification comprises a score based on the following: labial gland with focal lymphocytic sialadenitis and focus score, anti-SSA (Ro) positive, ocular staining score and / or van Bijsterveld score, Schirmer score, and measurement of unstimulated whole salivary flow rate. In aspects, the labial gland with focal lymphocytic sialadenitis and focus score is >1. In aspects, the ocular staining score of at least one eye is >5. In aspects, the van Bijsterveld score is >4. In aspects, the Schirmer score of at least one eye is <5 mm / 5 min. In aspects, the unstimulated whole salivary flow rate is <0.1 mL / min. In aspects, one or more of the scores for the ACR / EULAR classification is weighted. In aspects, the labial gland with focal lymphocytic sialadenitis and focus score is weighted 3. In aspects, the ocular staining score is weighted 3. In aspects, the van Bijsterveld score is weighted 1. In aspects, the Schirmer score is weighted 1. In aspects, the unstimulated whole salivary flow rate is weighted 1. In aspects, the combined weighted score of the subject in need is >4. In aspects, the subject in need can be asked at least one of the following questions: 1) Do you have persistent, troubling dryness in both eyes every day that has lasted more than 3 months?; 2) Do you repeatedly feel like there is sand or gravel in your eyes?; 3) Do you use tear substitutes more than 3 times a day every day?; 4) Do you have a dry mouth every day that has lasted more than 3 months?; 5) Do you frequently drink water to help swallow dry food?

[0247] In aspects, the ACR / EULAR assessment can be performed at about -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, 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 treatment initiation). In aspects, the ACR / EULAR assessment can be performed at about -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, or about 0 days (after treatment initiation). In aspects, the ACR / EULAR is assessed at any time before, during, or after treatment with a Tn3 scaffold of the disclosure.

[0248] Ocular Surface Disease Index (OSDI)

[0249] In aspects, the assessment includes an OSDI evaluation. In aspects, the OSDI evaluation includes an OSDI questionnaire. The OSDI effectively differentiates between normal, mild to moderate, and severe dry eye disease. In aspects, the OSDI evaluation assesses three subsets: vision-related function, ocular symptoms, or environmental triggers, or a combination thereof.

[0250] In aspects, the OSDI evaluation results in a score. In aspects, the OSDI score ranges from about 0 to about 100: 0-12 is normal; 13-22 is mild dry eye disease; 23-32 is moderate dry eye disease; and 33-100 is severe dry eye disease. In aspects, the OSDI score ranges from about 0 to about 12, about 13 to about 22, about 23 to about 32, about 33 to about 100, about 20 to about 50, about 60 to about 100, about 40 to about 70, about 10 to about 30, or 5 to about 25.

[0251] In aspects, the OSDI score of a subject in need is reduced following administration of a Tn3 scaffold of the disclosure. In aspects, the OSDI score can be reduced as compared to an otherwise comparable method, wherein the subject of the otherwise comparable method did not administer a Tn3 scaffold as compared to the otherwise comparable method that lacked administration of a Tn3 scaffold. In aspects, the OSDI score is reduced by at least about or at most 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, 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 as compared to the otherwise comparable method that lacked administration.

[0252] In all aspects, OSDI evaluations can be conducted over 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, and 10 weeks. Evaluation should be performed at weeks 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, or at least approximately 56 weeks (after treatment initiation). OSDI should be evaluated at any time before, during, or after treatment with the Tn3 stent disclosed herein.

[0253] Sjögren's Syndrome Response Assessment Tool (STAR)

[0254] In various aspects, assessments may include the Sjögren's Syndrome Response Assessment Tool (STAR). STAR is a comprehensive response index developed by the NECESSITY Consortium, supported by an international panel of pSS experts, scientists, methodologists, and patients, assessing treatment efficacy based on improvements in disease activity (Seror et al., 2022). STAR comprises five domains: systemic activity, symptoms, lacrimal gland function, salivary gland function, and biomarkers of autoimmune activity. Each domain is assigned different weights. In various aspects, the STAR domains include another assessment disclosed herein.

[0255] In aspects, the STAR questionnaire score is about 1 to about 9. In aspects, the STAR questionnaire score is about 1, 2, 3, 4, 5, 6, 7, 8, or about 9. In aspects, the STAR questionnaire score is about 1 to about 3, about 1 to about 5, about 5 to about 9, about 6 to about 9, about 7 to about 9, or about 4 to about 9. In aspects, the STAR questionnaire score is about > 5. In aspects, the STAR questionnaire can include an assessment of a subject in need of administration of a Tn3 scaffold of the disclosure compared to baseline. In aspects, the subject’s STAR score is increased compared to a method otherwise comparable, wherein the subject of the method otherwise comparable is not administered a Tn3 scaffold of the disclosure. In aspects, the STAR score of a subject in need of administration of a Tn3 scaffold of the disclosure is increased compared to baseline. In aspects, the STAR score is increased by about 1, 2, 3, 4, 5, 6, 7, or 8 points.

[0256] In aspects, the STAR questionnaire can be assessed about -35 days, -34 days, -33 days, -32 days, -31 days, -30 days, -29 days, -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, 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 treatment initiation). In aspects, the STAR questionnaire can be assessed about 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 ± 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 treatment initiation). In aspects, the STAR questionnaire is assessed at any time before, during, or after treatment with a Tn3 scaffold of the disclosure.

[0257] Dry Syndrome Patient Reported Index Assessment Diary (DASPRI)

[0258] In aspects, the assessment can include a dryness syndrome patient reported index assessment diary (DASPRI). In aspects, the DASPRI is also referred to as a SS symptom diary (SSSD). The DASPRI is a questionnaire completed by the participant that measures the severity of core symptoms in patients with SS. Its recall period can be about 24 hours. Subjects rate the severity of each symptom “at its worst” in domains including dryness, fatigue (e.g., feeling tired), and pain (joint or muscle pain in the arms and / or legs) using a numerical rating scale (ranging from 0 [no symptoms] to 10 [the maximum severity imaginable]). The dryness domain assesses the severity of dryness specific to the site (mouth, eyes, skin, and genitalia). In addition, subjects will be asked to rank their most bothersome dryness site. In aspects, the DASPRI-based endpoint is defined as the average daily score over a 7-day period.

[0259] In aspects, the DASPRI domain score is about 0 to about 10. In aspects, the DASPRI question score is about 0 to about 2, about 1 to about 5, about 2 to about 7, about 0 to about 9, about 1 to about 10, about 8 to about 10, or about 6 to about 10. In aspects, the DASPRI composite score is about 0 to about 100. In aspects, the DASPRI composite score is about 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 about 100. In aspects, the DASPRI composite score is about 0 to about 10, about 5 to about 15, about 20 to about 20, about 15 to about 25, about 20 to about 30, about 20 to about 50, about 30 to about 60, about 40 to about 70, about 50 to about 80, about 60 to about 90, or about 70 to about 100.

[0260] In aspects, the DASPRI can include an assessment of a subject in need thereof administered a Tn3 scaffold of the disclosure compared to baseline. In aspects, the subject has a reduced DASPRI score compared to a method otherwise comparable, wherein the subject of the method otherwise comparable is not administered a Tn3 scaffold of the disclosure. In aspects, the DASPRI of a subject in need thereof administered a Tn3 scaffold of the disclosure is reduced compared to baseline. In aspects, the DASPRI score is reduced by about 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.

[0261] In aspects, the DASPRI investigation can be assessed about -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, 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 treatment initiation). In aspects, the DASPRI investigation can be assessed about -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 (after treatment initiation) and about once a week, twice a week, three times a week, four times a week, five times a week, six times a week, or seven times a week. In aspects, the DASPRI investigation is assessed at any time before, during, or after treatment with a Tn3 scaffold of the disclosure.

[0262] Pharmaceutical compositions

[0263] In aspects, pharmaceutical compositions are provided. The pharmaceutical compositions can comprise a Tn3 scaffold of the disclosure. In aspects, the pharmaceutical compositions are part of a therapeutic regimen comprising a Tn3 scaffold of the disclosure and one or more additional therapeutic agents provided herein.

[0264] For the subcutaneous route, the needle is inserted into the fatty tissue just beneath the skin. After the drug is injected, it then moves into small blood vessels (capillaries) and is carried away by the bloodstream. Alternatively, the drug reaches the bloodstream through lymphatic vessels. The intramuscular route is preferred over the subcutaneous route when a larger volume of drug product is needed. Because the muscle is located beneath the skin and fatty tissue, a longer needle is used. The drug is usually injected into the muscle of the upper arm, thigh, or buttocks. How quickly the drug is absorbed into the bloodstream depends in part on the blood supply to the muscle: the sparser the blood supply, the longer it takes for the drug to be absorbed. For the intravenous route, the needle is inserted directly into a vein. The solution containing the drug can be given in a single dose or by continuous infusion. For an infusion, the solution is moved by gravity (from a collapsible plastic bag) or, more commonly, by an infusion pump through a flexible thin tube to a tube (catheter) inserted into a vein, usually in the forearm.

[0265] In aspects, the pharmaceutical compositions provided herein are administered via infusion. Infusion can be performed over a period of time. For example, an infusion can be the administration of a medication over a period of time ranging from about 5 minutes to about 10 hours. An infusion can be performed over a period of time ranging from about 5 min, 10 min, 20 min, 30 min, 40 min, 50 min, 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 aspects, intravenous administration is used to deliver precise doses throughout the body quickly and in a well-controlled manner. It is also used for irritating solutions that, if injected subcutaneously or intramuscularly, would cause pain and damage tissue. When given intravenously, the drug is delivered directly to the bloodstream and tends to take effect more quickly than when given by any other route. Therefore, healthcare practitioners closely monitor people who receive intravenous injections for signs that the drug is working or is causing adverse side effects. In addition, the effects of drugs given by this route tend to last for a short time. Therefore, some drugs must be given by continuous infusion to keep their effects constant. In aspects, infusion reactions can occur and include headache, nausea, drowsiness, difficulty breathing, fever, muscle pain, skin rash, or other symptoms. Potential risks associated with administration of the Tn3 scaffold are infection, redness, swelling, pain, and induration at the site of administration. Prior to each IV infusion, the subject can receive prophylaxis of IV methylprednisolone, oral diphenhydramine, and oral acetaminophen or equivalent to reduce the risk or severity of potential reactions.

[0266] In aspects, the therapeutic regimen including the pharmaceutical composition can be dosed according to the body weight of the subject. In subjects determined to be obese (BMI > 35), it can be desirable to utilize actual body weight. In aspects, the dose can be calculated using body surface area.

[0267] In aspects, the pharmaceutical composition can be administered alone or with a pharmaceutically acceptable carrier or excipient by any route, and such administration can be in the form of single or multiple doses. More particularly, the pharmaceutical composition can be combined with various pharmaceutically acceptable inert carriers such as tableting agents, gelatin capsules, pastilles, troches, hard candies, powders, sprays, aqueous suspensions, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various nontoxic organic solvents, among others. Moreover, the pharmaceutical formulations can be suitably flavored and / or sweetened by various agents of the type commonly employed for such purposes. Exemplary carriers and excipients can include dextrose, sodium phosphate monobasic, sodium phosphate dibasic, sodium phosphate monobasic / sodium phosphate dibasic, 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 aspects, the pharmaceutical composition used in the methods of the present application comprises sodium phosphate monobasic / sodium phosphate dibasic, sucrose, and poloxamer 188 (pH 7.4).

[0268] Numbered Examples

[0269] Example Set 1

[0270] 1. A method of treating Sjogren’s Syndrome (SS) in a subject in need thereof, the method comprising: administering a Tn3 scaffold, wherein the Tn3 scaffold comprises a CD40L-specific monomer subunit, wherein the CD40L-specific monomer subunit comprises seven beta strands designated A, B, C, D, E, F, and G and six loop regions designated AB, BC, CD, DE, EF, and FG, wherein the AB loop comprises SEQ ID NO: 11, the BC loop comprises SEQ ID NO: 12, the CD loop comprises SEQ ID NO: 13, the DE loop comprises SEQ ID NO: 14, the EF loop comprises SEQ ID NO: 15, and the FG loop comprises SEQ ID NO: 16, wherein the Tn3 scaffold comprising the CD40L-specific monomer subunit is administered at a dose of about 1500 mg to about 3000 mg, and wherein the subject has moderate to severe systemic disease activity as determined by the European League Against Rheumatism (EULAR) Sjogren’s Syndrome Disease Activity Index (ESSDAI).

[0271] 2. The method of embodiment 1, wherein the subject has an ESSDAI score of 5-7, 5-10, 5-13, or 10-13 prior to administration of the Tn3 scaffold.

[0272] 3. The method of embodiment 2, wherein the subject has an ESSDAI score > 5.

[0273] 4. The method of any one of embodiments 1-3, wherein administration of the Tn3 scaffold is effective to reduce the EULAR Sjogren’s Syndrome Patient Reported Index (ESSPRI) score after administration.

[0274] 5. The method of embodiment 4, wherein the ESSPRI score is reduced by at least 2, 3, 4, or 5 points.

