WO2025248134A1

WO2025248134A1 - Treatment methods comprising administration of modified cd154 antibodies

Info

Publication number: WO2025248134A1
Application number: PCT/EP2025/065085
Authority: WO
Inventors: Seth Lederman; Bruce DAUGHERTY
Original assignee: Tonix Pharma Ltd Ireland
Current assignee: Tonix Pharma Ltd Ireland
Priority date: 2024-05-31
Filing date: 2025-05-30
Publication date: 2025-12-04
Anticipated expiration: 2026-11-30

Abstract

The present disclosure relates to methods of treating or preventing transplant rejection and/or treating immune-related diseases or disorders by administering to a subject anti-CD154 antibodies with reduced effector functions. Specifically, the disclosure relates to dosage regimens of the anti-CD154 antibodies with reduced effector function for the treatment or prevention of transplant rejection and/or the treatment of immune related diseases.

Description

TREATMENT METHODS COMPRISING ADMINISTRATION OF MODIFIED CD 154 ANTIBODIES

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and benefit of United States Provisional Application No. 63/654,530, filed May 31, 2024; United States Provisional Application No. 63/754,414, filed February 5, 2025; and United States Provisional Application No. 63/758,933, filed February 14, 2025, the contents of each application are hereby incorporated by reference in their entireties.

SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on May 30, 2025, is named 104545-0126-WOl-SL.xml and is 26,857 bytes in size.

FIELD OF THE DISCLOSURE

[0003] The present disclosure relates to methods of treating or preventing transplant rejection and/or treating immune-related diseases or disorders by administering to a subject anti-CD154 antibodies with reduced effector functions. Specifically, the disclosure relates to dosage regimens of the anti-CD154 antibodies with reduced effector function for the treatment or prevention of transplant rejection and/or the treatment of immune related diseases.

BACKGROUND OF THE DISCLOSURE

[0004] CD154 (also known as CD40 ligand, CD40L, gp39, TNF-related activation protein (TRAP), 5c8 antigen, T-BAM) is a protein primarily expressed on activated CD4+ T cells and is recognized as the molecular basis for T cell helper function (Lederman, S., etal. J. Exp. Med. 175: 1091-1101 (1992). CD154 is a member of the TNF superfamily of molecules and is functionally expressed as a homotrimer. Some of the CD 154 units, however, have shortened peptide chains, such that CD 154 trimers can be considered heterotrimers of elements all encoded by the CD154 gene (Karpusas M, et al. Structure. 3(10): 1031-9 (1995); Hsu YM, et al. J Biol Chem. 272(2):911-5 (1997)). CD154 binds to CD40 on antigen-presenting cells (APC), which leads to many effects depending on the target cell type. The primary binding partner for CD154 is CD40, although other binding partners aM[32 (Mac-1), ct.5|31 integrin and allbp3 have been described (El Fakhry Y, et al. JBiol Chem. 287: 18055 (2012); WolfD, etal. Circ Res. 109: 1269 (2011); Michel NA, et al Front Cardiovasc Med. 4:40 (2017)). CD154 acts as a costimulatory molecule for B cells and affects the function of CD4+ T follicular helper cells (TFH cells). On TFH cells, CD 154 promotes B cell maturation and function by engaging CD40 on the B cell surface and thereby facilitating cell-cell communication in a humoral immune response. CD40 triggering by CD 154 stimulates adaptive immune system processes in B cells including immunoglobulin class switch recombination and somatic hypermutation (Lederman S, et al. Curr Opin Hematol. 3(l):77-86 (1996)). Absence of CD154, for example, in the X-linked Hyper IgM syndrome, leads to deficiencies in the formation of germinal centers, class switch recombination and antibody affinity maturation. (Webster EA, et al. Arthritis Rheum. 42(6): 1291-6 (1999)). The CD40-CD154 interaction is involved in normal T- B cell interactions, including increased co-stimulation, T-cell priming, cytokine production, antibody-class switching and affinity maturation, and antibody production (Lederman, S., et al. J. Exp. Med. 175: 1091-1101 (1992); Lederman, S., et al., Journal of Immunol. 149:3817- 3826 (1992); Lederman, S., et al., Journal of Immunol. 152:2163 (1994); Cleary, A.M., et al., Journal of Immunol., 155:3329-3337 (1995); Muramatsu, MK et a/. Cell 102: 553 (2000); Xu Y and Song G, J. Biomed Sci. l l(4):426-38 (2004); Quezada SA et al., Annu Rev Immunol. 22:307-28 (2004); and U.S. Patent Nos. 5,474,771; 5,933,816; 6,331,615; 6,340,459; 6,403,091; 6,451,310; 6,455,044; 6,592,868; 6,610,294; 6,793,924; 7,070,777; and 9,765,150).

[0005] CD154 also interacts with CD40 on activated endothelial cells (Yellin MJ et al., J.

Exp. Med 182: 1857-1864 (1995)), activated fibroblasts (Yellin, MJ et al. J Leukoc Biol. 58:209-216 (1995)), in other cell types and in many cancers (Paulie, S, et al. Cancer Immunol Immunother, 20, 23-8 (1985)). Supernatants of severe acute respiratory syndrome-associated coronavirus (SARS-CoV) infected human lung epithelial Calu-3 cells and induce CD40 on dendritic cells (Yoshikawa T, et al. J. Virol. 83(7): 3039-3048 (2009)). In the retina, during inflammation, CD40 is expressed on endothelial cells, Muller glia (macroglia in the retina), microglia, ganglion cells, and retinal pigment epithelial cells (Subauste, CS, Front Immunol 10:2958 (2019); Portillo J-AC, et al. J Immunol. 181 :8719-26 (2008); Portillo J-AC, et al. Diabetologia. 57:2222-31(2014); Portillo J-AC, et al., Mol Vis. 15: 1383-9 (2009)). The roles of CD 154 in an immune response are normally tightly regulated in tissues over time. Dysfunctional immune responses can occur with abnormal CD 154 expression and function in certain tissues and at certain times, contributing to syndromes such as acute respiratory distress syndrome (ARDS), autoimmune diseases, vasculopathies and the promotion of cancers.

[0006] The soluble form of CD 154 (sCD154), which results from the shedding of membranebound CD 154, plays a role in the production of proinflammatory cytokines and has been linked to various autoimmune and vascular disorders (Yellin, MJ, et al., J Immunol. 152:598 (1994); Yacoub D et al., J Biol Chem. 288(50):36083-93 (2013)). Activated platelets produce CD154 and platelet derived CD 154, particularly soluble CD 154, has been linked to pathology. (Henn V, et al. Nature 391 :591-594 (1998); Xu H, et al. Transplantation. 72(11): 1858-61. (2001); Danese S, et al. Gut. 52(10): 1435-41. (2003); and Charafeddine AH, et al. Am J Transplant. 12(11):3143-51 (2012)).

[0007] Blockade of the CD40/CD154 signal is a potential immunomodulatory strategy for T- cell-mediated diseases, e.g., refractory immune thrombocytopenic purpura and multiple sclerosis, through selective suppression of autoreactive T and B cells to platelet antigens (Kuwana et al, Blood (2004) 103 (4): 1229-1236 and Fadul et al Neurol Neuroimmunol Neuroinflamm. 2021 Nov; 8(6): el096.). The use of CD154 antibodies has been useful for the treatment of several immune disorders, however, the half-life of many of the available antibodies are short-lived and require multiple infusions. TDR15526 study, a Phase 1, doubleblind, randomized, parallel design, placebo-controlled multiple ascending dose study investigating 5 dose levels of SAR441344 or placebo controls in healthy adult participants. SAR441344 was administered at a dose between 150 and 2100 mg was administered SC as 3 doses q2w in healthy male and female adult participants were safe and well tolerated. Mean terminal half-lives were estimated at 22 days at the lowest dose of 150 mg and between 29 and 33 days for doses ranging from 300 mg to 2100 mg (Vermersch et al. N Engl J Med 2024;390:589-600).

[0008] U.S. Patent No. 9,765,150 also described BMS-986003 (BMS-2h572-633-CT), which shares the same amino acid sequence as BMS-986004, except for a non-native glycine residue at its amino-terminus. BMS-986003, however, induced anti-drug antibodies (ADA) in treated monkeys. The ADA were directed to the Fab (non-Fc) portion of the molecule and these antibodies were shown to block the binding of BMS-986003 to CD 154 suggesting the ADA may be neutralizing. In addition, these ADA resulted in increased clearance of BMS- 986003 in several monkeys. In contrast, a chimeric murine 5c8 human IgGl chimeric antibody had expected long plasma half-life. (U.S. Patent No. 9,765,150). [0009] While BMS-986004 demonstrated efficacy in an immune thrombocytopenic purpura (ITP) clinical trial, the pharmacokinetic profile may be suboptimal (NCT02273960; “Study to Evaluate Safety and Efficacy in Adult Subjects With ITP (ITP)”; results accessed July 1, 2019).

[0010] To retain the efficacy of the parent 5c8-based molecule, TNX-1500 was developed by engineering the Fc region of IgG4 to decrease FcyRIIa binding. See, e.g., WO 2021/001458. Preclinical studies have shown that TNX-1500 maintains the activity of first-generation monoclonal antibodies (mAbs), yet with reduced risk of thrombotic complications. Further, TNX-1500 was found to prolong nonhuman primate renal allograft survival (see, e.g., Lassiter American. Journal of Transplanlalion 2 (?>) 1171-1181 (2023). Previous pharmacokinetic (PK) modeling indicated that the half-life of half-life of TNX-1500 in cynomolgus monkeys appeared to be approximately 14 days. The half-life in humans, however, was previously unknown. Increases in the half-life of antibodies have several benefits including reductions in frequency in dosing. Indeed, patient compliance and quality of life can increase with the reduction of frequency of dosing. Accordingly, there is a need in the art to establish protocols that increase PK values and allow for less frequent dosing (e.g., once a month instead of once every two weeks).

SUMMARY OF THE DISCLOSURE

[0011] The present disclosure relates to, among other things, methods of treating or preventing transplant rejection and/or methods of treating immune related diseases and disorders with modified anti-CD154 antibodies.

[0012] A first aspect of the present disclosure provides a method of treating or preventing a transplant rejection of a donor tissue engrafted in a transplant recipient comprising administrating to the transplant recipient a therapeutically effective amount of an anti-CD154 antibody, wherein the antibody comprises a humanized variable domain, wherein the variable domain comprises a heavy chain variable region (VH) and a light chain variable region (VL), and wherein the VH is operably linked to a human Fc region derived from IgG4 and comprising S228P and L235A amino acid modifications; wherein the VH comprises (a) a heavy chain CDR1 having the amino acid sequence of SEQ ID NO: 3, (b) a heavy chain CDR2 having the amino acid sequence of SEQ ID NO: 4, and (c) a heavy chain CDR3 having the amino acid sequence of SEQ ID NO: 5; and wherein the VL comprises (a) a light chain CDR1 having the amino acid sequence of SEQ ID NO: 6, (b) a light chain CDR2 having the amino acid sequence of SEQ ID NO: 7, and (c) a light chain CDR3 having the amino acid sequence of SEQ ID NO: 8.