[0275] 6. A method of treating Sjogren’s Syndrome (SS) in a subject in need thereof, the method comprising: administering a Tn3 scaffold, wherein the Tn3 scaffold comprises a CD40L-specific monomer subunit, wherein the CD40L-specific monomer subunit comprises seven beta strands designated A, B, C, D, E, F, and G and six loop regions designated AB, BC, CD, DE, EF, and FG, wherein the AB loop comprises SEQ ID NO: 11, the BC loop comprises SEQ ID NO: 12, the CD loop comprises SEQ ID NO: 13, the DE loop comprises SEQ ID NO: 14, the EF loop comprises SEQ ID NO: 15, and the FG loop comprises SEQ ID NO: 16, wherein the Tn3 scaffold comprising the CD40L-specific monomer subunit is administered at a dose of about 1500 mg to about 3000 mg, and wherein the subject has an ESSPRI score > 5.

[0276] 7. The method of embodiment 6, wherein the subject has an ESSDAI score < 5 prior to administration of the Tn3 scaffold.

[0277] 8. The method of any one of embodiments 6-7, wherein the subject has residual salivary gland function as defined by intact stimulated salivary flow greater than 0.1 mL / min.

[0278] 9. The method of any one of embodiments 1-8, wherein the subject is positive for anti-Ro autoantibodies, rheumatoid factor, or both anti-Ro autoantibodies and rheumatoid factor.

[0279] 10. The method of any one of embodiments 1-9, wherein the dose is 1500 mg.

[0280] 11. The method of any one of embodiments 1-9, wherein the dose is 3000 mg.

[0281] 12. The method of any one of embodiments 2-11, wherein the change from baseline in ESSDAI is determined after administration of the Tn3 scaffold.

[0282] 13. The method of embodiment 12, wherein the change from baseline is determined every four weeks after administration of the Tn3 scaffold until week 48.

[0283] 14. The method of any one of embodiments 2-13, wherein administration of the Tn3 scaffold is effective to reduce the ESSDAI score of the subject after administration.

[0284] 15. The method of embodiment 14, wherein the ESSDAI score is reduced by at least 1, 2, 3, 4, or 5 points.

[0285] 16. The method of embodiment 14, wherein the ESSDAI score is reduced by at least 5 points.

[0286] 17. The method of any one of embodiments 1-16, wherein administration of the Tn3 scaffold is effective to reduce the tender and swollen joint count baseline score of the subject after administration.

[0287] 18. The method of any one of embodiments 1-16, wherein administration of the Tn3 scaffold is effective to reduce the Short Form 36 (SF-36) Health Survey baseline score of the subject after administration.

[0288] 19. The method of any one of embodiments 1-18, wherein administration of the Tn3 scaffold is effective to reduce the baseline level of an inflammatory marker after administration, and wherein the marker is selected from the group consisting of immunoglobulin, beta-2 microglobulin, C-reactive protein, and combinations thereof.

[0289] 20. The method of any one of embodiments 1-19, wherein administration of the Tn3 scaffold is effective to reduce the baseline level of a biomarker, and wherein the biomarker is selected from the group consisting of plasma soluble CD40L, B cells, serum CXCL13, rheumatoid factor autoantibody, anti-Ro autoantibody, and combinations thereof.

[0290] 21. The method of any one of embodiments 1-20, wherein administration of the Tn3 scaffold is effective to reduce the baseline level of a disease symptom, and wherein the disease symptom is selected from the group consisting of fatigue, dry mouth, dry eyes, dry vagina, pain, and combinations thereof.

[0291] 22. The method of any one of embodiments 1-21, wherein the expression level of a gene associated with SS is reduced in a blood sample of the subject by week 48 after administration.

[0292] 23. The method of any one of embodiments 1-22, 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, in the subject’s blood sample is reduced by week 48 after administration.

[0293] 24. The method of any one of embodiments 1-23, wherein the Tn3 scaffold is administered as a loading dose and thereafter as a maintenance dose.

[0294] 25. The method of embodiment 24, wherein the loading dose comprises administration of the Tn3 scaffold about once every 2 weeks for at least 3 doses.

[0295] 26. The method of embodiment 24, wherein the maintenance dose comprises administration of the Tn3 scaffold about once every 4 weeks for at least 4 doses.

[0296] 27. The method of embodiment 24, wherein the time between the last loading dose and the first maintenance dose is about 4 weeks.

[0297] 28. The method of any one of embodiments 1-27, wherein the Tn3 scaffold is administered about once every 4 weeks, about once every 2 months, about once every 3 months, about once every 4 months, or about once every 6 months.

[0298] 29. The method of any one of embodiments 1-28, wherein the Tn3 scaffold is administered for at least 4 doses.

[0299] 30. The method of any one of embodiments 1-28, wherein the Tn3 scaffold is administered for at least 5 doses.

[0300] 31. The method of any one of embodiments 1-30, wherein the Tn3 scaffold is administered intravenously, subcutaneously, orally, intramuscularly, intrathecally, sublingually, rectally, vaginally, transdermally, systemically, topically, transdermally, or by inhalation.

[0301] 32. The method of embodiment 31, wherein the Tn3 scaffold is administered intravenously.

[0302] 33. The method of any one of embodiments 1-32, wherein the Tn3 scaffold comprises two CD40L-specific monomeric subunits linked in tandem.

[0303] 34. The method of embodiment 33, wherein the two CD40L-specific monomeric subunits each comprise SEQ ID NO: 3.

[0304] 35. The method of any of embodiments 33-34, wherein the CD40L-specific monomer subunits are linked by a linker.

[0305] 36. The method of any of embodiments 33-35, wherein at least one CD40L-specific monomer subunit is directly fused or conjugated to polyethylene glycol (PEG).

[0306] 37. The method of any of embodiments 33-35, wherein at least one CD40L-specific monomer subunit is fused or conjugated to polyethylene glycol (PEG) via a linker.

[0307] 38. The method of embodiment 37, wherein the linker comprises a peptide linker.

[0308] 39. The method of embodiment 37, wherein the linker comprises SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, or SEQ ID NO: 10.

[0309] 40. The method of any of embodiments 33-39, wherein at least one CD40L-specific monomer subunit is fused or conjugated to albumin.

[0310] 41. The method of embodiment 40, wherein the albumin is human serum albumin (HSA).

[0311] 42. The method of embodiment 41, wherein the HSA is a variant HSA comprising SEQ ID NO: 4.

[0312] 43. The method of any of embodiments 24-42, wherein the loading dose and the maintenance dose are the same.

[0313] 44. The method of any of embodiments 24-42, wherein the loading dose and the maintenance dose are different.

[0314] 45. The method of any of embodiments 1-44, wherein the Tn3 scaffold comprises SEQ ID NO: 1.

[0315] 46. The method of any of embodiments 10-45, wherein 1500 mg of the Tn3 scaffold is administered intravenously at week 0, week 2, and week 4, and then every 4 weeks thereafter.

[0316] 47. The method of any of embodiments 11-45, wherein 3000 mg of the Tn3 scaffold is administered intravenously at week 0, week 4, and week 12, and then every 12 weeks thereafter.

[0317] 48. A method of treating Sjogren’s Syndrome (SS) in a subject in need thereof, the method comprising: administering to the subject a Tn3 scaffold comprising SEQ ID NO: 1, wherein the Tn3 scaffold is administered at a dose of about 1500 mg, wherein the subject has an ESSDAI score > 5 prior to the administration, and wherein the administration is effective to reduce the ESSDAI score compared to an otherwise comparable subject dosed with placebo.

[0318] 49. The method of embodiment 48, wherein the 1500 mg is administered intravenously at week 0, week 2, and week 4, and then every 4 weeks thereafter.

[0319] 50. A method of treating Sjogren’s Syndrome (SS) in a subject in need thereof, the method comprising: administering to the subject a Tn3 scaffold comprising SEQ ID NO: 1, wherein the Tn3 scaffold is administered at a dose of about 3000 mg, wherein the subject has an ESSDAI score > 5 prior to the administration, and wherein the administration is effective to reduce the ESSDAI score compared to an otherwise comparable subject dosed with placebo.

[0320] 51. The method of embodiment 50, wherein the 3000 mg of the Tn3 scaffold is administered intravenously at week 0, week 4, and week 12, and then every 12 weeks thereafter.

[0321] 52. The method of any one of embodiments 48-51, wherein the ESSDAI score is reduced by 2 points, 3 points, 4 points, or 5 points.

[0322] 53. The method of any one of embodiments 48-52, wherein the subject has an ESSDAI score of 5-7, 5-10, 5-13, or 10-13.

[0323] 54. A method of treating Sjogren’s Syndrome (SS) in a subject in need thereof, the method comprising: administering to the subject a Tn3 scaffold comprising SEQ ID NO: 1, wherein the Tn3 scaffold is administered at a dose of about 1500 mg, wherein the subject has an European League Against Rheumatism (EULAR) Sjogren’s Disease Activity Index (ESSDAI) score < 5, and wherein the subject has an EULAR Sjogren’s Patient Reported Index (ESSPRI) score > 5 prior to the administration.

[0324] 55. The method of embodiment 54, wherein the 1500 mg is administered intravenously at week 0, week 2, and week 4, and then every 4 weeks thereafter.

[0325] 56. A method of treating Sjogren’s syndrome (SS) in a subject in need thereof, the method comprising: administering to the subject a Tn3 scaffold comprising SEQ ID NO: 1, wherein the Tn3 scaffold is administered at a dose of about 3000 mg, wherein the subject has a European League Against Rheumatism (EULAR) Sjogren’s Disease Activity Index (ESSDAI) score < 5, and wherein the subject has an EULAR Sjogren’s Syndrome Patient Reported Index (ESSPRI) score > 5 prior to the administration.

[0326] 57. The method of embodiment 56, wherein 3000 mg of the Tn3 scaffold is administered intravenously at week 0, week 4, and week 12, and then every 12 weeks thereafter.

[0327] 58. The method of any one of embodiments 54-57, wherein the subject has an ESSPRI score of 5-6, 5-7, 6-8, 6-9, or 5-10 prior to the administration.

[0328] EMBODIMENT SET 2

[0329] 1. A method of treating Sjogren’s syndrome (SS) in a subject in need thereof, the method comprising: administering a Tn3 scaffold, wherein the Tn3 scaffold comprises a CD40L-specific monomer subunit, wherein the CD40L-specific monomer subunit comprises seven beta strands designated A, B, C, D, E, F, and G and six loop regions designated AB, BC, CD, DE, EF, and FG, wherein the AB loop comprises SEQ ID NO: 11, the BC loop comprises SEQ ID NO: 12, the CD loop comprises SEQ ID NO: 13, the DE loop comprises SEQ ID NO: 14, the EF loop comprises SEQ ID NO: 15, and the FG loop comprises SEQ ID NO: 16, wherein the Tn3 scaffold comprising the CD40L-specific monomer subunit is administered at a dose of about 1500 mg to about 3000 mg, and wherein the subject has moderate to severe systemic disease activity as determined by the European League Against Rheumatism (EULAR) Sjogren’s Disease Activity Index (ESSDAI).

[0330] 2. The method of embodiment 1, wherein the subject has an ESSDAI score of 5-7, 5-10, 5-13, or 10-13 prior to the administration of the Tn3 scaffold.

[0331] 3. The method of embodiment 2, wherein the subject has an ESSDAI score > 5.

[0332] 4. The method of any one of embodiments 1-4, wherein administration of the Tn3 scaffold is effective to reduce the EULAR Sjogren’s Syndrome Patient Reported Index (ESSPRI) score following administration.

[0333] 5. The method of embodiment 4, wherein the ESSPRI score is reduced by at least 2, 3, 4, or 5 points.

[0334] 6. A method of treating Sjogren’s Syndrome (SS) in a subject in need thereof, the method comprising: administering a Tn3 scaffold, wherein the Tn3 scaffold comprises a CD40L specific monomer subunit, wherein the CD40L specific monomer subunit comprises seven beta strands designated A, B, C, D, E, F, and G and six loop regions designated AB, BC, CD, DE, EF, and FG, wherein the AB loop comprises SEQ ID NO: 11, the BC loop comprises SEQ ID NO: 12, the CD loop comprises SEQ ID NO: 13, the DE loop comprises SEQ ID NO: 14, the EF loop comprises SEQ ID NO: 15, and the FG loop comprises SEQ ID NO: 16, wherein the Tn3 scaffold comprising the CD40L specific monomer subunit is administered at a dose of about 1500 mg to about 3000 mg, and wherein the subject has an ESSPRI score of > 5.

[0335] 7. The method of embodiment 6, wherein the subject has an ESSDAI score of < 5 prior to administration of the Tn3 scaffold.

[0336] 8. The method of any one of embodiments 6-7, wherein the subject has residual salivary gland function as defined by intact stimulated salivary flow of greater than 0.1 mL / min.

[0337] 9. The method of any one of embodiments 1-8, wherein the subject is positive for anti-Ro autoantibodies, rheumatoid factor, or both anti-Ro autoantibodies and rheumatoid factor.

[0338] 10. The method of any one of embodiments 1-9, wherein the dose is 1500 mg.

[0339] 11. The method of any one of embodiments 1-9, wherein the dose is 3000 mg.

[0340] 12. The method of any one of embodiments 2-11, wherein the change from baseline in ESSDAI is determined following administration of the Tn3 scaffold.

[0341] 13. The method of embodiment 12, wherein the change from baseline is determined every four weeks following administration of the Tn3 scaffold until week 48.

[0342] 14. The method of any one of embodiments 2-13, wherein administration of the Tn3 scaffold is effective to reduce the subject’s ESSDAI score following administration.

[0343] 15. The method of embodiment 14, wherein the ESSDAI score is reduced by at least 1, 2, 3, 4, 5, 6, or 7 points.

[0344] 16. The method of embodiment 14, wherein the ESSDAI score is reduced by at least 6 points.