[0013] A second aspect of the present disclosure provides an anti-CD154 antibody for use in treating or preventing a transplant rejection of a donor tissue engrafted in a transplant recipient, wherein the antibody comprises a humanized variable domain, wherein the variable domain comprises a heavy chain variable region (VH) and a light chain variable region (VL), and wherein the VH is operably linked to a human Fc region derived from IgG4 and comprising S228P and L235A amino acid modifications; wherein the VH comprises (a) a heavy chain CDR1 having the amino acid sequence of SEQ ID NO: 3, (b) a heavy chain CDR2 having the amino acid sequence of SEQ ID NO: 4, and (c) a heavy chain CDR3 having the amino acid sequence of SEQ ID NO: 5; and wherein the VL comprises (a) a light chain CDR1 having the amino acid sequence of SEQ ID NO: 6, (b) a light chain CDR2 having the amino acid sequence of SEQ ID NO: 7, and (c) a light chain CDR3 having the amino acid sequence of SEQ ID NO: 8.

[0014] A third aspect of the present disclosure provides the use of an anti-CD154 antibody in the manufacture of a medicament for treating or preventing a transplant rejection of a donor tissue engrafted in a transplant recipient, wherein the antibody comprises a humanized variable domain, wherein the variable domain comprises a heavy chain variable region (VH) and a light chain variable region (VL), and wherein the VH is operably linked to a human Fc region derived from IgG4 and comprising S228P and L235A amino acid modifications; wherein the VH comprises (a) a heavy chain CDR1 having the amino acid sequence of SEQ ID NO: 3, (b) a heavy chain CDR2 having the amino acid sequence of SEQ ID NO: 4, and (c) a heavy chain CDR3 having the amino acid sequence of SEQ ID NO: 5; and wherein the VL comprises (a) a light chain CDR1 having the amino acid sequence of SEQ ID NO: 6, (b) a light chain CDR2 having the amino acid sequence of SEQ ID NO: 7, and (c) a light chain CDR3 having the amino acid sequence of SEQ ID NO: 8.

[0015] In some embodiments of any of the above aspects, the transplant is an allogeneic transplant, autologous transplant or a xenogeneic transplant. In some embodiments of any of the above aspects, the transplant rejection is associated with a hematopoietic cell or bone marrow transplant, an allogeneic transplant of pancreatic islet cells, graft vs host disease, or a solid organ transplant. In some embodiments, the solid organ transplant is selected from the group consisting of a heart transplant, a kidney transplant, a liver transplant, a lung transplant, a pancreas transplant, a kidney-pancreas transplant, a heart-lung transplant, kidney-heart transplant, a kidney-heart-pancreas transplant, a heart-liver transplant, a heart-liver-kidney transplant, a heart-lung-kidney transplant, a heart-lung-liver transplant, a lung-kidney transplant, a lung-liver transplant, a liver-intestines-pancreas transplant, an intestines-pancreas transplant, a liver-kidney -intestines-pancreas transplant, and a kidney-intestines transplant.

[0016] A fourth aspect of the present disclosure provides a method of treating an immune- related disease comprising administrating to a subject in need of treatment a therapeutically effective amount of an anti-CD154 antibody, wherein the antibody comprises a humanized variable domain, wherein the variable domain comprises a heavy chain variable region (VH) and a light chain variable region (VL), and wherein the VH is operably linked to a human Fc region derived from IgG4 and comprising S228P and L235A amino acid modifications; wherein the VH comprises (a) a heavy chain CDR1 having the amino acid sequence of SEQ ID NO: 3, (b) a heavy chain CDR2 having the amino acid sequence of SEQ ID NO: 4, and (c) a heavy chain CDR3 having the amino acid sequence of SEQ ID NO: 5; and wherein the VL comprises (a) a light chain CDR1 having the amino acid sequence of SEQ ID NO: 6, (b) a light chain CDR2 having the amino acid sequence of SEQ ID NO: 7, and (c) a light chain CDR3 having the amino acid sequence of SEQ ID NO: 8.

[0017] A fifth aspect of the present disclosure provides an anti-CD154 antibody for use in treating an immune-related disease in a subject in need thereof, wherein the antibody comprises a humanized variable domain, wherein the variable domain comprises a heavy chain variable region (VH) and a light chain variable region (VL), and wherein the VH is operably linked to a human Fc region derived from IgG4 and comprising S228P and L235A amino acid modifications; wherein the VH comprises (a) a heavy chain CDR1 having the amino acid sequence of SEQ ID NO: 3, (b) a heavy chain CDR2 having the amino acid sequence of SEQ ID NO: 4, and (c) a heavy chain CDR3 having the amino acid sequence of SEQ ID NO: 5; and wherein the VL comprises (a) a light chain CDR1 having the amino acid sequence of SEQ ID NO: 6, (b) a light chain CDR2 having the amino acid sequence of SEQ ID NO: 7, and (c) a light chain CDR3 having the amino acid sequence of SEQ ID NO: 8.

[0018] A sixth aspect of the present disclosure provides the use of an anti-CD154 antibody in the manufacture of a medicament for treating an immune-related disease in a subject in need thereof, wherein the antibody comprises a humanized variable domain, wherein the variable domain comprises a heavy chain variable region (VH) and a light chain variable region (VL), and wherein the VH is operably linked to a human Fc region derived from IgG4 and comprising S228P and L235A amino acid modifications; wherein the VH comprises (a) a heavy chain CDR1 having the amino acid sequence of SEQ ID NO: 3, (b) a heavy chain CDR2 having the amino acid sequence of SEQ ID NO: 4, and (c) a heavy chain CDR3 having the amino acid sequence of SEQ ID NO: 5; and wherein the VL comprises (a) a light chain CDR1 having the amino acid sequence of SEQ ID NO: 6, (b) a light chain CDR2 having the amino acid sequence of SEQ ID NO: 7, and (c) a light chain CDR3 having the amino acid sequence of SEQ ID NO: 8.

[0019] In some embodiments of the above aspects, the immune-related disease is selected from the group consisting of Amyotrophic Lateral Sclerosis, Inflammatory Bowel Disease, Irritable Bowel Syndrome, Idiopathic Thrombocytopenic Purpura, Systemic Lupus Erythematosus, Lupus Nephritis, Multiple Sclerosis, Psoriasis, Rheumatoid Arthritis, Systemic Scleroderma, Interstitial Lung Disease, Atopic Dermatitis, Antiphospholipid Syndrome, Sarcoidosis, Myositis, Pneumocystis, Type 1 Diabetes, Sjogren syndrome, and Graft versus host disease. Optionally, the immune-related disease is selected from the group consisting of Systemic Lupus Erythematosus, Multiple Sclerosis, Type 1 Diabetes, and Sjogren syndrome. The immune-related disease may be Systemic Lupus Erythematosus. In some embodiments, the immune-related disease is Multiple Sclerosis. Optionally, the immune-related disease is Type 1 Diabetes. The immune-related disease may be Sjogren syndrome. In some embodiments, the Multiple Sclerosis is Secondary Progressive Multiple Sclerosis or Relapsing Remitting Multiple Sclerosis. In some embodiments, the Inflammatory Bowel Disease is Ulcerative Colitis.

[0020] In some embodiments of any of the above aspects, the human Fc region comprises the amino acid sequence of SEQ ID NO: 1 or 2. In some embodiments of any of the above aspects, the human Fc region comprises the amino acid sequence of SEQ ID NO: 1. In some embodiments of any of the above aspects, the human Fc region comprises the amino acid sequence of SEQ ID NO: 2. In some embodiments of any of the above aspects, the anti-CD154 antibody comprises a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 12 or 13. In some embodiments of any of the above aspects, the anti-CD154 antibody comprises a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 12. In some embodiments of any of the above aspects, the anti-CD154 antibody comprises a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 13. In some embodiments of any of the above aspects, the VH comprises the amino acid sequence of SEQ ID NO: 9. In some embodiments of any of the above aspects, the VL comprises the amino acid sequence of SEQ ID NO: 10. In some embodiments of any of the above aspects, the VH comprises the amino acid sequence of SEQ ID NO: 9, and the VL comprises the amino acid sequence of SEQ ID NO: 10.

[0021 ] In some embodiments of any of the above aspects, the anti-CD 154 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 14 or 15. In some embodiments of any of the above aspects, the anti-CD 154 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 14. In some embodiments of any of the above aspects, the anti-CD 154 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 15. In some embodiments of any of the above aspects, the anti- CD154 antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 16. In some embodiments of any of the above aspects, the anti-CD 154 antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 16 and a heavy chain comprising an amino acid sequence of SEQ ID NO: 14 or 15. In some embodiments of any of the above aspects, the anti-CD 154 antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 16 and a heavy chain comprising an amino acid sequence of SEQ ID NO: 14. In some embodiments of any of the above aspects, the anti-CD154 antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 16 and a heavy chain comprising an amino acid sequence of SEQ ID NO: 15.

[0022] In some embodiments of any of the above aspects, the antibody is administered at a dose selected from the group consisting of 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30mg/kg, 35mg/kg, 40 mg/kg, 45mg/kg, and 50 mg/kg. In some embodiments of any of the above aspects, the antibody is formulated to be administered at a dose selected from the group consisting of 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30mg/kg, 35mg/kg, 40 mg/kg, 45mg/kg, and 50 mg/kg. In some embodiments of any of the above aspects, the antibody is administered at a dose of 20 mg/kg. In some embodiments of any of the above aspects, the antibody is formulated to be administered at a dose for 20 mg/kg.

[0023] In some embodiments of any of the above aspects, the antibody is administered at a flat dose selected from the group consisting of 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg, and 2000 mg. In some embodiments of any of the above aspects, the antibody is formulated to be administered at a flat dose selected from the group consisting of 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg, and 2000 mg. In some embodiments of any of the above aspects, the antibody is administered at a flat dose of 1200 mg. In some embodiments of any of the above aspects, the antibody is formulated to be administered at a flat dose of 1200 mg.

[0024] In some embodiments of any of the above aspects, the antibody is administered at a frequency selected from the group consisting of Q1W, Q2W, Q3W, Q4W, Q5W and Q6W. In some embodiments of any of the above aspects, the antibody is formulated to be administered at a frequency selected from the group consisting of Q1W, Q2W, Q3W, Q4W, Q5W and Q6W. In some embodiments of any of the above aspects, the antibody is administered at a frequency of Q4W. In some embodiments of any of the above aspects, the antibody is formulated to be administered at a frequency of Q4W. In some embodiments of any of the above aspects, the antibody is administered at a frequency of once per month. In some embodiments of any of the above aspects, the antibody is formulated to be administered at a frequency of once per month. In some embodiments of any of the above aspects, the antibody is administered at a frequency of Q4W at a dose of 20 mg/kg. In some embodiments of any of the above aspects, the antibody is formulated to be administered at a frequency of Q4W at a dose of 20 mg/kg. In some embodiments of any of the above aspects, the antibody is administered at a frequency of Q4W at a dose of 1200 mg. In some embodiments of any of the above aspects, the antibody is formulated to be administered at a frequency of Q4W at a dose of 1200 mg. In some embodiments of any of the above aspects, the antibody is administered at a frequency of once per month at a dose of 20 mg/kg. In some embodiments of any of the above aspects, the antibody is formulated to be administered at a frequency of once per month at a dose of 20 mg/kg. In some embodiments of any of the above aspects, the antibody is administered at a frequency of once per month at a dose of 1200 mg. In some embodiments of any of the above aspects, the antibody is formulated to be administered at a frequency of once per month at a dose of 1200 mg.

[0025] In some embodiments of any of the above aspects, the antibody is administered at or formulated to be administered at a loading dose followed by a maintenance dose. In some embodiments, the loading dose is administered until a serum concentration of TNX-1500 > 750 pg/ml is obtained. In some embodiments, the loading dose is 20 mg/kg on days 0, 2, 5, 7 and weekly until a serum concentration of TNX-1500 > 750 pg/ml is obtained. In some embodiments, the loading dose is 20 mg/kg on days 0, 2, 5, 7 and weekly for one to six weeks. In some embodiments, the loading dose is 1800 mg. In some embodiments, the loading dose is 1800 mg on Day 1 followed by maintenance doses administered Q4W starting at Week 4. In some embodiments, the loading dose is 1800 mg on Day 1 followed by maintenance doses administered monthly starting at one month after the loading dose. In some embodiments, the maintenance dose is 1200 mg at a frequency of Q4W. In some embodiments, the maintenance dose is 1200 mg at a frequency of once per month. In some embodiments, the loading dose is 1800 mg on Day 1 followed by maintenance doses of 1200 mg administered Q4W starting at Week 4. In some embodiments, the loading dose is 1800 mg on Day 1 followed by maintenance doses of 1200 mg administered monthly starting at one month after the loading dose.

[0026] In some embodiments of any of the above aspects, the antibody is administered as a pharmaceutical composition comprising the antibody and a pharmaceutically acceptable carrier. In some embodiments of any of the above aspects, the antibody is formulated to be administered as a pharmaceutical composition comprising the antibody and a pharmaceutically acceptable carrier. In some embodiments of any of the above aspects, the antibody is administered intravenously. In some embodiments of any of the above aspects, the antibody is formulated to be administered intravenously.

BRIEF DISCRIPTION OF THE DRAWINGS

[0027] Figure 1A provides serum creatinine levels in nonhuman primates who received ‘standard-dose’ (z.e., 20 mg/kg, given 4 times in the first 2 weeks and weekly thereafter) TNX- 1500 monotherapy (stTNX/Mono) weekly. Figure IB provides serum TNX-1500 levels in nonhuman primates who received stTNX/mono weekly. Figure 1C provides serum creatinine levels in nonhuman primates who received a low dose of TNX-1500 in combination with my cophenolate mofetil (loTNX/MMF). TNX-1500 was administered weekly through day 42 followed by every other week (q2 weeks) through day 180. MMF was administered daily through day 180. Figure ID provides serum TNX-1500 levels in nonhuman primates who received loTNX/MMF. TNX-1500 was administered weekly through day 42 followed by every other week (q2 weeks) through day 180. MMF was administered daily through day 180. TCMR = T cell-mediated rejection. GI compl = gastrointestinal complications. N = 6 [0028] Figure 2A provides renal allograft at autopsy on day 28 from a nonhuman primate transplant recipient in the stTNX/mono group who demonstrated T cell-mediated rejection (TCMR) type 3. Figures 2B and 2C demonstrate that the remaining 4 recipients did well without rejection. For example, a representative biopsy on day 174 from a nonhuman primate transplant recipient who did not suffer TCMR shows no histological abnormality (Figure 2B) and no staining for complement component C4d (Figure 2C). Figure 2D provides a biopsy on day 47 from a nonhuman primate transplant recipient in the loTNX/MMF group, which showed TCMR type 3 and positive C4d staining (Figure 2E). Figure 2F provides representative biopsy taken on day 184 from a nonhuman primate transplant recipient in the loTNX/MMF group, which showed no rejection. loTNX/MMF, low-dose TNX + my cophenolate mofetil; stTNX/mono, standard-dose TNX monotherapy.

[0029] Figure 3 provides Kaplan-Meier renal allograft survival plot in nonhuman transplant recipients comparing stTNX/mono (n = 6), loTNX/MMF (n = 6), conventional immunosuppression (Conv IS) (n = 37), and no immunosuppression (No IS) (n = 5).

[0030] Figure 4 provides the mean (±SD) TNX-1500 serum concentration-time profiles by cohort and dose (Cohort, dose in mg/kg) in a linear-linear scale.

[0031] Figure 5 provides the mean (±SD) TNX-1500 serum concentration-time profiles by cohort and dose (Cohort, dose in mg/kg) in a log-linear scale.

[0032] Figures 6A and 6B summarize TNX-1500 serum concentration (pg/mL) of cohort 1 over time.

[0033] Figures 7A and 7B summarize TNX-1500 serum concentration (pg/mL) of cohort 2 over time.

[0034] Figures 8A and 8B summarize TNX-1500 serum concentration (pg/mL) of cohort 3 over time.

[0035] Figure 9 summarizes TNX-1500 pharmacokinetic (PK) parameters (Cmax, AUCo-t, AUCo-oo and ti/2 ) of cohorts 1-3.

[0036] Figure 10 provides the TNX-1500 tmax (h) in cohorts 1-3.

[0037] Figures 11A and 11B summarize TNX-1500 dose-normalized PK parameters (Cmax, AUCo-oo and AUCo-t) of cohorts 1-3. [0038] Figure 12 compares the mean (±SD) dose-normalized Cmax of TNX-1500 to the dose administered.

[0039] Figure 13 compares the mean (±SD) dose-normalized AUCo-t of TNX-1500 to the dose administered.

[0040] Figure 14 compares the mean (±SD) dose normalized AUCo-® of TNX-1500 to the dose administered.

[0041] Figure 15 graphs the mean anti-KLH antibody response (±SE) in four cohorts of participants dosed with 3 mg/kg, 10 mg/kg, or 30 mg/kg TNX-1500 or placebo and immunized with KLH at Day 2 and Day 29.

[0042] Figure 16 graphs the mean soluble CD 154 (±SE) in all participants at 1 hour postdose, 2 hours post-dose, 3 hours post-dose, 4 hours post-dose, 8 hours post dose, Day 2, Day 3, Day 8, Day 29, Day 50 and Day 120.

[0043] Figure 17 provides a schematic of a study of the use of TNX-1500 for treatment of allogeneic heart transplant in non-human primates. Briefly, after non-human primate were given allogeneic heart transplants and separated into 4 treatment groups: TNX-1500 alone (n=19); TNX-1500 in combination with mycophenolate mofetil (MMF; TNX-1500/MMF; 200 mg/d PO; n=4), TNX-1500 in combination with Rapamycin (Rapa; TNX-1500/Rapa; target trough 5-10 ng/ml; n=13), or TNX-1500 in combination with Tacrolimus (Tac; TNX- 1500/Tac; target trough 3-5 ng/ml; n=7). TNX-1500 was administered at 30 mg/kg twice a week for two weeks and then administered 20 mg/kg week.

[0044] Figure 18A graphs the graft survival rate of the groups treated with TNX-1500 alone, TNX-1500/MMF, TNX-1500/Rapa, and TNX-1500/Tac. Mean International Society for Heart and Lung Transplantation (ISHLT) acute rejection scores and cardiac allograft vasculopathy (CAV) scores are also provided. The treatment groups as the cross the X-axis (from left to right) are TNX-1500/Tac, TNX-1500/MMF, TNX-1500 monotherapy, and TNX-1500/RAPA. Figure 18B and Figure 18C graph the individual ISHLT and CAV scores, respectively.

DETAILED DESCRIPTION OF THE DISCLOSURE Definitions and General Techniques

[0045] Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings that are commonly understood by those of ordinary skill in the art. Generally, nomenclature used in connection with, and techniques of, cell and tissue culture, molecular biology, immunology, microbiology, genetics and protein and nucleic acid chemistry and hybridization described herein are those well-known and commonly used in the art. In case of conflict, the present specification, including definitions, will control.

[0046] The methods and techniques of the present disclosure will employ, unless otherwise indicated, conventional techniques of molecular biology (including recombinant techniques), microbiology, cell biology, biochemistry and immunology, which are within the skill of the art. Such techniques are explained fully in the literature, such as Green MR & Sambrook J. Molecular Cloning: A Laboratory Manual, 4th ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (2012); Ausubel el al., Short Protocols in Molecular Biology: A Compendium of Methods from Current Protocols in Molecular Biology, 5^th ed., Wiley, John & Sons, Inc. (2002); Harlow and Lane Using Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1998); and Coligan etal., Short Protocols in Protein Science, Wiley, John & Sons, Inc. (2003); Strohl WR and Strohl LM, Therapeutic Antibody Engineering, Woodhead Publishing, Philadelphia, PA (2012); Greenfield EA, Antibodies: A Laboratory Manual, Cold Spring Harbor Press, Cold Spring Harbor, N.Y. (2013), each of which is incorporated herein by reference.

[0047] Enzymatic reactions and purification techniques are performed according to manufacturer's specifications, as commonly accomplished in the art or as described herein. The nomenclature used in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those well-known and commonly used in the art.

[0048] Throughout this specification and embodiments, the word “comprise,” or variations such as “comprises” or “comprising,” will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers. “Comprising” may be synonymous with “including” or “containing.”

[0049] It is understood that wherever embodiments are described herein with the language “comprising,” otherwise analogous embodiments described in terms of “consisting of’ and/or “consisting essentially of’ are also provided. As used herein, “consisting of’ excludes any element, step, or ingredient not specifically recited, and “consisting essentially of’ limits the scope of a disclosure to the specified materials or steps and those that do not materially affect the basic and novel character! stic(s) of the disclosure.

[0050] The term “including” is used to mean “including but not limited to.” “Including” and “including but not limited to” are used interchangeably.

[0051] Any example(s) following the term “e.g.” or “for example” is not meant to be exhaustive or limiting.

[0052] Unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

[0053] The articles “a,” “an” and “the” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. As used herein, the term “about” modifying the quantity of an ingredient, parameter, calculation, or measurement in the compositions of the disclosure or employed in the methods of the disclosure refers to variation in the numerical quantity that can occur, for example, through typical measuring and liquid handling procedures used for making isolated polypeptides or pharmaceutical compositions in the real world; through inadvertent error in these procedures; through differences in the manufacture, source, or purity of the ingredients employed to make the compositions or carry out the methods; and the like without having a substantial effect on the chemical or physical attributes of the compositions or methods of the disclosure. Such variation can be typically within 10%, more typically still within 5%, of a given value or range. The term “about” also encompasses amounts that differ due to different equilibrium conditions for a composition resulting from a particular initial mixture. Whether or not modified by the term “about,” the paragraphs include equivalents to the quantities. Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X.” Numeric ranges are inclusive of the numbers defining the range.

[0054] Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the disclosure are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements. Moreover, all ranges disclosed herein are to be understood to encompass any and all subranges subsumed therein. For example, a stated range of “1 to 10” should be considered to include any and all subranges between (and inclusive of) the minimum value of 1 and the maximum value of 10; that is, all subranges beginning with a minimum value of 1 or more, e.g., 1 to 6.1, and ending with a maximum value of 10 or less, e.g., 5.5 to 10.

[0055] Exemplary methods and materials are described herein, although methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present application. The materials, methods, and examples are illustrative only and not intended to be limiting.