[0345] 17. The method of any one of embodiments 1-16, wherein administration of the Tn3 scaffold is effective to reduce the subject’s tender and swollen joint count baseline score following administration.

[0346] 18. The method of any one of embodiments 1-16, wherein administration of the Tn3 scaffold is effective to reduce the subject’s Short Form 36 (SF-36) Health Survey baseline score through week 48 following administration.

[0347] 19. The method of any one of embodiments 1-16, wherein administration of the Tn3 scaffold is effective to improve the subject’s baseline score, wherein the baseline score is selected from the group consisting of: Functional Assessment of Chronic Therapy Fatigue Scale (FACIT-Fatigue), PROMIS Fatigue Short Form 10a, Ocular Surface Disease Index (OSDI), EQ-5D-5L, and Patient Global Impression-Severity (PGIS).

[0348] 20. The method of any one of embodiments 1-18, wherein administration of the Tn3 scaffold is effective to reduce baseline levels of inflammatory markers following administration, and wherein the markers are selected from the group consisting of: immunoglobulin, beta-2 microglobulin, C-reactive protein, and combinations thereof.

[0349] 21. The method of any one of embodiments 1-19, wherein administration of the Tn3 scaffold is effective to reduce baseline levels of biomarkers, and wherein the biomarkers are selected from the group consisting of: plasma soluble CD40L, B cells, serum CXCL13, rheumatoid factor autoantibody, anti-SSA autoantibody (i.e., anti-Ro autoantibody), anti-SSB autoantibody (i.e., anti-La autoantibody), and combinations thereof.

[0350] 22. The method of any one of embodiments 1-20, wherein administration of the Tn3 scaffold is effective to reduce baseline levels of disease symptoms, and wherein the disease symptoms are selected from the group consisting of: fatigue, dry mouth, dry eyes, dry vagina, pain, and combinations thereof.

[0351] 23. The method of any one of embodiments 1-21, wherein the expression level of a gene associated with SS is reduced in a blood sample of the subject by week 48 after administration.

[0352] 24. The method of any one of embodiments 1-22, 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 is reduced in a blood sample of the subject by week 48 after administration.

[0353] 25. The method of any one of embodiments 1-23, wherein the Tn3 scaffold is administered in a loading dose and thereafter in a maintenance dose.

[0354] 26. The method of embodiment 24, wherein the loading dose comprises administration of the Tn3 scaffold once about every 2 weeks for at least 3 doses.

[0355] 27. The method of embodiment 24, wherein the maintenance dose comprises administration of the Tn3 scaffold once about every 4 weeks for at least 4 doses.

[0356] 28. The method of embodiment 24, wherein the time between the last loading dose and the first maintenance dose is about 4 weeks.

[0357] 29. The method of any one of embodiments 1-27, wherein the Tn3 scaffold is administered once about every 4 weeks, once about every 2 months, once about every 3 months, once about every 4 months, or once about every 6 months.

[0358] 30. The method of any one of embodiments 1-28, wherein the Tn3 scaffold is administered for at least 4 doses.

[0359] 31. The method of any one of embodiments 1-28, wherein the Tn3 scaffold is administered for at least 5 doses.

[0360] 32. The method of any one of embodiments 1-30, wherein the Tn3 scaffold is administered intravenously, subcutaneously, orally, intramuscularly, intrathecally, sublingually, rectally, vaginally, transdermally, systemically, topically, transdermally, or by inhalation.

[0361] 33. The method of embodiment 31, wherein the Tn3 scaffold is administered intravenously.

[0362] 34. The method of any one of embodiments 1-32, wherein the Tn3 scaffold comprises two CD40L-specific monomer subunits linked in tandem.

[0363] 35. The method of embodiment 33, wherein the two CD40L-specific monomer subunits each comprise SEQ ID NO: 3.

[0364] 36. The method of any one of embodiments 33-34, wherein the CD40L-specific monomer subunits are linked by a linker.

[0365] 37. The method of any one of embodiments 33-35, wherein at least one CD40L-specific monomer subunit is directly fused or conjugated to polyethylene glycol (PEG).

[0366] 38. The method of any one of embodiments 33-35, wherein at least one CD40L-specific monomer subunit is fused or conjugated to polyethylene glycol (PEG) via a linker.

[0367] 39. The method of embodiment 37, wherein the linker comprises a peptide linker.

[0368] 40. The method of embodiment 37, wherein the linker comprises SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, or SEQ ID NO: 10.

[0369] 41. The method of any one of embodiments 33-39, wherein at least one CD40L-specific monomer subunit is fused or conjugated to albumin.

[0370] 42. The method of embodiment 40, wherein the albumin is human serum albumin (HSA).

[0371] 43. The method of embodiment 41, wherein the HSA is a variant HSA comprising SEQ ID NO: 4.

[0372] 44. The method of any one of embodiments 24-42, wherein the loading dose and the maintenance dose are the same.

[0373] 45. The method of any one of embodiments 24-42, wherein the loading dose and the maintenance dose are different.

[0374] 46. The method of any one of embodiments 1-44, wherein the Tn3 scaffold comprises SEQ ID NO: 1.

[0375] 47. The method of any one of embodiments 10-45, wherein 1500 mg of the Tn3 scaffold is administered intravenously at week 0, week 2, and week 4, and then every 4 weeks thereafter.

[0376] 48. The method of any of embodiments 11-45, wherein 3000 mg of the Tn3 scaffold is administered intravenously at week 0, week 2, and week 4, and then every 4 weeks thereafter.

[0377] 49. A method of treating Sjogren’s Syndrome (SS) in a subject in need thereof, the method comprising: administering to the subject a Tn3 scaffold comprising SEQ ID NO: 1, wherein the Tn3 scaffold is administered at a dose of about 1500 mg, wherein the subject has an ESSDAI score of > 5 prior to the administration, and wherein the administration is effective to reduce the ESSDAI score compared to an otherwise comparable subject dosed with placebo.

[0378] 50. The method of embodiment 48, wherein the 1500 mg is administered intravenously at week 0, week 2, and week 4, and then every 4 weeks thereafter.

[0379] 51. A method of treating Sjogren’s Syndrome (SS) in a subject in need thereof, the method comprising: administering to the subject a Tn3 scaffold comprising SEQ ID NO: 1, wherein the Tn3 scaffold is administered at a dose of about 3000 mg, wherein the subject has an ESSDAI score of > 5 prior to the administration, and wherein the administration is effective to reduce the ESSDAI score compared to an otherwise comparable subject dosed with placebo.

[0380] 52. The method of embodiment 50, wherein 3000 mg of the Tn3 scaffold is administered intravenously at week 0, week 4, and week 12, and then every 12 weeks thereafter.

[0381] 53. The method of any of embodiments 48-51, wherein the ESSDAI score is reduced by 2 points, 3 points, 4 points, 5 points, 6 points, or 7 points after the administration.

[0382] 54. The method of any of embodiments 48-51, wherein the subject has an ESSDAI score of 5-7, 5-10, 5-13, or 10-13 prior to the administration.

[0383] 55. A method of treating Sjogren’s Syndrome (SS) in a subject in need thereof, the method comprising: administering to the subject a Tn3 scaffold comprising SEQ ID NO: 1, wherein the Tn3 scaffold is administered at a dose of about 1500 mg, wherein the subject has an European League Against Rheumatism (EULAR) Sjogren’s Disease Activity Index (ESSDAI) score of < 5, and wherein the subject has an EULAR Sjogren’s Patient Reported Index (ESSPRI) score of > 5 prior to the administration.

[0384] 56. The method of embodiment 54, wherein the 1500 mg is administered intravenously at week 0, week 2, and week 4, then every 4 weeks thereafter.

[0385] 57. A method of treating Sjogren’s syndrome (SS) in a subject in need thereof, the method comprising: administering to the subject a Tn3 scaffold comprising SEQ ID NO: 1, wherein the Tn3 scaffold is administered at a dose of about 3000 mg, wherein the subject has a European League Against Rheumatism (EULAR) Sjogren’s Disease Activity Index (ESSDAI) score of < 5, and wherein the subject has an EULAR Sjogren’s Patient Reported Index (ESSPRI) score of > 5 prior to the administration.

[0386] 58. The method of embodiment 56, wherein 3000 mg of the Tn3 scaffold is administered intravenously at week 0, week 4, and week 12, then every 12 weeks thereafter.

[0387] 59. The method of any one of embodiments 54-57, wherein the subject has an ESSPRI score of 5-6, 5-7, 6-8, 6-9, or 5-10 prior to the administration.

[0388] 60. The method of any one of embodiments 5-58, wherein the administration is effective to achieve a reduction in ESSPRI score of at least 0.6 points, 0.8 points, 1 point, 1.8 points, or 2 points compared to baseline.

[0389] 61. A method of treating Sjogren’s syndrome (SS) in a subject in need thereof, the method comprising: administering a Tn3 scaffold, wherein the Tn3 scaffold comprises a CD40L-specific monomer subunit, wherein the CD40L-specific monomer subunit comprises seven beta strands designated A, B, C, D, E, F, and G and six loop regions designated AB, BC, CD, DE, EF, and FG, wherein the AB loop comprises SEQ ID NO: 11, the BC loop comprises SEQ ID NO: 12, the CD loop comprises SEQ ID NO: 13, the DE loop comprises SEQ ID NO: 14, the EF loop comprises SEQ ID NO: 15, and the FG loop comprises SEQ ID NO: 16, wherein the subject is positive for anti-SSA / Ro antibodies.

[0390] 62. A method of treating Sjogren’s syndrome (SS) in a subject in need thereof, the method comprising: administering a Tn3 scaffold, wherein the Tn3 scaffold comprises a CD40L-specific monomer subunit, wherein the CD40L-specific monomer subunit comprises seven beta strands designated A, B, C, D, E, F, and G, and six loop regions designated AB, BC, CD, DE, EF, and FG, wherein the AB loop comprises SEQ ID NO: 11, the BC loop comprises SEQ ID NO: 12, the CD loop comprises SEQ ID NO: 13, the DE loop comprises SEQ ID NO: 14, the EF loop comprises SEQ ID NO: 15, and the FG loop comprises SEQ ID NO: 16, wherein the subject is positive for RF antibodies.

[0391] 63. The method of any of embodiments 1-60, wherein the administration is effective to reduce the ESSPRI score by >5%, 10%, 15%, 20%, 40%, or 60% compared to an otherwise comparable subject administered a placebo or compared to the subject’s baseline level.

[0392] EMBODIMENT SET 3

[0393] 1. A method of treating Sjogren’s syndrome (SS) in a subject in need thereof, the method comprising: administering a Tn3 scaffold, wherein the Tn3 scaffold comprises a CD40L-specific monomer subunit, wherein the CD40L-specific monomer subunit comprises seven beta strands designated A, B, C, D, E, F, and G, and six loop regions designated AB, BC, CD, DE, EF, and FG, wherein the AB loop comprises SEQ ID NO: 11, the BC loop comprises SEQ ID NO: 12, the CD loop comprises SEQ ID NO: 13, the DE loop comprises SEQ ID NO: 14, the EF loop comprises SEQ ID NO: 15, and the FG loop comprises SEQ ID NO: 16, wherein the Tn3 scaffold comprising the CD40L-specific monomer subunit is administered at a dose of about 1500 mg to about 3000 mg, and wherein the subject has moderate to severe systemic disease activity as determined by the European League Against Rheumatism (EULAR) Sjogren’s Disease Activity Index (ESSDAI).

[0394] 2. The method of embodiment 1, wherein the subject has an ESSDAI score of 5-7, 5-10, 5-13, or 10-13 prior to administration of the Tn3 scaffold.

[0395] 3. The method of embodiment 2, wherein the subject has an ESSDAI score of >5.

[0396] 4. The method of any one of embodiments 1-3, wherein administration of the Tn3 scaffold is effective to reduce the EULAR Sjogren’s Syndrome Patient Reported Index (ESSPRI) score following administration.

[0397] 5. The method of embodiment 4, wherein the ESSPRI score is reduced by at least 2, 3, 4, or 5 points.

[0398] 6. The method of any one of embodiments 1-3, wherein administration of the Tn3 scaffold is effective to reduce the DASPRI score.

[0399] 7. The method of embodiment 6, wherein the DASPRI score is reduced by at least about 5, 10, 15, or 20 points.

[0400] 8. A method of treating Sjogren’s Syndrome (SS) in a subject in need thereof, the method comprising: administering a Tn3 scaffold, wherein the Tn3 scaffold comprises a CD40L-specific monomer subunit, wherein the CD40L-specific monomer subunit comprises seven beta strands designated A, B, C, D, E, F, and G and six loop regions designated AB, BC, CD, DE, EF, and FG, wherein the AB loop comprises SEQ ID NO: 11, the BC loop comprises SEQ ID NO: 12, the CD loop comprises SEQ ID NO: 13, the DE loop comprises SEQ ID NO: 14, the EF loop comprises SEQ ID NO: 15, and the FG loop comprises SEQ ID NO: 16, wherein the Tn3 scaffold comprising the CD40L-specific monomer subunit is administered at a dose of about 1500 mg to about 3000 mg, and wherein the subject has an ESSPRI score of > 5.

[0401] 9. The method of embodiment 8, wherein the subject has an ESSDAI score of < 5 prior to administration of the Tn3 scaffold.

[0402] 10. The method of any one of embodiments 8-9, wherein the subject has residual salivary gland function as defined by intact stimulated salivary flow of greater than 0.1 mL / min.