Definitions

[0056] The following terms, unless otherwise indicated, shall be understood to have the following meanings:

[0057] As used herein, the term “antibody” or “Ab” refers to an immunoglobulin molecule (e.g., complete antibodies or modified antibodies) capable of recognizing and binding to a specific target or antigen, such as a carbohydrate, polynucleotide, lipid, polypeptide, etc., through at least one antigen recognition site, located in the variable region of the immunoglobulin molecule. As used herein, the term “antibody” can encompass any type of antibody, including but not limited to monoclonal antibodies, polyclonal antibodies, human antibodies, engineered antibodies (including humanized antibodies, fully human antibodies, chimeric antibodies, single-chain antibodies, artificially selected antibodies, CDR-granted antibodies, etc.) that specifically bind to a given antigen (e.g., CD 154). In some embodiments, the antibody is a monoclonal antibody. Further, “antibody” and/or “immunoglobulin” (Ig) refers to a polypeptide comprising at least two heavy (H) chains (about 50-70 kDa) and two light (L) chains (about 25 kDa), optionally inter-connected by disulfide bonds. There are two types of light chain: X and K. In humans, X and K light chains are similar, but only one type is present in each antibody. Heavy chains are classified as mu, delta, gamma, alpha, or epsilon, and define the antibody’s isotype as IgM, IgD, IgG, IgA, and IgE, respectively. See generally, Fundamental Immunology Ch. 7 (Paul, W., ed., 2nd ed. Raven Press, N.Y. (1989)) (incorporated by reference in its entirety). The antibodies disclosed herein may be “functionally divalent” or “functionally monovalent”. In other words, the antibodies disclosed herein may have one antigen-binding site (monovalent) or two antigen-binding sites that are typically linked by disulfide bonds (divalent). In some embodiments, the anti-CD154 antibody is an IgG4 antibody. In some embodiments, the anti-CD154 antibody is derived from an IgG4 antibody. In some embodiments, the anti-CD154 antibody does not contain the final lysine residue at its C-terminal end in order to improve antibody stability. See e.g., Jiang G et al., J Pharm Sci. Jul;105(7):2066-72 (2016); and Hintersteiner B. MAbs. 2016 Nov/Dec;8(8): 1548- 1560 (2016). It is known in the art that each heavy chain and light chain is expressed comprising a leader sequence (also known as a signal sequence) at its N terminus, which is used to transport the newly synthesized chains into the endoplasmic reticulum. During post- translational processing, the leader sequences are removed and, therefore, are not present in the final chain or the mature antibody.

[0058] As used herein, the term “antibody fragment” refers to a molecule other than an intact antibody that comprises a portion of an intact antibody that binds the antigen to which the intact antibody binds. Examples of antibody fragments include but are not limited to Fv, Fab, Fab’, Fab’ SH, F(ab’)2; diabodies; linear antibodies; single chain antibody molecules (e.g., scFv, and scFab); single domain antibodies (dAbs); and multi-specific antibodies formed from antibody fragments. For a review of certain antibody fragments, see Holliger and Hudson, Nature Biotechnology 23: 1126 1136 (2005).

[0059] As used herein, the term “monoclonal antibody” or “mAb” refers to an antibody that is produced by an identical set of immune cells that are each clones of a unique parent cell. Monoclonal antibodies have monovalent affinity (i.e., they bind to the same epitope).

[0060] As used herein, the term “chimeric” antibody refers to an antibody or antigen-binding fragment thereof comprising portions from two or more different species (e.g., mouse and human). Chimeric antibodies can be produced with mouse variable regions of desired specificity spliced onto human constant domain gene segments (for example, U.S. patent No. 4,816,567). In this manner, non-human antibodies can be modified to make them more suitable for human clinical application. The term “chimeric” may refer to a non-native sequence that has been manipulated to have one or more changes relative a native sequence. A chimeric antibody as used herein means an antibody that comprises regions from two or more different antibodies. [0061] As used herein, the term “humanized” antibodies refers to chimeric antibodies from a non-human species, whose amino acid sequences have been modified to increase their similarity to antibodies produced in humans. In some embodiments, “humanized” antibodies are chimeric immunoglobulins, immunoglobulin chains, or antibody fragments thereof (such as Fv, Fab, Fab’, F(ab')2 or other antigen binding subsequences of antibodies) that contain minimal sequence derived from a non-human immunoglobulin. Optionally, humanized antibodies are derived from human immunoglobulins (i.e., recipient antibodies) in which residues from one or more complementary determining regions (CDRs) of the recipient antibody are replaced by residues from one or more CDRs of an antibody from a non-human species (donor antibody) having the desired specificity, affinity, and capacity. In some embodiments, the non-human species is a mouse, a rat, or a rabbit. Humanized or CDR-grafted mAbs are particularly useful as therapeutic agents for humans because they are not cleared from the circulation as rapidly as mouse antibodies and do not typically provoke an adverse immune reaction. Generally, a humanized antibody has one or more amino acid residues introduced into it from a non-human source.

[0062] In some embodiments, the chimeric antibody is a humanized antibody, e.g., a humanized anti-CD154 antibody. A humanized anti-CD154 antibody may comprise the amino acid sequence of one or more human framework regions and/or the amino acid sequence from at least a portion of a human constant region and further comprises sequences derived from a non-human antibody, for example non-human (e.g., mouse) CDR sequences. In some embodiments, the humanized antibody comprises a human constant region. Optionally, all of the framework regions in the humanized antibody are human framework regions.

[0063] Humanized antibodies can be generated by replacing non-human sequences of the Fv variable region that are not directly involved in antigen binding with equivalent sequences from human Fv variable regions. General methods for generating humanized antibodies are provided by Morrison, S. L., Science, 229: 1202-1207 (1985), by Oi etal., BioTechniques, 4:214 (1986), by Jones et al.. Nature 321 :522-525 (1986), by Riechmann et al.. Nature, 332:323-327 (1988), by Verhoeyen et al., Science, 239: 1534-1536 (1988)), by Staelens et al. 2006 Mol Immunol 43: 1243-1257, and by U.S. Pat. No. 5,225,539; U.S. Pat. No. 5,585,089; U.S. Pat. No. 5,693,761; U.S. Pat. No. 5,693,762; U.S. Pat. No. 5,859,205; and U.S. Pat. No. 6,407,213, each incorporated herein by reference. Those methods include isolating, manipulating, and expressing the nucleic acid sequences that encode all or part of immunoglobulin Fv variable regions from at least one of a heavy or light chain. Sources of such nucleic acid are well known to those skilled in the art and, for example, may be obtained from a hybridoma producing an antibody against a predetermined target, as described above, from germline immunoglobulin genes, or from synthetic constructs. The recombinant DNA encoding the humanized antibody can then be cloned into an appropriate expression vector. Humanized antibodies are typically human antibodies in which some CDR residues and possibly some framework residues are substituted by residues from analogous sites in rodent antibodies. See, for example, U.S. Patent Nos. 5,225,539; 5,585,089; 5,693,761; 5,693,762; 5,859,205, each incorporated herein by reference. See also U.S. Patent No. 6,180,370, and PCT International Publication No. WO 01/27160 (each incorporated herein by reference), where humanized antibodies and techniques for producing humanized antibodies having improved affinity for a predetermined antigen are disclosed. Furthermore, humanized and chimeric antibodies can be modified to comprise residues that are not found in the recipient antibody or in the donor antibody in order to further improve antibody properties, such as, for example, affinity or effector function.

[0064] As used herein, the term “amino acid modification” refers to at least one amino acid substitution, insertion, deletion or mutation in an amino acid sequence compared to a wild-type amino acid sequence. Such modifications are within the ordinary skill of an artisan. Certain modifications, including amino acid deletions, substitutions and additions, of the Fc region have been demonstrated to alter the binding of the Fc region to its ligands and/or receptors resulting in a concomitant change in effector function (see, e.g., (Shields et al., J Biol Chem 276:6591-6604 (2001); Presta et al., Biochem Soc Trans 30:487-490 (2002); Escobar-Cabrera E etal. Antibodies. 6: 7 (2017); Duncan AR etal. Nature. 1988; 332: 738-740 (1988); Duncan AR et al. Nature. 332: 563-564 (1988); Hezareh M et al. J Virol. 75: 12161-12168 (2001); Oganesyan V et al. Acta Crystallogr D Biol Crystallogr, 64: 700-704 (2008); Schlothauer T etal. Protein Eng Des Sei. Oct; 29(10):457-466 (2016); Tao MH et al. J. Immunol. 143: 2595- 2601 (1989); Von Kreudenstein TS et al. MAbs. 5(5):646-654 (2013); Wang X et al. Protein Cell. 9(l):63-73 (2018); U.S. Patent Publications 20040132101; 20070111260; 20110287032; 20180194860; U.S. Patent No. US 8409568; International Publication No. WO2017/177337, incorporated by reference in their entirety. An amino acid deletion is indicated as “A,” and an insertion is indicated as “In”. For instance, a deletion of the amino acid sequence from E216 to E222 is indicated as AE216-E222. An insertion of an arginine (R) between amino acid residues 234 and 235, e.g., would be indicated as InR234/235. [0065] As used herein, the term “Fc domain” refers to the crystallizable fragment of an antibody following papain digestion. The Fc domain comprises two identical protein fragments derived from the hinge region and the second and third constant domains of IgA, IgD, and IgG antibody isotypes or the hinge region and the second, third, and fourth constant domains of IgM and IgE antibody isotypes. The Fc domain is the portion of an antibody that binds to cell surface Fc receptors and certain proteins of the complement system. The term “Fc region” refers to the Fc domain in combination with a hinge region. The hinge region is typically between the C-terminus of a variable domain and the N-terminus of the Fc domain. Although the boundaries of the Fc region may vary, the human IgG heavy chain Fc region as defined herein comprises residue E216 to its carboxyl-terminus of the CH3 domain (or the CH4 domain for IgM and IgE antibodies), wherein the numbering is in the EU format as in Edelman GM et al., (1969) Proc. Natl. Acad. USA, 63, 78-85. The “EU format as set forth in Edelman” refers to the residue numbering of the human IgGl EU antibody as described in Edelman GM et al. supra. The human IgG2 and human IgG4 residue numbering is also in the EU format (See Dillon TM, et al., J Biol Chem. Jun 6;283(23): 16206-15 (2008); Aalberse RC and Schuurman J et al., Immunology 105:9-19 (2002); and Scholthauer T et al, Protein Engineering, Design and Selection, 29(10): 457-466, (2016). The terms “Fc domain” and “Fc region” may refer to these sequences in isolation, or these sequences in the context of an antibody, antibody fragment, or Fc fusion protein. An Fc variant protein may be an antibody, Fc fusion, or any protein or protein domain that comprises an Fc domain or an Fc region. The amino acid sequence of a non-naturally occurring Fc domain or Fc region (also referred to herein as a “variant Fc domain” or a “variant Fc region,” respectively) may comprise an amino acid modification. Any new amino acid residue appearing in the sequence of a variant Fc domain or a variant Fc region as a result of an insertion or substitution may be referred to as a non- naturally occurring amino acid residue. Polymorphisms have been observed at a number of Fc domain positions, including but not limited to positions 270, 272, 312, 315, 356, and 358, and thus slight differences between the presented sequence and sequences disclosed in the art may exist.

[0066] As used herein, the term “affinity” of an antibody refers to the strength of interaction between the antibody’s antigen-binding site and an epitope. An antibody’s affinity for an antigen is typically expressed as the binding affinity equilibrium dissociation constant (KD) of a particular antibody-antigen interaction. An antibody is said to specifically bind an antigen when the KD is < 1 mM, preferably < 100 nM. High affinity antibodies are generally considered to have a KD in the low nanomolar (1 O’⁹) range, and very high affinity antibodies are generally considered to have a KD in picomolar (10’¹²) range. A KD binding affinity constant can be measured by surface plasmon resonance, for example using the BIACORE® system (Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, N.J.) as discussed in Example 4. See also, Jonsson et al., Ann. Biol. Clin. 51 : 19-26 (1993); Jonsson et al., Biotechniques 11 :620-627 (1991); Jonsson et al., J. Mol. Recognit. 8:125-131 (1995); Johnsson et al., Anal. Biochem. 198:268-277 (1991); Hearty S et al., Methods Mol Biol. 907:411-42 (2012), each incorporated herein by reference. The KD may also be measured using a KINEXA® system (Sapidyne Instruments, Hanover, Germany and Boise, ID).