[0403] 11. The method of any one of embodiments 1-10, wherein the subject’s sample is positive for anti-Ro autoantibodies, rheumatoid factor autoantibodies, or both anti-Ro autoantibodies and rheumatoid factor autoantibodies.

[0404] 12. The method of any one of embodiments 1-11, wherein the dose is 1500 mg.

[0405] 13. The method of any one of embodiments 1-11, wherein the dose is 3000 mg.

[0406] 14. The method of any one of embodiments 2-13, wherein the change from baseline in ESSDAI is determined after administration of the Tn3 scaffold.

[0407] 15. The method of embodiment 14, wherein the change from baseline is determined every four weeks after administration of the Tn3 scaffold until week 48.

[0408] 16. The method of any one of embodiments 2-15, wherein administration of the Tn3 scaffold is effective to reduce the ESSDAI score of the subject after administration.

[0409] 17. The method of embodiment 16, wherein the ESSDAI score is reduced by at least 1, 2, 3, 4, 5, 6, or 7 points.

[0410] 18. The method of embodiment 16, wherein the ESSDAI score is reduced by at least 6 points.

[0411] 19. The method of any one of embodiments 8-18, wherein administration of the Tn3 scaffold is effective to reduce the DASPRI score.

[0412] 20. The method of embodiment 19, wherein the DASPRI score is reduced by at least about 5, 10, 15, or 20 points.

[0413] 21. The method of any one of embodiments 1-20, wherein administration of the Tn3 scaffold is effective to reduce the tender and swollen joint count baseline score of the subject after administration.

[0414] 22. The method of any one of embodiments 1-21, wherein administration of the Tn3 scaffold is effective to reduce the Short Form 36 (SF-36) Health Survey baseline score of the subject through week 48 after administration.

[0415] 23. The method of any one of embodiments 1-22, wherein administration of the Tn3 scaffold is effective to improve the baseline score of the subject, wherein the baseline score is selected from the group consisting of: Functional Assessment of Chronic Therapy Fatigue Scale (FACIT-Fatigue), PROMIS Fatigue Short Form 10a, Ocular Surface Disease Index (OSDI), EQ-5D-5L, and Patient Global Impression-Severity (PGIS).

[0416] 24. The method of any one of embodiments 1-23, wherein administration of the Tn3 scaffold is effective to reduce the baseline level of an inflammatory marker after administration, and wherein the markers are selected from the group consisting of: immunoglobulin, beta-2 microglobulin, C-reactive protein, and combinations thereof.

[0417] 25. The method of any one of embodiments 1-24, wherein administration of the Tn3 scaffold is effective to reduce baseline levels of a biomarker, and wherein the biomarker is selected from the group consisting of: plasma soluble CD40L, B cells, serum CXCL13, rheumatoid factor autoantibody, anti-SSA autoantibody (i.e., anti-Ro autoantibody), anti-SSB autoantibody (i.e., anti-La autoantibody), and combinations thereof.

[0418] 26. The method of any one of embodiments 1-25, wherein administration of the Tn3 scaffold is effective to reduce baseline levels of a symptom of disease, and wherein the symptom of disease is selected from the group consisting of: fatigue, dry mouth, dry eyes, dry vagina, pain, and combinations thereof.

[0419] 27. The method of any one of embodiments 1-26, wherein the expression level of a gene associated with SS is reduced in a blood sample of the subject by week 48 after administration.

[0420] 28. The method of any one of embodiments 1-27, 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 is reduced in a blood sample of the subject by week 48 after administration.

[0421] 29. The method of any one of embodiments 1-28, wherein the Tn3 scaffold is administered in a loading dose and thereafter in a maintenance dose.

[0422] 30. The method of embodiment 29, wherein the loading dose comprises administration of the Tn3 scaffold about once every 2 weeks for at least 3 doses.

[0423] 31. The method of embodiment 30, wherein the maintenance dose comprises administration of the Tn3 scaffold about once every 4 weeks for at least 4 doses.

[0424] 32. The method of embodiment 31, wherein the time between the last loading dose and the first maintenance dose is about 4 weeks.

[0425] 33. The method of any one of embodiments 1-31, wherein the Tn3 scaffold is administered about once every 4 weeks, about once every 2 months, about once every 3 months, about once every 4 months, or about once every 6 months.

[0426] 34. The method of any one of embodiments 1-33, wherein the Tn3 scaffold is administered for at least 4 doses.

[0427] 35. The method of any one of embodiments 1-33, wherein the Tn3 scaffold is administered for at least 5 doses.

[0428] 36. The method of any one of embodiments 1-35, wherein the Tn3 scaffold is administered intravenously, subcutaneously, orally, intramuscularly, intrathecally, sublingually, rectally, vaginally, transdermally, systemically, topically, transdermally, or by inhalation.

[0429] 37. The method of embodiment 36, wherein the Tn3 scaffold is administered intravenously.

[0430] 38. The method of any one of embodiments 1-37, wherein the Tn3 scaffold comprises two CD40L-specific monomeric subunits linked in tandem.

[0431] 39. The method of embodiment 38, wherein the two CD40L-specific monomeric subunits each comprise SEQ ID NO: 3.

[0432] 40. The method of any one of embodiments 38-39, wherein the CD40L-specific monomeric subunits are linked by a linker.

[0433] 41. The method of any one of embodiments 38-40, wherein at least one CD40L-specific monomeric subunit is directly fused or conjugated to polyethylene glycol (PEG).

[0434] 42. The method of any one of embodiments 38-40, wherein at least one CD40L-specific monomeric subunit is fused or conjugated to polyethylene glycol (PEG) via a linker.

[0435] 43. The method of embodiment 42, wherein the linker comprises a peptide linker.

[0436] 44. The method of embodiment 43, wherein the linker comprises SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, or SEQ ID NO: 10.

[0437] 45. The method of any one of embodiments 38-40, wherein at least one CD40L-specific monomeric subunit is fused or conjugated to albumin.

[0438] 46. The method of embodiment 45, wherein the albumin is human serum albumin (HSA).

[0439] 47. The method of embodiment 46, wherein the HSA is a variant HSA comprising SEQ ID NO: 4.

[0440] 48. The method of any one of embodiments 29-47, wherein the loading dose and the maintenance dose are the same.

[0441] 49. The method of any of embodiments 29-47, wherein the loading dose and the maintenance dose are different.

[0442] 50. The method of any of embodiments 1-49, wherein the Tn3 scaffold comprises SEQ ID NO: 1.

[0443] 51. The method of any of embodiments 12-50, wherein 1500 mg of the Tn3 scaffold is administered intravenously at week 0, week 2, and week 4, and then every 4 weeks thereafter.

[0444] 52. The method of any of embodiments 13-50, wherein 3000 mg of the Tn3 scaffold is administered intravenously at week 0, week 2, and week 4, and then every 4 weeks thereafter.

[0445] 53. A method of treating Sjogren’s Syndrome (SS) in a subject in need thereof, the method comprising: administering to the subject a Tn3 scaffold comprising SEQ ID NO: 1, wherein the Tn3 scaffold is administered at a dose of about 1500 mg, wherein the subject has an ESSDAI score of > 5 prior to the administration, and wherein the administration is effective to reduce the ESSDAI score compared to an otherwise comparable subject dosed with placebo.

[0446] 54. The method of embodiment 49, wherein the 1500 mg is administered intravenously at week 0, week 2, and week 4, and then every 4 weeks thereafter.

[0447] 55. A method of treating Sjogren’s Syndrome (SS) in a subject in need thereof, the method comprising: administering to the subject a Tn3 scaffold comprising SEQ ID NO: 1, wherein the Tn3 scaffold is administered at a dose of about 3000 mg, wherein the subject has an ESSDAI score of > 5 prior to the administration, and wherein the administration is effective to reduce the ESSDAI score compared to an otherwise comparable subject dosed with placebo.

[0448] 56. The method of embodiment 55, wherein 3000 mg of the Tn3 scaffold is administered intravenously at week 0, week 4, and week 12, and then every 12 weeks thereafter.

[0449] 57. The method of any of embodiments 49-56, wherein the ESSDAI score is reduced by 2 points, 3 points, 4 points, 5 points, 6 points, or 7 points after the administration.

[0450] 58. The method of any of embodiments 49-57, wherein the subject has an ESSDAI score of 5-7, 5-10, 5-13, or 10-13 prior to the administration.

[0451] 59. A method of treating Sjogren’s syndrome (SS) in a subject in need thereof, the method comprising: administering to the subject a Tn3 scaffold comprising SEQ ID NO: 1, wherein the Tn3 scaffold is administered at a dose of about 1500 mg, wherein the subject has a European League Against Rheumatism (EULAR) Sjogren’s Syndrome Disease Activity Index (ESSDAI) score of <5, and wherein the subject has an EULAR Sjogren’s Syndrome Patient Reported Index (ESSPRI) score of >5 prior to the administration.

[0452] 60. The method of embodiment 59, wherein the 1500 mg is administered intravenously at week 0, week 2, and week 4, and then every 4 weeks thereafter.

[0453] 61. A method of treating Sjogren’s syndrome (SS) in a subject in need thereof, the method comprising: administering to the subject a Tn3 scaffold comprising SEQ ID NO: 1, wherein the Tn3 scaffold is administered at a dose of about 3000 mg, wherein the subject has a European League Against Rheumatism (EULAR) Sjogren’s Syndrome Disease Activity Index (ESSDAI) score of <5, and wherein the subject has an EULAR Sjogren’s Syndrome Patient Reported Index (ESSPRI) score of >5 prior to the administration.

[0454] 62. The method of embodiment 61, wherein the 3000 mg of the Tn3 scaffold is administered intravenously at week 0, week 4, and week 12, and then every 12 weeks thereafter.

[0455] 63. The method of any one of embodiments 59-62, wherein the subject has an ESSPRI score of 5-6, 5-7, 6-8, 6-9, or 5-10 prior to the administration.

[0456] 64. The method of any one of embodiments 4-63, wherein the administration is effective to achieve a reduction in ESSPRI score of at least 0.6 points, 0.8 points, 1 point, 1.8 points, or 2 points compared to baseline.

[0457] 65. A method of treating Sjogren’s Syndrome (SS) in a subject in need thereof, the method comprising: administering a Tn3 scaffold, wherein the Tn3 scaffold comprises a CD40L-specific monomer subunit, wherein the CD40L-specific monomer subunit comprises seven beta strands designated A, B, C, D, E, F, and G and six loop regions designated AB, BC, CD, DE, EF, and FG, wherein the AB loop comprises SEQ ID NO: 11, the BC loop comprises SEQ ID NO: 12, the CD loop comprises SEQ ID NO: 13, the DE loop comprises SEQ ID NO: 14, the EF loop comprises SEQ ID NO: 15, and the FG loop comprises SEQ ID NO: 16, wherein the subject is positive for anti-SSA / Ro antibodies.

[0458] 66. A method of treating Sjogren’s Syndrome (SS) in a subject in need thereof, the method comprising: administering a Tn3 scaffold, wherein the Tn3 scaffold comprises a CD40L-specific monomer subunit, wherein the CD40L-specific monomer subunit comprises seven beta strands designated A, B, C, D, E, F, and G and six loop regions designated AB, BC, CD, DE, EF, and FG, wherein the AB loop comprises SEQ ID NO: 11, the BC loop comprises SEQ ID NO: 12, the CD loop comprises SEQ ID NO: 13, the DE loop comprises SEQ ID NO: 14, the EF loop comprises SEQ ID NO: 15, and the FG loop comprises SEQ ID NO: 16, wherein the subject is positive for RF antibodies.

[0459] 67. The method of any of embodiments 1-66, wherein the administering is effective to achieve a reduction of > 5%, 10%, 15%, 20%, 40%, or 60% in ESSPRI score compared to an otherwise comparable subject administered a placebo or compared to the subject’s baseline level.

[0460] 68. The method of any of embodiments 1-67, wherein the administering is effective to achieve a reduction of > 5%, 10%, 15%, 20%, 40%, or 60% in DASPRI score compared to an otherwise comparable subject administered a placebo or compared to the subject’s baseline level.

[0461] EMBODIMENT SET 4

[0462] 1. A Tn3 scaffold for use in treating Sjogren’s Syndrome (SS), the Tn3 scaffold comprising a CD40L-specific monomer subunit, wherein the CD40L-specific monomer subunit comprises seven beta strands designated A, B, C, D, E, F, and G, and six loop regions designated AB, BC, CD, DE, EF, and FG, wherein the AB loop comprises SEQ ID NO: 11, the BC loop comprises SEQ ID NO: 12, the CD loop comprises SEQ ID NO: 13, the DE loop comprises SEQ ID NO: 14, the EF loop comprises SEQ ID NO: 15, and the FG loop comprises SEQ ID NO: 16, wherein the Tn3 scaffold comprising the CD40L-specific monomer subunit is administered to a subject at a dose of about 1500 mg once every 4 weeks, wherein the subject has moderate to severe systemic disease activity as determined by a European League Against Rheumatism (EULAR) Sjogren’s Syndrome Disease Activity Index (ESSDAI) of > 5.

[0463] 2. The Tn3 scaffold for use according to embodiment 1, wherein the subject is administered at least 3 loading doses prior to the administration once every 4 weeks.

[0464] 3. The Tn3 scaffold for use according to embodiment 2, wherein the at least 3 loading doses occur at week 0, week 2, and week 4.