[0067] As used herein, the terms “ka” or “affinity constant” and “kd” or “dissociation constant” refer to the amount of antibody-antigen complex that exists at the point when equilibrium concentration between antibody and antigen is reached. KD is the ratio of kd to ka.

[0068] As used herein, the term “avidity” refers to the overall strength of an antibody-antigen complex. Avidity relates to three major parameters: the affinity of the antibody for the epitope; the valency of both the antibody and antigen; and the structural arrangement of the parts that interact. As used herein, “avidity” describes the increased affinity that occurs as result of multiple antigen binding sites on an immunoglobulin.

[0069] As used herein, the term “linker” refers to a polypeptide sequence that joins two or more antibody domains. The characteristics of linkers and their suitability for particular purposes are known in the art. See, e.g., Chen etal. Adv Drug Deliv Rev. October 15; 65(10): 1357-1369 (2013) (disclosing various types of linkers, their properties, and associated linker designing tools and databases), which is incorporated herein by reference. The linker may be flexible, rigid, or in vivo cleavable. Preferably, the linker is flexible. Flexible linkers typically comprise small non-polar (e.g. Gly) or polar (e.g., Ser or Thr) amino acids. The most commonly used flexible linkers have sequences consisting primarily of stretches of Gly and Ser residues (“GS” linker). Optionally, flexible linkers comprise repeats of 5 Gly and Ser residues. Non-limiting examples of flexible linker include (Gly-Gly-Gly-Gly-Ser)_n (SEQ ID NO: 17), (Ser-Ser-Ser-Ser-Gly)n (SEQ ID NO: 18), (Gly-Ser-Ser-Gly-Gly)n (SEQ ID NO: 19), and (Gly-Gly-Ser-Gly-Gly)n (SEQ ID NO: 20), where n may be any integer between 1 and 5. The linker is optionally between 5 and 25 amino acid residues long. Other suitable linkers may be selected from the group consisting of AS, AST, TVAAPS (SEQ ID NO: 21), TVA, ASTSGPS (SEQ ID NO: 22), KESGSVSSEQLAQFRSLD (SEQ ID NO: 23), EGKSSGSGSESKST (SEQ ID NO: 24), (Gly)₆ (SEQ ID NO: 25), (Gly)₈ (SEQ ID NO: 26), and GSAGSAAGSGEF (SEQ ID NO: 27). In general, a flexible linker should provide good flexibility and solubility and may serve as a passive linker to keep a distance between functional domains. The length of the flexible linkers can be adjusted to allow for proper folding or to achieve optimal biological activity of the fusion proteins.

[0070] As used herein, the twenty conventional amino acids and their abbreviations follow conventional usage. See Immunology — A Synthesis (2^nd Edition, E. S. Golub and D. R. Gren, Eds., Sinauer Associates, Sunderland, Mass. (1991)), which is incorporated herein by reference.

[0071] A “conservative amino acid substitution” is one in which an amino acid residue is replaced with a different amino acid residue with similar biochemical properties (e.g., charge, hydrophobicity, or size). Typically, conservative amino acid substitutions do not substantially change a protein’s functional properties. When comparing proteins with conservative substitutions, the percent sequence identity or degree of similarity may be adjusted to account for the conservative nature of the substitution. Such adjustments are well-known to those of skill in the art. See, e.g., Pearson, Methods Mol. Biol. 243:307-31 (1994).

[0072] Groups of amino acids with similar biochemical properties that may be used in conservative substitutions include 1) amino acid residues with aliphatic side chains: glycine, alanine, valine, leucine, and isoleucine; 2) amino acid residues with aliphatic-hydroxyl side chains: serine and threonine; 3) amino acid residues with amide-containing side chains: asparagine and glutamine; 4) amino acid residues with aromatic side chains: phenylalanine, tyrosine, and tryptophan; 5) amino acid residues with basic side chains: lysine, arginine, and histidine; 6) amino acid residues with acidic side chains: aspartic acid and glutamic acid; and 7) amino acid residues with sulfur-containing side chains: cysteine and methionine. Preferred conservative amino acids substitution groups include: valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine-valine, glutamate-aspartate, and asparagineglutamine.

[0073] Each heavy chain is comprised of a heavy chain variable domain (VH) and multiple heavy chain constant domains (CH). For IgA, IgD, and IgG antibodies, the heavy chain typically comprises three domains: CHI, CH2 and CH3. For IgM and IgE antibodies, the heavy chain typically comprises four domains: CHI, CH2, CH3, and CH4. In some embodiments, the antibody comprises two domains: CH2 and CH3. Each light chain comprises a light chain variable domain (VL) and a light chain constant domain. The light chain typically comprises one domain: CL. Light chain variable domains are encoded by two gene segments: a variable (V) gene segment, which encodes the first 95-101 amino acids of the light chain, and a joining (J) gene segment, which encodes about 12 or more amino acids. Heavy chain variable domains are encoded by three gene segments and include a diversity (D) gene segment, which encodes about 3 or more amino acids, between the V and J gene segments. The VH and VL domains can be further subdivided into regions of hypervariability, called “complementarity determining regions” (CDR) that are separated by more conserved “framework regions” (FR). Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxyl-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.

[0074] The pairing of the variable domains of the heavy chain and light chain (VH and VL) forms the antibody binding site that interacts with an antigen. Thus, each antibody typically has two binding sites. With the exception of multifunctional/multispecific (e.g., bifunctional or bispecific) antibodies, the two binding sites are the same. The Fc regions of the constant regions of the antibodies typically mediate the binding of antibodies to host tissues and factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system.

[0075] Residues in a variable domain are numbered according to Edelman, also known as the EU numbering system, which is a numbering system used for heavy chain variable domains or light chain variable domains of the compilation of antibodies. See, Edelman Proc Natl Acad Sci USA. May;63(l):78-85 (1969) and Kabat, E. A., Wu, T. T., Perry, H., Gottesman, K., and Foeller, C. (1991) Sequences of Proteins of Immunological Interest, 5^th ed., NIH Publication No. 91-3242, Bethesda, MD. The Eu numbering of residues may be determined for a given antibody by alignment at regions of homology of the sequence of the antibody with a “standard” EU numbered sequence. Variable region CDRs (CDR LI, CDR L2, CDR L3, CDR Hl, CDR H2, CDR H3) are identified according to contact based on crystal structures as defined in Karpusas etal. Structure. Apr 4;9(4):321-9 (2001) and numbered in accordance with Edelman.

[0076] As used herein, the term “operably linked” refers to a first structure that has been placed in a functional relationship with a second structure. In the context of an antibody, a targeting structure may be operably linked to a structure that confers effector function. For example, the antigen-binding sequence of an antibody (e.g., variable region or VH or VL domain) may be operatively linked to a Fc region. In the context of a polynucleotide, a coding sequence may be operatively linked to a non-coding regulatory sequence, such as a promoter, an enhance, a signal sequence, a ribosome binding sequence, a splice acceptor sequence, a splice donor sequence, a termination sequence, etc. Two operably linked structures may be directly connected. Alternatively, two operably linked structures may be connected via one or more intermediary structures. For example, the antigen-binding portion of an antibody may be operably linked to the Fc region via a CHI domain, a hinge region and/or a linker sequence. Similarly, operably linked non-coding regulatory sequences include both sequences that are contiguous with the coding sequence and sequences that act in trans or at a distance to control the coding sequence.

[0077] As used herein, the term “effector function” refers to the responses triggered by the interaction of antibodies and antibody-antigen complexes with cells of the immune system. These effector functions typically involve one of three major mechanisms: antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and opsonization and phagocytosis. In ADCC, Fc receptors on cytotoxic T cells, natural killer (NK) cells, or macrophages bind to the Fc regions of antibodies bound to a target cell, resulting in the secretion of substances, such as lytic enzymes, perforin, granzymes and tumor necrosis factor, which mediate the destruction of the target cell. In CDC, cell death is induced via activation of the complement cascade. See Daeron, Annu. Rev. Immunol., 15:203-234 (1997); Ward and Ghetie, Therapeutic Immunol., 2:77-94 (1995); and Ravetch and Kinet, Annu. Rev. Immunol. 9:457-492 (1991)). In opsonization and phagocytosis, the Fc region of a pathogenbound antibody binds to a Fc receptor on the surface of a phagocyte, inducing phagocytosis. Such effector functions generally require the Fc region to be combined with a binding domain (e.g., an antibody variable domain) and can be assessed using standard assays that are known in the art (see, e.g., WO 05/018572, WO 05/003175, and U.S. Pat. No. 6,242,195). The Fc domain of the antibody mediates immune effector mechanisms. IgG antibodies activate effector pathways of the immune system by binding to members of the family of cell surface Fey receptors and to Clq of the complement system. Ligation of effector proteins by clustered antibodies triggers a variety of responses, including release of inflammatory cytokines, regulation of antigen production, endocytosis, and cell killing. These responses can provoke unwanted side effects such as inflammation and thrombosis. Accordingly, the present disclosure further relates to anti-CD154 antibodies, with modified effector functions, including antibodies in which one or more effector functions is reduced or eliminated. Without being bound by theory, it is believed that the anti-CD154 antibodies disclosed herein do not cause platelet activation or aggregation, because the antibodies comprising the mutated Fc regions do not bind FcyRIIa (also known as CD32a) on the platelet surface.

[0078] As used herein, the term “modified effector functions” refers to a Fc domain or an Fc region whose effector functions differ from a wild-type immunoglobulin Fc domain or Fc region. In some embodiments, one or more effector functions are reduced. Optionally, one or more effector functions are eliminated. The modified or reduced effector functions may be the result of lower binding affinity of the Fc region of the antibodies disclosed herein to effector molecules (e.g., FcyRs and/or Clq). For example, the anti-CD154 antibodies disclosed herein have reduced Fc receptor binding and complement activation compared with that of wild-type anti-CD154 antibodies. In some embodiments, a variant Fc region has a reduced antibody dependent cell-mediated cytotoxicity (ADCC). Effector function of an anti-CD154 antibody may be determined using one of many known assays, including the CDC assay, the ADCC assay, and the phagocytosis assay (see Xu-Rong Jiang et al., Nature Reviews Drug Discovery 10: 101-111 (2011) and Liu et al., The Journal of Biological Chemistry 292: 1876-1883 (2017)). The anti-CD154 one or more of the antibody's effector functions may be reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% relative to the effector function of a wild-type anti-CD154 antibody.

[0079] As used herein, the terms “CD 154,” “CD40 ligand” and “CD40L” may be used interchangeably and refer to a mammalian protein that is primarily expressed on the surfaces of activated T cells, a soluble form of CD 154 that is cleaved and released by activated T cells, is a member of the TNF superfamily, and binds the CD40 protein on antigen presenting cells. The term CD 154 is intended to include recombinant CD 154 and recombinant chimeric forms of CD 154, which can be prepared by standard recombinant expression methods. In some embodiments, CD 154 refers to human CD 154.