[0465] 4. A Tn3 scaffold for use in treating Sjogren’s Syndrome (SS), the Tn3 scaffold comprising a CD40L-specific monomer subunit, wherein the CD40L-specific monomer subunit comprises seven beta strands designated A, B, C, D, E, F, and G, and six loop regions designated AB, BC, CD, DE, EF, and FG, wherein the AB loop comprises SEQ ID NO: 11, the BC loop comprises SEQ ID NO: 12, the CD loop comprises SEQ ID NO: 13, the DE loop comprises SEQ ID NO: 14, the EF loop comprises SEQ ID NO: 15, and the FG loop comprises SEQ ID NO: 16, wherein the Tn3 scaffold comprising the CD40L-specific monomer subunit is administered to a subject at a dose of about 3000 mg once every 12 weeks, wherein the subject has moderate to severe systemic disease activity as determined by a European League Against Rheumatism (EULAR) Sjogren’s Syndrome Disease Activity Index (ESSDAI) of > 5.

[0466] 5. The Tn3 scaffold for use according to embodiment 4, wherein the subject is administered at least 3 loading doses prior to the administration once every 12 weeks.

[0467] 6. The Tn3 scaffold for use according to embodiment 5, wherein the at least 3 loading doses occur at week 0, week 4 and week 12.

[0468] 7. A Tn3 scaffold for use in the treatment of Sjogren’s Syndrome (SS), comprising a CD40L-specific monomer subunit, wherein the CD40L-specific monomer subunit comprises seven beta strands designated A, B, C, D, E, F, and G, and six loop regions designated AB, BC, CD, DE, EF, and FG, wherein the AB loop comprises SEQ ID NO: 11, the BC loop comprises SEQ ID NO: 12, the CD loop comprises SEQ ID NO: 13, the DE loop comprises SEQ ID NO: 14, the EF loop comprises SEQ ID NO: 15, and the FG loop comprises SEQ ID NO: 16, wherein the Tn3 scaffold comprising the CD40L-specific monomer subunit is administered to a subject at a dose of about 1500 mg once every 4 weeks, wherein the subject has a moderate to severe symptom status defined by an ESSPRI score > 5, and low systemic disease activity defined by an ESSDAI score < 5.

[0469] 8. The Tn3 scaffold for use according to embodiment 7, wherein the subject is administered at least 3 loading doses prior to the administration once every 4 weeks.

[0470] 9. The Tn3 scaffold for use according to embodiment 8, wherein the at least 3 loading doses occur at week 0, week 2 and week 4.

[0471] 10. A Tn3 scaffold for use in the treatment of Sjogren’s Syndrome (SS), comprising a CD40L-specific monomer subunit, wherein the CD40L-specific monomer subunit comprises seven beta strands designated A, B, C, D, E, F, and G, and six loop regions designated AB, BC, CD, DE, EF, and FG, wherein the AB loop comprises SEQ ID NO: 11, the BC loop comprises SEQ ID NO: 12, the CD loop comprises SEQ ID NO: 13, the DE loop comprises SEQ ID NO: 14, the EF loop comprises SEQ ID NO: 15, and the FG loop comprises SEQ ID NO: 16, wherein the Tn3 scaffold comprising the CD40L-specific monomer subunit is administered to a subject at a dose of about 3000 mg once every 12 weeks, wherein the subject has a moderate to severe symptom status defined by an ESSPRI score > 5, and low systemic disease activity defined by an ESSDAI score < 5.

[0472] 11. The Tn3 scaffold for use according to embodiment 10, wherein the subject is administered at least 3 loading doses prior to the once every 12 weeks administration.

[0473] 12. The Tn3 scaffold for use according to embodiment 11, wherein the at least 3 loading doses occur at week 0, week 4, and week 12.

[0474] 13. The Tn3 scaffold for use according to any one of embodiments 1-5, wherein the subject has an ESSDAI score of 5-7, 5-10, 5-13, or 10-13 prior to administration of the Tn3 scaffold.

[0475] 14. The Tn3 scaffold for use according to any one of embodiments 1-5, wherein administration is effective to reduce the ESSDAI.

[0476] 15. The Tn3 scaffold for use according to embodiment 14, wherein the ESSDAI score is reduced by at least 1, 2, 3, 4, 5, 6, or 7 points.

[0477] 16. The Tn3 scaffold for use according to embodiment 15, wherein the ESSDAI score is reduced by at least 6 points.

[0478] 17. The Tn3 scaffold for use according to any one of embodiments 13-16, wherein the ESSDAI score is reduced 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 first loading dose compared to the baseline ESSDAI score.

[0479] 18. The Tn3 scaffold for use according to embodiment 17, wherein the ESSDAI score is reduced 11 months after administration of the first loading dose.

[0480] 19. The Tn3 scaffold for use according to any one of embodiments 7-12, wherein the subject includes intact stimulated salivary flow of >0.1 mL / min at baseline.

[0481] 20. The Tn3 scaffold for use according to embodiment 19, wherein the ESSPRI score is reduced by at least about 1.5, 2, 3, 4, or 5 points after administration of the loading dose at week 0.

[0482] 21. The Tn3 scaffold for use according to any one of embodiments 7-12, wherein the DASPRI score is reduced after administration.

[0483] 22. The Tn3 scaffold for use according to embodiment 21, wherein the DASPRI score is reduced by at least about 5, 10, 15, or 20 points after administration of the loading dose at week 0.

[0484] 23. The Tn3 scaffold for use according to any one of embodiments 1-22, wherein administration of the Tn3 scaffold is effective to reduce the subject’s tender and swollen joint count baseline score after administration.

[0485] 24. The Tn3 scaffold for use according to any one of embodiments 1-23, wherein administration of the Tn3 scaffold is effective to reduce the subject’s Short Form 36 (SF-36) Health Survey baseline score after administration.

[0486] 25. The Tn3 scaffold for use according to any one of embodiments 1-22, wherein administration of the Tn3 scaffold is effective to improve the subject’s baseline score, wherein the baseline score is selected from the group consisting of: Functional Assessment of Chronic Therapy Fatigue Scale (FACIT-Fatigue), PROMIS Fatigue Short Form 10a, Ocular Surface Disease Index (OSDI), EQ-5D-5L, and Patient Global Impression-Severity (PGIS).

[0487] 24. The Tn3 scaffold for use according to any one of embodiments 1-23, wherein administration of the Tn3 scaffold is effective to reduce baseline levels of inflammatory markers after administration, and wherein the markers are selected from the group consisting of: immunoglobulin, beta-2 microglobulin, C-reactive protein, and combinations thereof.

[0488] 25. The Tn3 scaffold for use according to any one of embodiments 1-24, wherein administration of the Tn3 scaffold is effective to reduce baseline levels of biomarkers, and wherein the biomarkers are selected from the group consisting of: plasma soluble CD40L, Ki67+CD27+ memory B cells, plasmablasts, CD11c bright / high B cells, CD3, CD4, CD8, Tfh cells, serum CXCL13, rheumatoid factor, anti-SSA autoantibodies (i.e., anti-Ro autoantibodies), anti-SSB autoantibodies (i.e., anti-La autoantibodies), and combinations thereof.

[0489] 26. The Tn3 scaffold for use according to any one of embodiments 1-25, wherein administration of the Tn3 scaffold is effective to reduce baseline levels of disease symptoms, and wherein the disease symptoms are selected from the group consisting of: fatigue, dry mouth, dry eyes, dry vagina, pain, and combinations thereof.

[0490] 27. The Tn3 scaffold for use according to any of embodiments 1-26, wherein the expression level of a gene associated with SS is reduced in a blood sample of the subject by week 48 after administration.

[0491] 28. The Tn3 scaffold for use according to any of embodiments 1-27, 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 is reduced in a blood sample of the subject by week 48 after administration.

[0492] 29. The Tn3 scaffold for use according to any of embodiments 1-28, wherein the Tn3 scaffold is administered intravenously.

[0493] 30. The Tn3 scaffold for use according to any of embodiments 1-29, wherein the Tn3 scaffold comprises two CD40L-specific monomer subunits linked in tandem.

[0494] 31. The Tn3 scaffold of embodiment 30, wherein the two CD40L-specific monomer subunits each comprise SEQ ID NO: 3.

[0495] 32. The Tn3 scaffold for use according to any of embodiments 30-31, wherein the CD40L-specific monomer subunits are linked by a linker.

[0496] 33. The Tn3 scaffold for use according to any of embodiments 30-32, wherein at least one CD40L-specific monomer subunit is directly fused or conjugated to polyethylene glycol (PEG).

[0497] 34. The Tn3 scaffold for use according to any of embodiments 30-33, wherein at least one CD40L-specific monomer subunit is fused or conjugated to polyethylene glycol (PEG) via a linker.

[0498] 35. The Tn3 scaffold for use according to embodiment 34, wherein the linker comprises a peptide linker.

[0499] 36. The Tn3 scaffold for use according to embodiment 35, wherein the linker comprises SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, or SEQ ID NO: 10.

[0500] 37. The Tn3 scaffold for use according to any of embodiments 30-36, wherein at least one CD40L-specific monomer subunit is fused or conjugated to albumin.

[0501] 38. The Tn3 scaffold for use according to embodiment 37, wherein the albumin is human serum albumin (HSA).

[0502] 39. The Tn3 scaffold for use according to embodiment 38, wherein the HSA is a variant HSA comprising SEQ ID NO: 4.

[0503] 40. The Tn3 scaffold for use according to any one of embodiments 1-39, wherein the Tn3 scaffold comprises SEQ ID NO: 1.

[0504] Embodiment Set 5

[0505] 1. A method of treating Sjogren’s syndrome (SS) in a subject in need thereof, the method comprising: administering a Tn3 scaffold, wherein the Tn3 scaffold comprises a CD40L-specific monomer subunit, wherein the CD40L-specific monomer subunit comprises seven beta strands designated A, B, C, D, E, F, and G and six loop regions designated AB, BC, CD, DE, EF, and FG, wherein the AB loop comprises SEQ ID NO: 11, the BC loop comprises SEQ ID NO: 12, the CD loop comprises SEQ ID NO: 13, the DE loop comprises SEQ ID NO: 14, the EF loop comprises SEQ ID NO: 15, and the FG loop comprises SEQ ID NO: 16, wherein the Tn3 scaffold is administered at a dose of about 1500 mg once every 4 weeks, wherein the subject has moderate to severe systemic disease activity as determined by a European League Against Rheumatism (EULAR) Sjogren’s Syndrome Disease Activity Index (ESSDAI) of > 5.

[0506] 2. The method of embodiment 1, wherein the subject is administered at least 3 loading doses each of 1500 mg prior to the once every 4 weeks dosing.

[0507] 3. The method of embodiment 2, wherein the at least 3 loading doses are administered at week 0, week 2, and week 4.

[0508] 4. A method of treating Sjogren’s Syndrome (SS) in a subject in need thereof, the method comprising: administering a Tn3 scaffold, wherein the Tn3 scaffold comprises a CD40L-specific monomer subunit, wherein the CD40L-specific monomer subunit comprises seven beta strands designated A, B, C, D, E, F, and G, and six loop regions designated AB, BC, CD, DE, EF, and FG, wherein the AB loop comprises SEQ ID NO: 11, the BC loop comprises SEQ ID NO: 12, the CD loop comprises SEQ ID NO: 13, the DE loop comprises SEQ ID NO: 14, the EF loop comprises SEQ ID NO: 15, and the FG loop comprises SEQ ID NO: 16, wherein the Tn3 scaffold is administered at a dose of about 3000 mg once every 12 weeks, wherein the subject has moderate to severe systemic disease activity as determined by a European League Against Rheumatism (EULAR) Sjogren’s Syndrome Disease Activity Index (ESSDAI) > 5.

[0509] 5. The method of embodiment 4, wherein the subject is administered at least 3 loading doses of 3000 mg each prior to the administration once every 12 weeks.

[0510] 6. The method of embodiment 5, wherein the at least 3 loading doses are administered at week 0, week 4, and week 12.

[0511] 7. A method of treating Sjogren’s Syndrome (SS) in a subject in need thereof, the method comprising: administering a Tn3 scaffold, wherein the Tn3 scaffold comprises a CD40L-specific monomer subunit, wherein the CD40L-specific monomer subunit comprises seven beta strands designated A, B, C, D, E, F, and G, and six loop regions designated AB, BC, CD, DE, EF, and FG, wherein the AB loop comprises SEQ ID NO: 11, the BC loop comprises SEQ ID NO: 12, the CD loop comprises SEQ ID NO: 13, the DE loop comprises SEQ ID NO: 14, the EF loop comprises SEQ ID NO: 15, and the FG loop comprises SEQ ID NO: 16, wherein the Tn3 scaffold is administered at a dose of about 1500 mg once every 4 weeks, wherein the subject has moderate to severe symptom status as defined by an ESSPRI score > 5, has low systemic disease activity as defined by an ESSDAI score < 5, and wherein the subject’s Sjogren’s Syndrome Patient-Reported Index Assessment Diary (DASPRI) score is reduced following administration.

[0512] 8. The method of embodiment 7, wherein the subject is administered at least 3 loading doses of 1500 mg each prior to the administration once every 4 weeks.

[0513] 9. The method of embodiment 8, wherein the at least 3 loading doses are administered at week 0, week 2, and week 4.