[0080] As used herein, the term “inhibits” refers to the property of an antibody, or other molecule, that prevents the interaction of CD 154 with CD40 or one that inhibits the binding of CD 154 to CD40, or one that inhibits CD 154 cleavage or shedding. In some embodiments, the antibody inhibits the binding of CD 154 to CD40 by at least about 20%, preferably 40%, more preferably 60%, even more preferably 80%, or even more preferably 85%. Optionally, the antibody inhibits CD 154 cleavage or shedding by at least about 20%, preferably 40%, more preferably 60%, even more preferably 80%, or even more preferably 85%. The inhibitory potential of anti-CD154 antibodies may be determined, for example, by their ability to inhibit up-regulation of a specific downstream target gene of CD40. For example, an anti-CD154 antibody may alter the expression, activity, or activation of kinases and genes that respond to CD154-CD40 signaling. An anti-CD154 antibody may inhibit the upregulation of CD23 expression, inhibit the upregulation of CD69 expression, inhibit the upregulation and activity of activation-induced cytidine deaminase (AID), inhibit rescue from apoptosis, inhibit upregulation of NF-KB activity, inhibit immunoglobulin isotype class switching, inhibit immunoglobulin CDR somatic hypermutation, alter the expression or activity of molecules within the TNF-receptor associated factor (TRAF) family such as TRAF-2, TRAF3 (also known as CRAF1), TRAF-5 and TRAF-6, kinase activation or inhibit the expression of other genes that respond to CD154-CD40 signaling. See, for example, Lederman, S., et al. J. Exp. Med. 175:1091-1101. (1992); Lederman, S., et al., Journal of Immunol. 149:3817-3826. (1992); Lederman, S., et al., Journal of Immunol. 152:2163. (1994); Cleary, A.M., et al., Journal of Immunol. , 155:3329-3337 (1995); Cheng et al., Science. 267(5203): 1494-8 (1995), Bankert KC et al., Journal of Immunol. 194:4319-4327 (2015), Ishida TK et al Proc Natl Acad Sci USA. 93(18):9437-42 (1996). Muramatsu, MK et al. 2000. Cell 102: 553 (2000); Buchta CM and Bishop GA., Journal of Immunol. 192(1): 145-50. (2014), Arcipowski KM, et al. International Immunology. 26(3): 149-58 (2014); Mambetsariev N, et al., Proc Natl Acad Sci USA. 113(4): 1032-7 (2016), Arcipowski KM, Bishop GA., PLoS One. 7(7) (2012); Bishop GA. Journal of Immunol. 91(7):3483-5. (2013); Peters AL and Bishop GA. Journal of Immunol. 185(11):6555-62. (2010); Rowland SL, et al. , Journal of Immunol. 179(7):4645-53. (2007), Benson RJ, et al., European Journal of Immunol. 6(9):2535-43. (2006).

[0081] As used herein, the term “immune response” refers to reaction of body’s immune system to the presence of a substance which is not recognized as a constituent of the body itself. An immune response may be a humoral immune response, a cell-mediated immune response, or a mixed humoral and cell-mediated immune response. A humoral response may be an antibody-mediated response. A cell-mediated response may be one or more of a cytotoxic T- cell mediated immune response, a macrophage mediated response, a natural killer (NK) cell mediated immune response or a cytokine mediated response. A mixed humoral and cell- mediated response may be one or more of an antibody-mediated response, a cytotoxic T-cell mediated immune response, a macrophage mediated response, a natural killer (NK) cell mediated immune response or a cytokine mediated response. The immune response can refer to an adaptive and/or an innate immune response. For the various types of immune responses, see David Chaplin J Allergy Clin Immunol February; 125(2 Suppl 2): S3-23 (2010).

[0082] As used herein, the term “transplantation” refers to process of surgically removing a cell or tissue or organ from a first organism (the donor) and placing it into a second organism (the recipient). The donor may be a human or a non-human organism. In some embodiments, the donor is a primate. The donor may be a non-human primate. Optionally, the donor is a human. In some embodiments, the donor is a pig or mini-swine. The recipient may be a human or a non-human organism. Preferably, the recipient is a human. Optionally, the recipient is a non-human primate. The cell, tissue or organ being transferred is referred to as the “transplant” or “graft.” A “xenotransplant” refers to the transfer of a cell or tissue or organ from a donor of a certain species (such as a monkey or pig) into a recipient of a different species (such as a human). Successful xenotransplantation of a pig organs into human recipients has been reported in the art. See, e.g., Mallapaty S. and Kozlov M., Nature, 2024, vol. 628: 13-14; and Cooper DK and Cozzi E., Transplant. 2024, vol 37: 12592.

[0083] As used herein, the term “engineered cell” refers to a cell that is modified from its natural state. An engineered cell may be modified using one or more techniques such as transduction to express a cDNA, a CRISPR/Cas9 system, RNAi technology and retroviral technology. For example, the cell may be modified to express a chimeric antigen receptor (CAR) on its surface. Examples of cells that may be transplanted include, but are not limited to a stem cell, a regulatory T (Treg) cell, a CAR-T cell (see Zhang, C etal. Biomarker Research (5)22. (2017), a CAR-B cell (Voss JE et al., Elife. Jan 17;8. (2019), and a tumor-infiltrating lymphocyte (TIL) (Zhang L et al., Clin Cancer Res. May 15;21(10):2278-88. doi: 10.1158/1078-0432. CCR-14-2085 (2015).

[0084] As used herein, the term “ex-vivo expanded cell” refers to a cell that is produced in an ex-vivo method to enhance the yield of that cell (such as a hematopoietic stem cell (HSC)) to be used in clinical applications, such as transplantation. See, e.g., Xie J, and Zhang C Sci China Life Sci. Sep;58(9):839-53 (2015) which reviews the methods to expand the numbers of HSCs, including culture systems such as stroma/HSC co-culture, continuous perfusion and fed- batch cultures, and those supplemented with extrinsic ligands, membrane transportable transcription factors, complement components, protein modification enzymes, metabolites, or small molecule chemicals. The desired cell to be transplanted may also be expanded ex-vivo by applying endogenous Notch-signaling activators (see, e.g., Ex vivo expansion of human hematopoietic stem and progenitor cells Dahlberg A, et aL, Blood 117:6083-6090 (2011).

[0085] As used herein, the term “transplant rejection” refers to the phenomenon that occurs when a transplanted cell, tissue, or organ from a donor is rejected by the recipient’s immune system. The recipient’s immune system may mount an adaptive immune response (cellular immunity) mediated by killer T cells inducing apoptosis of the donor cells, a humoral immunity mediated by activated B cells secreting antibodies, and/or an innate immune response mediated by phagocytes and soluble immune proteins (see Ochanda J et al., Cell Mol Immunol. Apr; 16(4): 350-356 (2019); Koo J, and Wang HL. Surg Pathol Clin. Jun; 11(2):431-452 (2018); Wang H, and Yang YG, Curr Opin Organ Transplant. Apr; 17(2): 162-7 (2012); and da Silva MB, World J Transplant. Feb 24;7(1): 1-25 (2017)).

[0086] As used herein, the term “immune-related disease” refers to a condition in which the host immune system plays an integral role in mediated the disease and contributes to the progress of the disease. The term encompasses “autoimmune disease” which is a condition that arises when a specific adaptive immune response is mounted against self-antigens, as a result of which the effector pathways of immunity cause chronic inflammatory injury to tissues. Autoimmune diseases include, but are not limited to Amyotrophic Lateral Sclerosis, Inflammatory Bowel Disease, Irritable Bowel Syndrome, Idiopathic Thrombocytopenic Purpura, Systemic Lupus Erythematosus, Lupus Nephritis, Multiple Sclerosis, Relapsing Remitting Multiple Sclerosis, Secondary Progressive Multiple Sclerosis, Psoriasis, Rheumatoid Arthritis, Systemic Scleroderma, Interstitial Lung Disease, Atopic Dermatitis, Antiphospholipid Syndrome, Sarcoidosis, Myositis, Ulcerative Colitis, Pneumocystis, Type 1 Diabetes, Sjogren syndrome, and Graft versus host disease. Immune-related disease may also refer to an allergic disease which includes, but is not limited to allergic rhinitis, asthma, atopic eczema, anaphylaxis, insect venom allergy, drug allergy, and food allergy.

[0087] As used herein, the term “primary response” refers to the immune response of the body to an antigen that occurs on the first occasion that it is encountered. The term “secondary response” refers to the immune response that involves both B- and T cells, following a subsequent encounter with the same antigen and is more rapid leading to the activation of previously generated memory cells. A secondary response has some quantitative and qualitative differences from the primary response as reviewed in Ademokun and Dunn- Walters, Immune Responses: Primary and Secondary; John Wiley & Sons, (2010) and Kuby Immunology Macmillan; 8th edition (2018). In a primary immune response, the responding cell is a naive B-cell and T-cell while in a secondary response, the responding cell is a memory cell.

[0088] As used herein, the term “hematopoietic chimerism” refers to the coexistence of both host and donor hematopoietic cells that arises due to the engraftment of donor pluripotent hematopoietic stem cells into the host. The host and donor cells may be tolerant of each other. Mechanisms of hematopoietic chimerism are known in the art. See Pasquet L, et al. Front Immunol. 2:80 (2011) and Nikolic B, and Sykes M, Immunol Res. 16(3):217-28. (1997) incorporated herein by reference. In some embodiments, such hematopoietic chimerism results in “central tolerance.” The mechanisms of “central tolerance” in such chimeras may involve central, intrathymic clonal deletion, selection of regulatory T cells and/or other related immune mechanisms. See, e.g., Nikolic B, and Sykes M, Immunol Res. 16(3):217-28. (1997) and Hogquist KA et al., Nature Reviews Immunology 5:772-782 (2005), incorporated herein by reference. In some embodiments, the hematopoietic stem cells are isolated or purified. Optionally, the hematopoietic stem cells are passenger cells that are transplanted with an organ, e.g., a kidney or liver transplant. Stem cells may be derived from bone marrow or fat cells/adipose tissue of the donor.

[0089] As used herein, the term “conditioning” or “conditioned” refers to the preparation of a recipient for stem cell transplantation, such as a hematopoietic cell transplantation. Gyurkocza B and Sandmaier BM Blood 124:344-353 (2014) provides a review of high-dose, reduced-intensity, and nonmyeloablative conditioning regiments and the most commonly used agents, such as total body irradiation, fludarabine phosphate, cyclophosphamide, T celldepleting antibodies, cyclosporine A (CsA). Monoclonal antibodies, such as anti-CD20 Ab, anti-CD33 Ab, and anti-CD45 Ab, may also be used alone or in combination with conventional therapies as part of a conditioning regimen to prevent transplant rejection. See, e.g., Topcuoglu P et al; Progress in Stem Cell Transplantation,' December (2015). Other agents that may be used in conditioning regimens include, but are not limited to, BCL-2 inhibitors (Perini GF et al., Journal of Hematology & Oncology 11 :65 (2018) and anti-CTLA4 Abs (Pree I et al., Transplantation. Mar 15; 83(5): 663-667 (2007). Conditioning regimens may include chemotherapeutic agents including, but not limited to, Alemtuzumab (CAMPATH™), Busulfan, Carboplatin, Carmustine, Cyclophosphamide, Cytarabine (Ara-C), Daunorubicin, Etoposide (VP-16), Fludarabine, Melphalan, Rituximab, and Vincristine.

[0090] The terms “patient,” “subject,” and “individual” are used interchangeably herein and refer to either a human or a non-human animal in need to treatment. These terms include mammals, such as humans, and non-human primates (e.g., monkey). In some embodiments, the subject is in need of inhibition or reduction of an immune response. In some embodiments, the subject is a transplant recipient.

[0091] The term “primate” refers to a mammal of the order primates, which includes the anthropoids and prosimians, characterized by refined development of the hands and feet, a shortened snout, and a large brain. The mammalian order Primates includes humans, apes, monkeys, and prosimians, or lower primates.