[0514] 10. A method of treating Sjogren’s Syndrome (SS) in a subject in need thereof, the method comprising: administering a Tn3 scaffold, wherein the Tn3 scaffold comprises a CD40L- specific monomer subunit, wherein the CD40L-specific monomer subunit comprises seven beta strands designated A, B, C, D, E, F, and G and six loop regions designated AB, BC, CD, DE, EF, and FG, wherein the AB loop comprises SEQ ID NO: 11, the BC loop comprises SEQ ID NO: 12, the CD loop comprises SEQ ID NO: 13, the DE loop comprises SEQ ID NO: 14, the EF loop comprises SEQ ID NO: 15, and the FG loop comprises SEQ ID NO: 16, wherein the Tn3 scaffold is administered at a dose of about 3000 mg once every 12 weeks, wherein the subject has a moderate to severe symptom status defined by an ESSPRI score of > 5, has low systemic disease activity defined by an ESSDAI score of < 5, and wherein after administration the subject has a reduced Sjogren’s Syndrome Patient-Reported Index Assessment Diary (DASPRI) score.

[0515] 11. The method of embodiment 10, wherein the subject is administered at least 3 loading doses of 3000 mg each prior to the administration once every 12 weeks.

[0516] 12. The method of embodiment 11, wherein the at least 3 loading doses are administered at week 0, week 4, and week 12.

[0517] 13. The method of any one of embodiments 1-5, wherein the subject has an ESSDAI score of 5-7, 5-10, 5-13, or 10-13 prior to administration of the Tn3 scaffold.

[0518] 14. The method of any one of embodiments 1-6, wherein an effective reduction in the ESSDAI score is administered.

[0519] 15. The method of embodiment 14, wherein the ESSDAI score is reduced by at least 1, 2, 3, 4, 5, 6, or 7 points.

[0520] 16. The method of embodiment 15, wherein the ESSDAI score is reduced by at least 6 points.

[0521] 17. The method of any one of embodiments 15-16, wherein the ESSDAI score is reduced as compared to the baseline ESSDAI score 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 first loading dose.

[0522] 18. The method of embodiment 17, wherein the ESSDAI score is reduced at 11 months after administration of the first loading dose.

[0523] 19. The method of any one of embodiments 7-18, wherein salivary gland function is improved in the subject at about 3 weeks, 1 month, 2 months, or 4 months after administration of the Tn3 scaffold.

[0524] 20. The method of embodiment 19, wherein salivary gland function is determined by complete stimulated saliva flow.

[0525] 21. The method of any one of embodiments 9-20, wherein the ESSPRI score is reduced by at least about 1.5, 2, 3, 4, or 5 points after administration of the loading dose.

[0526] 22. The method of any one of embodiments 7-21, wherein the DASPRI score is reduced at 2 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months after the administration.

[0527] 23. The method of embodiment 22, wherein the DASPRI score is reduced by at least about 5, 10, 15, or 20 points after administration of the loading dose.

[0528] 24. The method of any one of embodiments 1-23, wherein administration of the Tn3 scaffold is effective to reduce the subject’s tender and swollen joint count baseline score after administration.

[0529] 25. The method of any one of embodiments 1-24, wherein administration of the Tn3 scaffold is effective to reduce the subject’s Short Form 36 (SF-36) Health Survey baseline score after administration.

[0530] 26. The method of any one of embodiments 1-25, wherein administration of the Tn3 scaffold is effective to improve the subject’s baseline score, wherein the baseline score is selected from the group consisting of: Functional Assessment of Chronic Illness Therapy Fatigue Scale (FACIT-Fatigue), PROMIS Fatigue Short Form 10a, Ocular Surface Disease Index (OSDI), EQ-5D-5L, and Patient Global Impression-Severity (PGIS).

[0531] 27. The method of any one of embodiments 1-26, wherein administration of the Tn3 scaffold is effective to reduce baseline levels of inflammatory markers following administration, and wherein the markers are selected from the group consisting of: immunoglobulin, beta-2 microglobulin, C-reactive protein, and combinations thereof.

[0532] 28. The method of any one of embodiments 1-27, wherein administration of the Tn3 scaffold is effective to reduce baseline levels of biomarkers, and wherein the biomarkers are selected from the group consisting of: plasma soluble CD40L, Ki67+CD27+ memory B cells, CD19, CD20, CD27, CD38, CD138, CD11c 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.

[0533] 29. The method of any one of embodiments 1-28, wherein administration of the Tn3 scaffold is effective to reduce baseline levels of disease symptoms, and wherein the disease symptoms are selected from the group consisting of: fatigue, dry mouth, dry eyes, dry vagina, pain, and combinations thereof.

[0534] 30. The method of any one of embodiments 1-29, wherein to week 48 following administration, the subject has reduced levels of expression of genes associated with SS or levels of proteins encoded by the genes in a blood sample of the subject.

[0535] 31. The method of any one of embodiments 1-30, wherein to week 48 following administration, the subject has reduced levels of B cells selected from the group consisting of: CD27+ memory B cells, marginal zone B cells, plasmablasts, plasma cells, and combinations thereof, in a blood sample of the subject.

[0536] 32. The method of any one of embodiments 1-31, wherein the subject is positive for anti-Ro autoantibody, rheumatoid factor (RF), or both anti-Ro autoantibody and RF.

[0537] 33. The method of any one of embodiments 1-32, wherein the Tn3 scaffold is administered intravenously.

[0538] 34. The method of any one of embodiments 1-33, wherein the Tn3 scaffold comprises two CD40L-specific monomeric subunits linked in tandem.

[0539] 35. The method of embodiment 34, wherein the two CD40L-specific monomeric subunits each comprise SEQ ID NO: 3.

[0540] 36. The method of any one of embodiments 34-35, wherein the CD40L-specific monomer subunits are linked by a linker.

[0541] 37. The method of any one of embodiments 34-36, wherein at least one CD40L-specific monomer subunit is directly fused or conjugated to polyethylene glycol (PEG).

[0542] 38. The method of any one of embodiments 34-37, wherein at least one CD40L-specific monomer subunit is fused or conjugated to polyethylene glycol (PEG) via a linker.

[0543] 39. The method of embodiment 38, wherein the linker comprises a peptide linker.

[0544] 40. The method of embodiment 39, wherein the linker comprises SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, or SEQ ID NO: 10.

[0545] 41. The method of any one of embodiments 34-40, wherein at least one CD40L-specific monomer subunit is fused or conjugated to albumin.

[0546] 42. The method of embodiment 41, wherein the albumin is human serum albumin (HSA).

[0547] 43. The method of embodiment 42, wherein the HSA is a variant HSA comprising SEQ ID NO: 4.

[0548] 44. The method of any one of embodiments 1-42, wherein the Tn3 scaffold comprises SEQ ID NO: 1.

[0549] Example Set 6

[0550] 1. Use of a Tn3 scaffold for the manufacture of a medicament for the treatment of Sjogren’s Syndrome (SS) in a subject in need thereof, wherein the medicament is formulated for administration at a dose of 1500 mg once every 4 weeks, wherein the Tn3 scaffold comprises a CD40L specific monomeric subunit, wherein the CD40L specific monomeric subunit comprises seven beta strands designated A, B, C, D, E, F, and G and six loop regions designated AB, BC, CD, DE, EF, and FG, wherein the AB loop comprises SEQ ID NO: 11, the BC loop comprises SEQ ID NO: 12, the CD loop comprises SEQ ID NO: 13, the DE loop comprises SEQ ID NO: 14, the EF loop comprises SEQ ID NO: 15, and the FG loop comprises SEQ ID NO: 16, wherein the subject has moderate to severe systemic disease activity as determined by a European League Against Rheumatism (EULAR) Sjogren’s Syndrome Disease Activity Index (ESSDAI) of > 5.

[0551] 2. The use of embodiment 1, wherein the subject is administered at least 3 loading doses each of 1500 mg prior to the administration once every 4 weeks.

[0552] 3. The use of embodiment 2, wherein the at least 3 loading doses are administered at week 0, week 2, and week 4.

[0553] 4. Use of a Tn3 scaffold for the manufacture of a medicament for the treatment of Sjogren’s Syndrome (SS) in a subject in need thereof, wherein the medicament is formulated for administration at a dose of 3000 mg once every 12 weeks, wherein the Tn3 scaffold comprises a CD40L specific monomeric subunit, wherein the CD40L specific monomeric subunit comprises seven beta strands designated A, B, C, D, E, F, and G and six loop regions designated AB, BC, CD, DE, EF, and FG, wherein the AB loop comprises SEQ ID NO: 11, the BC loop comprises SEQ ID NO: 12, the CD loop comprises SEQ ID NO: 13, the DE loop comprises SEQ ID NO: 14, the EF loop comprises SEQ ID NO: 15, and the FG loop comprises SEQ ID NO: 16, wherein the subject has moderate to severe systemic disease activity as determined by a European League Against Rheumatism (EULAR) Sjogren’s Syndrome Disease Activity Index (ESSDAI) of > 5.

[0554] 5. The use of embodiment 4, wherein the subject is administered at least 3 loading doses each of 3000 mg prior to the administration once every 12 weeks.

[0555] 6. The use of embodiment 5, wherein the at least 3 loading doses are administered at week 0, week 4, and week 12.

[0556] 7. Use of a Tn3 scaffold for the manufacture of a medicament for the treatment of Sjogren’s Syndrome (SS) in a subject in need thereof, wherein the medicament is formulated for administration at a dose of 1500 mg once every 4 weeks, wherein the Tn3 scaffold comprises a CD40L specific monomeric subunit, wherein the CD40L specific monomeric subunit comprises seven beta strands designated A, B, C, D, E, F, and G and six loop regions designated AB, BC, CD, DE, EF, and FG, wherein the AB loop comprises SEQ ID NO: 11, the BC loop comprises SEQ ID NO: 12, the CD loop comprises SEQ ID NO: 13, the DE loop comprises SEQ ID NO: 14, the EF loop comprises SEQ ID NO: 15, and the FG loop comprises SEQ ID NO: 16, wherein the subject has a moderate to severe symptom status defined by an ESSPRI score > 5 and low systemic disease activity defined by an ESSDAI score < 5, and wherein following administration the subject has a reduced Sjogren’s Syndrome Patient Reported Index Assessment Diary (DASPRI) score.

[0557] 8. The use of embodiment 7, wherein the subject is administered at least 3 loading doses each of 1500 mg prior to the once every 4 weeks dosing.

[0558] 9. The use of embodiment 8, wherein the at least 3 loading doses are administered at week 0, week 2, and week 4.

[0559] 10. Use of a Tn3 scaffold for the manufacture of a medicament for the treatment of Sjogren’s Syndrome (SS) in a subject in need thereof, wherein the medicament is formulated for administration at a dose of 3000 mg once every 12 weeks, wherein the Tn3 scaffold comprises a CD40L specific monomeric subunit, wherein the CD40L specific monomeric subunit comprises seven beta strands designated A, B, C, D, E, F, and G and six loop regions designated AB, BC, CD, DE, EF, and FG, wherein the AB loop comprises SEQ ID NO: 11, the BC loop comprises SEQ ID NO: 12, the CD loop comprises SEQ ID NO: 13, the DE loop comprises SEQ ID NO: 14, the EF loop comprises SEQ ID NO: 15, and the FG loop comprises SEQ ID NO: 16, wherein the subject has a moderate to severe symptom status defined by an ESSPRI score > 5 and low systemic disease activity defined by an ESSDAI score < 5, and wherein following administration the subject has a reduced Sjogren’s Syndrome Patient Reported Index Assessment Diary (DASPRI) score.

[0560] 11. The use of embodiment 10, wherein the subject is administered at least 3 loading doses each of 3000 mg prior to the once every 12 weeks administration.

[0561] 12. The use of embodiment 11, wherein the at least 3 loading doses are administered at week 0, week 4, and week 12.

[0562] 13. The use of any one of embodiments 1-5, wherein the subject has an ESSDAI score of 5-7, 5-10, 5-13, or 10-13 prior to administration of the Tn3 scaffold.

[0563] 14. The use of any one of embodiments 1-6, wherein the ESSDAI score is reduced.

[0564] 15. The use of embodiment 14, wherein the ESSDAI score is reduced by at least 1, 2, 3, 4, 5, 6, or 7 points.

[0565] 16. The use of embodiment 15, wherein the ESSDAI score is reduced by at least 6 points.

[0566] 17. The use of any one of embodiments 15-16, wherein the ESSDAI score is reduced 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 first loading dose compared to the baseline ESSDAI score.

[0567] 18. The use of embodiment 17, wherein the ESSDAI score is reduced 11 months after administration of the first loading dose.

[0568] 19. The use of any one of embodiments 7-18, wherein the subject has improved salivary gland function about 3 weeks, 1 month, 2 months, or 4 months after administration of the Tn3 scaffold.

[0569] 20. The use of embodiment 19, wherein salivary gland function is determined by complete stimulated saliva flow.

[0570] 21. The use of any one of embodiments 9-20, wherein the ESSPRI score is reduced by at least about 1.5, 2, 3, 4, or 5 points after administration of the loading dose.

[0571] 22. The use of any one of embodiments 7-21, wherein the DASPRI score is reduced 2 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months after the administration.

[0572] 23. The use of any of embodiments 22, wherein the DASPRI score is reduced by at least about 5, 10, 15, or 20 points after administration of the loading dose.

[0573] 24. The use of any of embodiments 1-23, wherein administration of the Tn3 scaffold is effective to reduce the subject’s baseline score of tender and swollen joint counts after administration.