[0092] As used herein, “pharmaceutically acceptable carrier” and “pharmaceutically acceptable excipient” are used interchangeably refer to any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. Pharmaceutically acceptable carriers are well known in the art. See, e.g., Remington's Pharmaceutical Sciences and U.S. Pharmacopeia: National Formulary, Mack Publishing Company, Easton, PA (1984), incorporated herein by reference.

[0093] As used herein, the term “therapeutically effective amount” refers to that amount of the therapeutic agent being administered which will relieve to some extent one or more of the symptoms of the condition being treated. With respect to the treatment of transplant rejection, a therapeutically effective amount refers to that amount which has at least one of the following effects: reduces, inhibits or prevents acute or chronic rejection of the transplanted cell, tissue or organ and one or more symptoms associated with the rejection, prolongs graft survival, reduces thrombosis, reduces the risk of life-threatening infections, cancers and other complications, such as cardiovascular diseases, and kidney failure. See, for example, Romano et al. Front Immunol. 10:43 (2019) and Ingulli E. Pediatr Nephrol. 25(1):61— 74 (2010) for mechanisms of cellular rejection in transplantation. With respect to the treatment of autoimmune disease and antibody-mediated inflammatory disease, a therapeutically effective amount refers to that amount which has at least one of the following effects: reduces one or more symptoms associated with the autoimmune disease such as fatigue, muscle aches, low fever, inflammation, skin rashes, etc. [0094] The pharmaceutical compositions may include a therapeutically effective amount, or a prophylactically effective amount, of an antibody disclosed herein. A therapeutically effective amount of the antibody may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the antibody or antibody portion to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of the antibody are outweighed by the therapeutically beneficial effects. It is routine in the art for the skilled artisan to determine a therapeutically effective amount of an antibody disclosed herein based on these factors. A “prophylactically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, since a prophylactic dose is used in subjects prior to transplantation or at an earlier stage of transplant rejection, the prophylactically effective amount may be less than the therapeutically effective amount.

[0095] As used herein, the terms “treat,” “treating” and “treatment” refer the administration of a therapeutic agent, such as a composition containing any of the antibodies disclosed herein, internally or externally to a subject or patient having one or more disease symptoms, or being suspected of having a disease, for which the agent has therapeutic activity. “Treat,” “treating” and “treatment” refer to therapeutic treatments. Therapeutic treatment includes, e.g., a method of alleviating or reducing the severity of a condition or abolishing a condition and includes alleviating or reducing the severity of one or more symptoms of the condition. The alleviation or reduction of a disease symptom can be assessed by any clinical measurement typically used by physicians or other skilled artisans to assess the severity or progression of that symptom. The terms further refer to a postponement of development of one or more disease symptoms and/or a reduction in the severity of one or more disease symptoms. The terms further include ameliorating existing uncontrolled or unwanted disease symptoms, preventing additional disease symptoms, and ameliorating or preventing the underlying causes of such disease symptoms. Thus, the terms denote that a beneficial result has been conferred on the subject.

[0096] With respect to the treatment of transplant rejection, treatment may refer to the alleviation, reduction, or delay of rejection of the transplanted cell, tissue or organ or one or more symptoms associated with the rejection. Treatment may also result in prolonging graft survival, reducing thrombosis, and/or reducing the risk of life-threatening infections, cancers and other complications, such as cardiovascular diseases, and kidney failure. With respect to the treatment of autoimmune disease, treatment may refer to dampening of the body’s immune responses and controlling the autoimmune reaction. With respect to the treatment of antibody- mediated inflammatory disease, treatment may refer to reducing one or more symptoms associated with the autoimmune disease such as fatigue, muscle aches, low fever, inflammation, skin rashes, etc. With regard to treatment with the antibodies disclosed herein, these terms may simply mean that the life expectancy and quality of life of an individual receiving a transplant or an individual affected with an autoimmune or inflammatory disease will be increased or that one or more of the symptoms associated with transplant rejection or the autoimmune or inflammatory disease will be reduced.

[0097] As used herein, the terms “prevent,” “preventing” and “prevention” refer to the prevention or delay of the recurrence or onset of, or a reduction in one or more symptoms of a condition in a subject as a result of the administration of an anti-CD154 antibody of the disclosure. “Prevent,” “preventing” and “prevention” refer to prophylactic treatments. If a therapy is administered prior to clinical manifestation of a condition, the therapy is considered prophylactic. For example, in the context of the administration of a therapy to a subject, “prevent,” “preventing” and “prevention” refer to the inhibition, reduction, or delay in the development or onset of the rejection of that transplant or associated thrombosis or the prevention or delay of the recurrence, onset, or development of one or more symptoms associated with the transplantation in a subject (e.g., a solid organ transplant) or the administration of a combination of therapies (e.g., a combination of a solid organ transplant and an immunosuppressant).

[0098] As used herein, the terms “administering” or “administration of’ the antibodies or compositions of this disclosure to a subject refers to refers to contacting the antibodies or compositions to the subject or to a cell, tissue, organ, or biological fluid of the subject. Such administration can be carried out using one of a variety of methods known to those skilled in the art. For example, an antibody or a composition of this disclosure can be administered systemically or locally. In some embodiments, the composition can be administered intravenously. Administering can also be performed, for example, once, a plurality of times, and/or over one or more extended periods. In some embodiments, the administration includes both direct administration (including self-administration) and indirect administration, including the act of prescribing a drug. Anti-CD154 Antibodies

[0099] The methods of the present disclosure utilize anti-CD154 antibodies with modified effector functions that bind to human CD 154. In some embodiments, one or more effector functions are reduced.

[0100] In some embodiments, the anti-CD154 antibody is a humanized antibody. In some embodiments, the anti-CD154 antibody is a monoclonal antibody. In some embodiments, the anti-CD154 antibody comprises one or more of the amino acid sequences provided in Table 1. In some embodiments, the anti-CD154 antibody is derived from the 5c8 antibody. In some embodiments, the anti-CD154 antibody comprises a humanized variable domain, wherein the variable domain comprises a heavy chain variable region (VH) and a light chain variable region (VL) derived from the 5c8 antibody. In some embodiments, the VH comprises (a) a heavy chain CDR1 having the amino acid sequence of SEQ ID NO: 3, (b) a heavy chain CDR2 having the amino acid sequence of SEQ ID NO: 4, and (c) a heavy chain CDR3 having the amino acid sequence of SEQ ID NO: 5; and the VL comprises (a) a light chain CDR1 having the amino acid sequence of SEQ ID NO: 6, (b) a light chain CDR2 having the amino acid sequence of SEQ ID NO: 7, and (c) a light chain CDR3 having the amino acid sequence of SEQ ID NO: 8. In some embodiments, the VH is operably linked to a human Fc region derived from IgG4 and comprising S228P and L235A amino acid modifications.

[0101] In some embodiments, the anti-CD154 antibody comprises a humanized variable domain, wherein the variable domain comprises a heavy chain variable region (VH) and a light chain variable region (VL), and wherein the VH is operably linked to a human Fc region derived from IgG4 and comprising S228P and L235A amino acid modifications; wherein the VH comprises (a) a heavy chain CDR1 having the amino acid sequence of SEQ ID NO: 3, (b) a heavy chain CDR2 having the amino acid sequence of SEQ ID NO: 4, and (c) a heavy chain CDR3 having the amino acid sequence of SEQ ID NO: 5; and wherein the VL comprises (a) a light chain CDR1 having the amino acid sequence of SEQ ID NO: 6, (b) a light chain CDR2 having the amino acid sequence of SEQ ID NO: 7, and (c) a light chain CDR3 having the amino acid sequence of SEQ ID NO: 8.

[0102] In some embodiments, the Fc region comprises the amino acid sequence of SEQ ID NO: 1 or 2. In some embodiments, the Fc region comprising the amino acid sequence of SEQ ID NO: 1. In some embodiments, the Fc region comprises the amino acid sequence of SEQ ID NO: 2.

[0103] In some embodiments, the anti-CD154 antibody comprises a heavy chain comprising a constant region comprising the amino acid sequence of SEQ ID NO: 12 or 13. In some embodiments, the anti-CD154 antibody comprises a heavy chain comprising a constant region comprising the amino acid sequence of SEQ ID NO: 12. In some embodiments, the anti-CD154 antibody comprises a heavy chain comprising a constant region comprising the amino acid sequence of SEQ ID NO: 13.

[0104] In some embodiments, the VH comprises the amino acid sequence of SEQ ID NO: 9. In some embodiments, the VL comprises the amino acid sequence of SEQ ID NO: 10. In some embodiments, the VH comprises the amino acid sequence of SEQ ID NO: 9, and the VL comprises the amino acid sequence of SEQ ID NO: 10.

[0105] In some embodiments, the anti-CD154 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 14 or 15. In some embodiments, the anti-CD154 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 14. In some embodiments, the anti-CD154 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 15.

[0106] In some embodiments, the anti-CD154 antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 16. In some embodiments, the anti-CD154 antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 16 and a heavy chain comprising an amino acid sequence of SEQ ID NO: 14 or 15. In some embodiments, the anti-CD154 antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 16 and a heavy chain comprising an amino acid sequence of SEQ ID NO: 14. In some embodiments, the anti-CD154 antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 16 and a heavy chain comprising an amino acid sequence of SEQ ID NO: 15. Table 1. Sequences of humanized anti-CD154 antibodies.

Pharmaceutical Compositions and Administration

[0107] The methods disclosed herein may also utilize a pharmaceutical composition comprising an anti-CD154 antibody disclosed herein and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of an anti-CD154 antibody disclosed herein.

[0108] The antibodies disclosed herein may be incorporated into pharmaceutical compositions suitable for administration to a subject. Typically, the pharmaceutical composition comprises an antibody disclosed herein and a pharmaceutically acceptable carrier. Some examples of pharmaceutically acceptable carriers are water, saline, phosphate buffered saline, dextrose, glycerol, ethanol and the like, as well as combinations thereof. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Additional examples of pharmaceutically acceptable substances are wetting agents or minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives, or buffers, which enhance the shelf life or effectiveness of the antibody. Pharmaceutical compositions may be prepared by mixing an antibody disclosed herein with acceptable carriers, excipients, or stabilizers in the form of, e.g., lyophilized powders, slurries, aqueous solutions or suspensions (see, e.g., Hardman, et al. (2001) Goodman and Gilman’s The Pharmacological Basis of Therapeutics, McGraw-Hill, New York, NY; Gennaro (2000) Remington: The Science and Practice of Pharmacy, Lippincott, Williams, and Wilkins, New York, NY; Avis, et al. (eds.) (1993) Pharmaceutical Dosage Forms: Parenteral Medications, Marcel Dekker, NY; Lieberman, et al. (eds.) (1990) Pharmaceutical Dosage Forms: Tablets, Marcel Dekker, NY; Lieberman, et al. (eds.) (1990) Pharmaceutical Dosage Forms: Disperse Systems, Marcel Dekker, NY; Weiner and Kotkoskie (2000) Excipient Toxicity and Safety, Marcel Dekker, Inc., New York, NY; each incorporated herein by reference).