[0574] 25. The use of any of embodiments 1-24, wherein administration of the Tn3 scaffold is effective to reduce the subject’s baseline score of the Short Form 36 (SF-36) Health Survey after administration.

[0575] 26. The use of any of embodiments 1-25, wherein administration of the Tn3 scaffold is effective to improve the subject’s baseline score, wherein the baseline score is selected from the group consisting of: Functional Assessment of Chronic Illness Therapy Fatigue Scale (FACIT-Fatigue), PROMIS Fatigue Short Form 10a, Ocular Surface Disease Index (OSDI), EQ-5D-5L, and Patient Global Impression-Severity (PGIS).

[0576] 27. The use of any of embodiments 1-26, wherein administration of the Tn3 scaffold is effective to reduce baseline levels of inflammatory markers after administration, and wherein the markers are selected from the group consisting of: immunoglobulin, beta-2 microglobulin, C-reactive protein, and combinations thereof.

[0577] 28. The use of any of embodiments 1-27, wherein administration of the Tn3 scaffold is effective to reduce baseline levels of biomarkers, and wherein the biomarkers are selected from the group consisting of: plasma soluble CD40L, Ki67+CD27+ memory B cells, CD19, CD20, CD27, CD38, CD138, CD11c bright / high B cells, CD3, CD4, CD8, Tfh cells, serum CXCL13, rheumatoid factor, anti-SSA autoantibodies (i.e., anti-Ro autoantibodies), anti-SSB autoantibodies (i.e., anti-La autoantibodies), and combinations thereof.

[0578] 29. The use of any of embodiments 1-28, wherein administration of the Tn3 scaffold is effective to reduce baseline levels of disease symptoms, and wherein the disease symptoms are selected from the group consisting of: fatigue, dry mouth, dry eyes, dry vagina, pain, and combinations thereof.

[0579] 30. The use of any of embodiments 1-29, wherein the expression level of a gene associated with SS or the level of a protein encoded by the genes in the subject’s blood sample is reduced by the 48th week after administration.

[0580] 31. The use of any one of embodiments 1-30, 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, is reduced in a blood sample of the subject to week 48 after administration.

[0581] 32. The use of any one of embodiments 1-31, wherein the subject is positive for anti-Ro autoantibodies, rheumatoid factor (RF), or both anti-Ro autoantibodies and RF.

[0582] 33. The use of any one of embodiments 1-32, wherein the Tn3 scaffold is administered intravenously.

[0583] 34. The use of any one of embodiments 1-33, wherein the Tn3 scaffold comprises two CD40L- specific monomeric subunits linked in tandem.

[0584] 35. The use of embodiment 34, wherein the two CD40L-specific monomeric subunits each comprise SEQ ID NO: 3.

[0585] 36. The use of any one of embodiments 34-35, wherein the CD40L-specific monomeric subunits are linked by a linker.

[0586] 37. The use of any one of embodiments 34-36, wherein at least one CD40L-specific monomeric subunit is directly fused or conjugated to polyethylene glycol (PEG).

[0587] 38. The use of any one of embodiments 34-37, wherein at least one CD40L-specific monomeric subunit is fused or conjugated to polyethylene glycol (PEG) via a linker.

[0588] 39. The use of embodiment 38, wherein the linker comprises a peptide linker.

[0589] 40. The use of embodiment 39, wherein the linker comprises SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, or SEQ ID NO: 10.

[0590] 41. The use of any one of embodiments 34-40, wherein at least one CD40L-specific monomeric subunit is fused or conjugated to albumin.

[0591] 42. The use of embodiment 41, wherein the albumin is human serum albumin (HSA).

[0592] 43. The use of embodiment 42, wherein the HSA is a variant HSA comprising SEQ ID NO: 4.

[0593] 44. The use of any one of embodiments 1-42, wherein the Tn3 scaffold comprises SEQ ID NO: 1.

[0594] Examples

[0595] Example 1 - A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Daroxolidelp in Participants with Sjogren’s Syndrome with Moderate to Severe Systemic Disease Activity

[0596] A Phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of daroxolidelp in participants with Sjogren’s Syndrome (SS) with moderate to severe systemic disease activity is disclosed herein.

[0597] Objectives and Endpoints:

[0598] Study objectives and endpoints are presented in Table 2.

[0599] Table 2. Exemplary Study Objectives and Endpoints

[0600]

[0601]

[0602] Study Design

[0603] This study is a Phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of daroxolidelp in participants, >18 years of age, diagnosed with Sjogren’s Syndrome (SS) with moderate to severe disease activity, as defined by an EULAR Sjogren’s Syndrome Disease Activity Index (ESSDAI) score >5. The study design is provided in Figure 1 .

[0604] Individuals will undergo a screening period of up to 28 days (see Table 3) followed by randomization and treatment through Week 44 visit. Approximately 510 participants will be randomized (1:1:1) to daroxolidelp Dose 1, daroxolidelp Dose 2, or placebo:

[0605] • daroxolidelp Dose 1: intravenous (IV) 1500 mg at Week 0, Week 2, and Week 4, then every 4 weeks (Q4W) (total of 13 doses: 13 doses of daroxolidelp) (n = 170)

[0606] • Dasotical 2: 3000 mg IV at Weeks 0, 4, and 12, then every 12 weeks (Q12W) (total of 13 doses: 5 doses of Dasotical; 8 doses of placebo) (n = 170)

[0607] • Placebo (total of 13 doses: 13 doses of placebo) (n = 170)

[0608] Participants will receive randomized treatment (Dasotical or placebo) until Week 44. The primary endpoint visit is at Week 48. At the Week 44 visit, eligible participants can provide written informed consent to be screened for the Open-Label Extension (OLE) study for open-label dosing of Dasotical. Participants who do not qualify for the OLE extension or who do not wish to enroll in the OLE extension will have a final study visit at Week 56, after the last dose of study product (IP). The expected overall duration of participation in this study (including screening) for each individual is up to 420 days.

[0609] Eligible participants interested in participating in the OLE will complete participation in this Phase 3 study after completing all assessments at the Week 48 visit. The values from these Week 48 visits will be used as the baseline (Day 1) for the OLE study, and the first dose of open-label Dasotical will be administered at or around the Week 48 visit (their last visit in the Phase 3 study). All participants, including those enrolling in the OLE, will remain blinded to their treatment assignment in the Phase 3 study until completion of the Phase 3 study.

[0610] The primary objective of this study is to evaluate the effect of Dasotical on systemic manifestations of SS in participants with moderate to severe systemic disease activity. This will be assessed by evaluating the change from baseline in Week 48 ESSDAI score.

[0611] Table 3. Example Screening Procedures Timeline

[0612]

[0613] ACR = American College of Rheumatology; ANA = antinuclear antibody; APL = antiphospholipid; b-hCG = b-human chorionic gonadotropin; C = complement; ESSDAI = EULAR Sjogren’s Syndrome Disease Activity Index; ESSPRI = EULAR Sjogren’s Syndrome Patient Reported Index; EULAR = European League Against Rheumatism; HIV = human immunodeficiency virus; Ig = immunoglobulin; IGRA = interferon gamma release assay; INR = international normalized ratio; PGIS = Patient Global Impression-Severity; PTT = partial thromboplastin time; FSH = follicle-stimulating hormone; TB = tuberculosis; V = visit.

[0614] a If cryoglobulin results are delayed such that the individual cannot complete screening within 28 days, and if the ESSDAI score is at least 5 without cryoglobulin results, the individual can be considered eligible.

[0615] b A chest X-ray is not required during screening if it was performed within 12 weeks prior to the screening visit and results are available.

[0616] Study Population

[0617] Inclusion Criteria

[0618] To be included in this study, an individual can meet all of the following criteria:

[0619] 1. Adult, > 18 years of age at the time of informed consent.

[0620] 2. Diagnosed with SS by meeting the 2016 American College of Rheumatology (ACR) / EULAR Classification Criteria.

[0621] 3. ESSDAI score > 5 at screening.

[0622] 4. Positive for anti-Ro autoantibodies, or rheumatoid factor (RF), or both at screening.

[0623] 5. Fertile women who have sexual intercourse with a male partner who is not sterilized must use a highly effective method of contraception from the time of signing the informed consent form (ICF) and must agree to continue using such preventive measures until the end of the study; cessation of contraception thereafter should be discussed with the responsible physician. Highly effective methods of contraception include:

[0624] a. Combined (containing estrogen and progestogen) hormonal contraception associated with inhibition of ovulation:

[0625] i. Oral

[0626] ii. Intravaginal

[0627] iii. Transdermal

[0628] iv. Injectable

[0629] b. Simple progestogen hormonal contraception associated with inhibition of ovulation:

[0630] i. Oral

[0631] ii. Injectable

[0632] iii. Implantable

[0633] c. Intrauterine device

[0634] d. Intrauterine hormone release system

[0635] e. Bilateral tubal occlusion

[0636] f. No sperm partner (either by vasectomy or for medical reasons)

[0637] i. No sperm is a highly effective method of contraception provided the partner is the only sexual partner of a woman of childbearing potential and no sperm has been confirmed. If not, another highly effective method of contraception should be used. The spermatogenic cycle is approximately 90 days.

[0638] g. Sexual abstinence

[0639] i. Sexual abstinence is considered a highly effective method only if it is the preferred and usual lifestyle of the participant and the participant agrees to avoid sexual intercourse with a member of the opposite sex from screening until the end of the study visit. Periodic abstinence, coitus reservatus, and withdrawal method are not acceptable methods of contraception. The (woman of childbearing potential) female partner of a male study participant should be advised to use a highly effective method of contraception other than barrier methods.

[0640] 1. A woman of childbearing potential is defined as a woman who has not undergone surgical sterilization (surgical sterilization includes bilateral tubal ligation, bilateral oophorectomy, or hysterectomy) or a woman who is not postmenopausal (defined as 12 months of amenorrhea in the absence of other identifiable medical reasons).

[0641] 2. A vasectomized partner is a highly effective method of contraception provided the partner is the only sexual partner of a woman of childbearing potential participating in the trial and the vasectomized partner has received a medical evaluation of the success of the surgery.

[0642] 6. A non-sterilized male participant who has sexual intercourse with a woman of childbearing potential must use a condom with a spermicide and avoid donating fresh unwashed semen from Day 1 until the end of the study. The female partner should also be informed of the benefits of using a highly effective method of contraception as condoms can break or leak.

[0643] 7. Participants are vaccinated against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at least 2 weeks prior to screening in accordance with current local authority guidelines, if any. Initial or subsequent COVID-19 vaccine administration is permitted during the study provided it is not administered during the screening period or within one week after dose 1; if a vaccine is to be administered during this window, screening should be delayed to complete the vaccination.

[0644] 8. Meet all of the following tuberculosis (TB) criteria:

[0645] a. No history of latent or active TB disease prior to screening, except for documented completion of appropriate local treatment for latent TB.

[0646] b. No signs or symptoms suggestive of active TB in medical history or physical examination.

[0647] c. No close contact (< 4 hours / week or living in the same household or in a house where the person with active TB is a regular visitor) with a person with active TB in the recent past (< 12 weeks of screening).

[0648] d. Negative interferon gamma release assay (IGRA) test for TB at screening, unless previously treated according to inclusion criterion 8(a). Subjects with an indeterminate test result can be retested, but are excluded if the repeat test is also indeterminate.

[0649] e. Chest radiograph (obtained during the screening period or at any time within 12 weeks prior to screening) without evidence of current active TB or other infection, or prior TB, malignancy, or clinically significant abnormalities suggestive of active processes (except for SS).

[0650] Exclusion Criteria

[0651] An individual is not eligible for this study if he or she meets any of the following criteria:

[0652] 1. Individuals with a confirmed medical history of deep venous thrombosis, pulmonary embolism, or arterial thromboembolism within 2 years of screening.

[0653] 2. History of or presence of associated polymyositis or dermatomyositis, or systemic sclerosis.

[0654] 3. Active malignancy or history of malignancy within the past 5 years, except for:

[0655] a. Cervical carcinoma in situ treated with curative therapy > 12 months prior to screening and apparent success; or,

[0656] b. Presumed curative therapy followed by a skin basal cell carcinoma.

[0657] 4. Individuals who are pregnant, or breastfeeding, or planning to become pregnant during the study.

[0658] 5. Individuals who are positive for hepatitis B or human immunodeficiency virus (HIV) infection or have received treatment. Positive for hepatitis B infection at screening is defined as: (1) positive for hepatitis B surface antigen; or (2) positive for hepatitis B core antibody. Individuals who are positive for hepatitis C or have a history of treatment for hepatitis C are excluded unless they have a confirmed, sustained viral response to an antiviral medication approved for the treatment of hepatitis C, defined as undetectable viral levels of hepatitis C RNA at least 24 weeks after completion of treatment. Individuals with advanced fibrosis or cirrhosis due to hepatitis C are not to be enrolled.

[0659] 6. Individuals who are positive for SARS-CoV-2 at the day of randomization, or have symptoms suggestive of SARS-CoV-2 at randomization, or have had a significant exposure to coronavirus disease 2019 (COVID-19) within 10 days prior to randomization. Individuals with COVID-19 or COVID-19 exposure can be delayed in randomization for 10 days and are randomized once recovered; otherwise, they will need to be rescreened.

[0660] 7. Individuals with the following characteristics:

[0661] a. History of more than one episode of herpes zoster and / or any opportunistic infection within the past 12 months (see Table 4), with the exception of non-invasive herpes simplex at any site, oral candidiasis, vaginal candidiasis, or cutaneous fungal infections, which are allowed within the previous 12 months unless of unusual severity.

[0662] b. Active infection requiring systemic therapy at the time of screening or up to randomization, or history of more than 2 infections requiring IV antibiotics within 12 months prior to screening.

[0663] 8. Individuals with a known history of severe hypersensitivity or reaction to any component of the IP formulation or to any other biologic therapy.

[0664] 9. Individuals with any severe cardiovascular, respiratory, endocrine, gastrointestinal, hematological, neurological, psychiatric, or systemic disorder, or any other condition that, in the investigator’s opinion, would place the individual at unacceptable risk of complications, interfere with the evaluation of the IP.

[0665] 10. Individuals who cannot or are unwilling to comply with protocol requirements (e.g., active drug, or alcohol abuse, or for other reasons).

[0666] 11. Individuals who received a live (attenuated) vaccine within 4 weeks prior to randomization or who plan to receive a live vaccine during the participation in the study. Non-live vaccines are allowed during the study (see Inclusion Criteria 7 for COVID-19 vaccines); however, for subjects who plan to receive a vaccine within one month after dose 1, completion of vaccination should be considered prior to starting dosing.

[0667] 12. Last administration of an experimental or investigational biologic or oral medication (other than those listed in Exclusion Criteria 16) <6 months prior to screening.

[0668] 13. Individuals who received prior treatment with any biologic B-cell depleting therapy (e.g., rituximab, ocrelizumab, inebilizumab, ofatumumab, or ublituximab) within 12 months prior to screening or other B-cell targeted therapy (e.g., belimumab) within <3 months.

[0669] 14. Received injectable corticosteroids (including intra-articular [IA] or intramuscular [IM]) or treatment with oral prednisone or equivalent at a dose >10 mg / day within 6 weeks prior to randomization. Concomitant treatment with oral corticosteroids and <10 mg / day prednisone or equivalent for potential SS, rheumatoid arthritis (RA), or systemic lupus erythematosus (SLE) is allowed, provided the dose is stable for >2 weeks prior to screening through randomization (Day 1) and is expected to remain stable for the duration of the treatment period. Inhaled, intranasal, or topical corticosteroids are allowed, provided the dose is expected to be stable during the study.

[0670] 15. Individuals who were treated with systemic corticosteroids for indications other than SS, RA, and SLE for a total of >2 weeks within 6 months prior to screening.

[0671] 16. Use of the following medications:

[0672] a. Antimalarials (e.g., chloroquine, hydroxychloroquine, quinacrine) if they have been initiated or if the dose has been changed within 8 weeks prior to screening.

[0673] b. Methotrexate (MTX) if the dose is >25 mg / week or if there has been any change or initiation of a new dose within 4 weeks prior to screening.

[0674] c. Azathioprine if the dose is >150 mg / day or if there has been any change in dose or initiation of a new dose within 4 weeks prior to screening.

[0675] d. Leflunomide if the dose is >20 mg / day or if there has been any change or initiation of a new dose within 4 weeks prior to screening.

[0676] e. Myfortic (MMF) if dose > 2 g / day, or if there have been any changes or initiation of a new dose within 4 weeks prior to screening.

[0677] f. Any other disease-modifying antirheumatic drug (DMARD), immunosuppressant or anti-proliferative agent if the last dose was taken within:

[0678] i. 4 weeks prior to screening; or

[0679] ii. 5 half-lives of the drug in question (if longer than 4 weeks).

[0680] g. Any medication that the investigator believes will interfere with the evaluation of the IP or the interpretation of the study results.

[0681] h. Any increase or initiation of a new dose of Restasis® cyclosporine eye drops or Xiidra® lifitegrast, eye drops within 2 weeks prior to screening.

[0682] i. If taken, no adjustment of the above medications is allowed during the screening period, and the medications are expected to remain stable throughout the study duration.

[0683] 17. Individuals who have received prior treatment with an anti-CD40L compound at any time prior to screening.

[0684] 18. Individuals who have blood tests at screening that are any of:

[0685] a. Aspartate aminotransferase (AST) > 2 x upper limit of normal (ULN)

[0686] b. Alanine aminotransferase (ALT) > 2 x ULN

[0687] c. Total bilirubin (TBL) > 2 x ULN, unless Gilbert’s syndrome is documented in the medical history

[0688] d. Hemoglobin < 75 g / L

[0689] e. Neutrophils < 0.8 x 10 9 / L

[0690] f. Lymphocytes < 0.8 x 10 9 / L

[0691] g. Platelets < 100 x 10 9 / L

[0692] h. International normalized ratio (INR) of prothrombin time > 1.3 x ULN

[0693] Table 4. Exemplary infections that meet exclusion criteria

[0694]

[0695]

[0696] CMV = Cytomegalovirus; EBV = Epstein-Barr virus; HBV = Hepatitis B virus; HCV = Hepatitis C virus; TB = Tuberculosis. Source: Winthrop et al. 2015.

[0697] a Generally does not occur in the absence of immunosuppression, but its presence indicates a potential or likely alteration in host immunity.

[0698] b May occur in patients without recognized forms of immunosuppression, but its presence indicates a potential or likely alteration in host immunity.

[0699] c Currently, there is a lack of published data, but experts believe that the risk can be elevated in the case of biologic therapies.

[0700] Lifestyle considerations

[0701] Meat and dietary restrictions: There are no dietary or fasting restrictions during the study.

[0702] Activities: There are no activity restrictions for this study.

[0703] Criteria for temporary delay of randomization

[0704] Individuals with COVID-19 or with COVID-19 exposure can delay randomization for 10 days and be randomized once recovered; otherwise, they can need to be rescreened (see exclusion criterion 11).

[0705] Study interventions and concomitant therapies

[0706] Study product administered

[0707] Administration of the IP will be performed by blinded administrators. Preparation of the IP will be performed by uninvolved, blinded pharmacists / IP administrators or study site staff. Prepared IP must be covered with a bag before being provided to the blinded administrator.

[0708] Table 5 includes a description of the IP used in this study, its dosage formulation, unit dose size, dose levels, route of administration, use, traceability, and packaging.

[0709] Table 5. Exemplary description of the IP used in this study

[0710]

[0711] Blinding and masking

[0712] Blinding

[0713] Participants will be randomized in a 1 : 1 : 1 ratio into study groups (see Table 6).

[0714] Table 6. Exemplary Study Groups

[0715]

[0716] IV = intravenous; Q4W = once every 4 weeks; Q12W = once every 12 weeks.

[0717] Continued access to IP after study completion

[0718] Participants will receive randomized treatment (daroxafinib or placebo) until Week 44. The primary endpoint visit is at Week 48. At the Week 44 visit, eligible participants can be screened for the OLE study to receive open-label dosing of daroxafinib that begins after completion of this study at Week 48.

[0719] The study evaluation schedule during the treatment period is provided in Table 7.

[0720] Prior therapy and concomitant therapy

[0721] Any medications or vaccines (including over-the-counter or prescription medications, recreational drugs, vitamins, and / or herbal supplements) or other specific categories of interest that the participant has received within the previous 12 months, is receiving at the time of enrollment, or will receive during the study must be recorded with:

[0722] 1. Name and indication

[0723] 2. Reason for use

[0724] 3. Date of administration, including start and end dates

[0725] 4. Dose information, including dose and frequency

[0726] Allowed concomitant therapy

[0727] All concomitant medications taken by the participant during the study (from Visit 1 onward) will be recorded. All medications required for the participant’s health are allowed. Prohibited medications are medications that can require discontinuation of IP. Participants must continue to complete the study even if a prohibited medication is taken.

[0728] Allowed medications are any needed medications that are not explicitly prohibited by the protocol during the clinical study period (i.e., from Visit 1 through the end of the safety follow-up period).

[0729] Prohibited concomitant medications

[0730] Prohibited medications are considered potentially confounding, unsafe, or both. Prohibited medications are:

[0731] • Medications that should be avoided if possible because they can confound the interpretation of the data.

[0732] • Medications that are potentially unsafe to co-administer with the IP and would result in discontinuation of the IP.

[0733] Participants who discontinue the IP can remain in the study and...

Claims

1. A method of treating Sjogren's syndrome (SS) in a subject in need thereof, the method comprising: administering a Tn3 scaffold, wherein the Tn3 scaffold comprises a CD40L specific monomeric subunit, wherein the CD40L specific monomeric subunit comprises seven beta strands designated A, B, C, D, E, F, and G and six loop regions designated AB, BC, CD, DE, EF, and FG, wherein the AB loop comprises SEQ ID NO: 11, the BC loop comprises SEQ ID NO: 12, the CD loop comprises SEQ ID NO: 13, the DE loop comprises SEQ ID NO: 14, the EF loop comprises SEQ ID NO: 15, and the FG loop comprises SEQ ID NO: 16, wherein the Tn3 scaffold is administered at a dose of about 1500 mg once every 4 weeks, wherein the subject has a moderate to severe symptom status defined by an ESSPRI score > 5, has a low systemic disease activity defined by an ESSDAI score < 5, and wherein following administration the subject has a reduced dryness symptoms patient reported index assessment diary (DASPRI) score.

2. The method of claim 1, wherein the subject is administered at least 3 loading doses of 1500 mg each prior to dosing every 4 weeks.

3. The method of claim 2, wherein the at least 3 loading doses are administered at weeks 0, 2, and 4.

4. A method of treating Sjogren's syndrome (SS) in a subject in need thereof, the method comprising: administering a Tn3 scaffold, wherein the Tn3 scaffold comprises a CD40L specific monomeric subunit, wherein the CD40L specific monomeric subunit comprises seven beta strands designated A, B, C, D, E, F, and G and six loop regions designated AB, BC, CD, DE, EF, and FG, wherein the AB loop comprises SEQ ID NO: 11, the BC loop comprises SEQ ID NO: 12, the CD loop comprises SEQ ID NO: 13, the DE loop comprises SEQ ID NO: 14, the EF loop comprises SEQ ID NO: 15, and the FG loop comprises SEQ ID NO: 16, wherein the Tn3 scaffold is administered at a dose of about 3000 mg once every 12 weeks, wherein the subject has a moderate to severe symptom status defined by an ESSPRI score > 5, has a low systemic disease activity defined by an ESSDAI score < 5, and wherein following administration the subject has a reduced dryness symptoms patient reported index assessment diary (DASPRI) score.

5. The method of claim 4, wherein the subject is administered at least 3 loading doses of 3000 mg each prior to dosing every 12 weeks.

6. The method of claim 5, wherein the at least 3 loading doses are administered at weeks 0, 4, and 12.

7. The method of any one of claims 1-6, wherein following administration of the Tn3 scaffold, the subject has improved salivary gland function about 3 weeks, 1 month, 2 months, or 4 months after the administration.

8. The method of claim 7, wherein salivary gland function is determined by complete stimulated saliva flow.

9. The method of any one of claims 1-8, wherein the ESSPRI score decreases after the application.

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

11. The method of any one of claims 1-10, wherein the DASPRI score decreases at 2 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months after the application.

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

13. The method of any one of claims 1-12, wherein the application of the Tn3 stent effectively reduces the baseline score of tender and swollen joint counts in the subject after application.

14. The method of any one of claims 1-13, wherein application of the Tn3 scaffold is effective in reducing the baseline score of the Short Form 36 (SF-36) health survey after application of the subject.

15. The method of any one of claims 1-14, wherein application of the Tn3 scaffold effectively improves the subject’s baseline score, wherein these baseline scores are selected from the group consisting of: Functional Assessment of Chronic Disease Treatment Fatigue Scale (FACIT-Fatigue), PROMIS Fatigue Summary 10a, Ocular Surface Disease Index (OSDI), EQ-5D-5L, and Patient Global Impression-Severity (PGIS).

16. The method of any one of claims 1-15, wherein application of the Tn3 scaffold effectively reduces baseline levels of inflammatory markers after application, and wherein these markers are selected from the group consisting of immunoglobulins, β-2 microglobulins, C-reactive protein, and combinations thereof.

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

18. The method of any one of claims 1-17, wherein the application of the Tn3 scaffold effectively reduces the baseline level of disease symptoms, and wherein the disease symptoms are selected from the group consisting of: fatigue, dry mouth, dry eyes, vaginal dryness, pain, and combinations thereof.

19. The method of any one of claims 1-18, wherein by week 48 after administration, the expression level of SS-related genes or the level of proteins encoded by those genes in the subject's blood sample is reduced.

20. The method of any one of claims 1-19, wherein the subject has a reduced level of B cells selected from the group consisting of CD27+ memory B cells, marginal zone B cells, plasmablasts, plasma cells, and combinations thereof in a blood sample of the subject at week 48 following the administration.

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

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

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

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

3.

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

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

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

28. The method of claim 27, wherein the linker comprises a peptide linker.

29. The method of claim 28, wherein the linker comprises SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, or SEQ ID NO:

10.

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

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

32. The method of claim 31, wherein the HSA is a variant HSA comprising SEQ ID NO:

4.

33. The method of any one of claims 1-32, wherein the Tn3 scaffold comprises SEQ ID NO:

1.

34. The method of any one of claims 1-33, wherein the subject has a coexisting autoimmune indication.

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

36. The method of claim 34, wherein the coexisting autoimmune indication is rheumatoid arthritis.

37. The method of claim 34, wherein the coexisting autoimmune indication is systemic lupus erythematosus.

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