[0109] The pharmaceutical compositions may be in a variety of forms, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories. The preferred form depends on the intended mode of administration and therapeutic application. In some embodiments, the pharmaceutical compositions are in the form of injectable or infusible solutions, such as compositions similar to those used for passive immunization of humans. Optionally, mode of administration is parenteral (e.g., intravenous). The pharmaceutical composition may be administered by intravenous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules, pre-filled syringes, or in multi-dose containers, with or without an added preservative. The pharmaceutical compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be prepared in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0110] Therapeutic compositions typically must be sterile and stable under the conditions of manufacture and storage. The composition may be formulated as a solution, microemulsion, dispersion, liposome, or other ordered structure suitable to high drug concentration. Sterile inj ectable solutions may be prepared by incorporating an anti-CD 154 antibody of the disclosure in an appropriate solvent with one or a combination of ingredients enumerated above, followed by filtered sterilization. Dispersions may be prepared by incorporating the anti-CD 154 antibody into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation include vacuum drying and freeze-drying that yield a powder of the anti-CD 154 antibody and any additional desired ingredient from a previously sterile-filtered solution thereof. The proper fluidity of a solution can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and/or by the use of surfactants. Prolonged absorption of injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, monostearate salts and gelatin.

[0111] In some embodiments, the pharmaceutical compositions may be prepared with a carrier that will protect the antibody against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems. Biodegradable, biocompatible polymers, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid, may be used. Methods for the preparation of such formulations are generally known to those skilled in the art. See, e.g., Sustained and Controlled Release Drug Delivery Systems J. R. Robinson, ed., Marcel Dekker, Inc., New York, 1978, which is incorporated herein by reference.

[0112] Additional active compounds also can be incorporated into the compositions. In certain embodiments, an anti-CD 154 antibody disclosed herein is co-formulated with and/or co-administered with one or more additional therapeutic agents. These agents include, without limitation, antibodies that bind other targets, anti -thrombotic drugs, anti-platelet drugs, nonsteroidal anti-inflammatory drugs (NSAIDs) and anti-allergy drugs. Such combination therapies may require lower dosages of the anti-CD154 antibody as well as the co-administered agents, thus avoiding possible toxicities or complications associated with the various monotherapies.

Method of preventing transplant rejection

[0113] A first aspect of the present disclosure provides a method of preventing transplant rejection in a transplant recipient. In some embodiments, the method comprises administering to the subject an effective amount of an anti-CD154 antibody disclosed herein. Optionally, a therapeutically effective amount of the anti-CD154 antibody is administered. In some embodiments, the anti-CD154 antibody is administered in a pharmaceutical composition disclosed herein.

[0114] A second aspect of the present disclosure provides an anti-CD154 antibody of the disclosure for use in treating or preventing a transplant rejection in a transplant recipient. Optionally, a therapeutically effective amount of the anti-CD154 antibody is used. In some embodiments, the anti-CD154 is formulated in a pharmaceutical composition disclosed herein. [0115] A third aspect of the present disclosure provides the use of an anti-CD154 antibody of the disclosure for in the manufacture of a medicament for treating or preventing a transplant rejection in a transplant recipient. Optionally, a therapeutically effective amount of the antiCD 154 antibody is used. In some embodiments, the anti-CD154 is formulated in a pharmaceutical composition disclosed herein.

[0116] In any of the above aspects, the anti-CD154 antibody may be administered simultaneously with the transplant. In any of the above aspects, the anti-CD154 antibody is formulated to be administered simultaneously with the transplant. In some embodiments of the above aspects, the anti-CD154 antibody is administered sequentially with the transplant. In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered sequentially with the transplant. Optionally, the anti-CD154 antibody is administered prior to the transplant. Optionally, in any of the above aspects, the anti-CD154 antibody is formulated administered prior to the transplant. In any of the above aspects, the anti-CD154 antibody may be administered subsequent to the transplant. In any of the above aspects, the anti-CD154 antibody may be formulated to be administered subsequent to the transplant. In some embodiments of the above aspects, the anti-CD154 is administered in a single dose. In some embodiments of the above aspects, the anti-CD154 is formulated to be administered in a single dose. Optionally, in any of the above aspects, the anti-CD154 antibody is administered in multiple doses. Optionally, in any of the above aspects the anti-CD154 antibody is formulated to be administered in multiple doses.

[0117] In any of the above aspects, the anti-CD154 antibody may be administered on a schedule such as once daily (Q1D), once every two days (Q2D), once every three days (Q3D), once weekly (Q1W), once every two weeks (Q2W), once every three weeks (Q3W), once every four weeks (Q4W), once every five weeks (Q5W), once every six weeks (Q6W), once every month (Q1M), once every two months (Q2M), or once every three months (Q3M). In some embodiments of the above aspects, the anti-CD154 antibody is administered once daily (Q1D). In some embodiments of the above aspects, the anti-CD154 antibody is administered once every two days (Q2D). In some embodiments of the above aspects, the anti-CD154 antibody is administered once every three days (Q3D). In some embodiments of the above aspects, the anti-CD154 antibody is administered once weekly (Q1W). In some embodiments of the above aspects, the anti-CD154 antibody is administered once every two weeks (Q2W). In some embodiments of the above aspects, the anti-CD154 antibody is administered once every three weeks (Q3W). In some embodiments of the above aspects, the anti-CD154 antibody is administered once every four weeks (Q4W). In some embodiments of the above aspects, the anti-CD154 antibody is administered once every five weeks (Q5W). In some embodiments of the above aspects, the anti-CD154 antibody is administered once every six weeks (Q6W). In some embodiments of the above aspects, the anti-CD154 antibody is administered once every month (Q1M). In some embodiments of the above aspects, the anti-CD154 antibody is administered once every two months (Q2M). In some embodiments of the above aspects, the anti-CD154 antibody is administered once every three months (Q3M).

[0118] In any of the above aspects, the anti-CD154 antibody may be formulated to be administered on a schedule such as once daily (Q1D), once every two days (Q2D), once every three days (Q3D), once weekly (Q1W), once every two weeks (Q2W), once every three weeks (Q3W), once every four weeks (Q4W), once every five weeks (Q5W), once every six weeks (Q6W), once every month (Q1M), once every two months (Q2M), or once every three months (Q3M). In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered once daily (Q1D). In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered once every two days (Q2D). In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered once every three days (Q3D). In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered once weekly (Q1W). In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered once every two weeks (Q2W). In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered once every three weeks (Q3W). In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered once every four weeks (Q4W). In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered once every five weeks (Q5W). In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered once every six weeks (Q6W). In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered once every month (Q1M). In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered once every two months (Q2M). In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered once every three months (Q3M).

[0119] In any of the above aspects, the anti-CD154 antibody may be administered at a dose of 5-50 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is administered at a dose of about 5 to about 50 mg/kg. In any of the above aspects, the anti- CD154 antibody may be administered at a dose of 5-30 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is administered at a dose of about 5 to about 30 mg/kg. Optionally, in any of the above aspects, the anti-CD154 antibody is administered at a dose of 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg or 50 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is administered at a dose of about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg or about 50 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is administered at a dose of about 5 mg/kg. In some embodiments of the above aspects, the antiCD 154 antibody is administered at a dose of about 10 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is administered at a dose of about 15 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is administered at a dose of about 20 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is administered at a dose of about 25 mg/kg. In some embodiments of the above aspects, the anti- CD154 antibody is administered at a dose of about 30 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is administered at a dose of about 35 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is administered at a dose of about 40 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is administered at a dose of about 45 mg/kg In some embodiments of the above aspects, the antiCD 154 antibody is administered at a dose of about 50 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is administered at a dose of 5 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is administered at a dose of 10 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is administered at a dose of 15 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is administered at a dose of 20 mg/kg. In some embodiments of the above aspects, the antiCD 154 antibody is administered at a dose of 25 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is administered at a dose of 30 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is administered at a dose of 35 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is administered at a dose of 40 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is administered at a dose of 45 mg/kg In some embodiments of the above aspects, the anti-CD154 antibody is administered at a dose of 50 mg/kg. In some embodiments of the above aspects, the antiCD 154 antibody is administered systemically. In any of the above aspects, the anti-CD154 antibody may be administered intravenously.

[0120] In any of the above aspects, the anti-CD154 antibody may be formulated to be administered at a dose of 5-50 mg/kg. In some embodiments of the above aspects, the antiCD 154 antibody is formulated to be administered at a dose of about 5 to about 50 mg/kg. In any of the above aspects, the anti-CD154 antibody may be formulated to be administered at a dose of 5-30 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered at a dose of about 5 to about 30 mg/kg. Optionally, in any of the above aspects, the anti-CD154 antibody is formulated to be administered at a dose of 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg or 50 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered at a dose of about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg or about 50 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered at a dose of about 5 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered at a dose of about 10 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered at a dose of about 15 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered at a dose of about 20 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered at a dose of about 25 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered at a dose of about 30 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered at a dose of about 35 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered at a dose of about 40 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered at a dose of about 45 mg/kg In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered at a dose of about 50 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered at a dose of 5 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered at a dose of 10 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered at a dose of 15 mg/kg. In some embodiments of the above aspects, the antiCD 154 antibody is formulated to be administered at a dose of 20 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered at a dose of 25 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered at a dose of 30 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered at a dose of 35 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered at a dose of 40 mg/kg. In some embodiments of the above aspects, the antiCD 154 antibody is formulated to be administered at a dose of 45 mg/kg In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered at a dose of 50 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered systemically. In any of the above aspects, the anti-CD154 antibody may be formulated to be administered intravenously.

[0121] In some embodiments of the above aspects, the antibody is administered at a flat dose selected from the group consisting of 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg, and 2000 mg. In some embodiments of the above aspects, the antibody is administered at a flat dose of 200 mg. In some embodiments of the above aspects, the antibody is administered at a flat dose of 300 mg. In some embodiments of the above aspects, the antibody is administered at a flat dose of 400 mg. In some embodiments of the above aspects, the antibody is administered at a flat dose of 500 mg. In some embodiments of the above aspects, the antibody is administered at a flat dose of 600 mg. In some embodiments of the above aspects, the antibody is administered at a flat dose of 700 mg. In some embodiments of the above aspects, the antibody is administered at a flat dose of 800 mg. In some embodiments of the above aspects, the antibody is administered at a flat dose of 900 mg. In some embodiments of the above aspects, the antibody is administered at a flat dose of 1000 mg. In some embodiments of the above aspects, the antibody is administered at a flat dose of 1100 mg. In some embodiments of the above aspects, the antibody is administered at a flat dose of 1200 mg of the above aspects. In some embodiments of the above aspects, the antibody is administered at a flat dose of 1300 mg. In some embodiments of the above aspects, the antibody is administered at a flat dose of 1400 mg. In some embodiments of the above aspects, the antibody is administered at a flat dose of 1500 mg. In some embodiments of the above aspects, the antibody is administered at a flat dose of 1600 mg. In some embodiments of the above aspects, the antibody is administered at a flat dose of 1700 mg. In some embodiments of the above aspects, the antibody is administered at a flat dose of 1800 mg of the above aspects. In some embodiments, the antibody is administered at a flat dose of 1900 mg of the above aspects. In some embodiments of the above aspects, the antibody is administered at a flat dose of 2000 mg. [0122] In some embodiments of the above aspects, the antibody is formulated to be administered at a flat dose selected from the group consisting of 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg, and 2000 mg. In some embodiments of the above aspects, the antibody is formulated to be administered at a flat dose of 200 mg. In some embodiments of the above aspects, the antibody is formulated to be administered at a flat dose of 300 mg. In some embodiments of the above aspects, the antibody is formulated to be administered at a flat dose of 400 mg. In some embodiments of the above aspects, the antibody is formulated to be administered at a flat dose of 500 mg. In some embodiments of the above aspects, the antibody is formulated to be administered at a flat dose of 600 mg. In some embodiments of the above aspects, the antibody is formulated to be administered at a flat dose of 700 mg. In some embodiments of the above aspects, the antibody is formulated to be administered at a flat dose of 800 mg. In some embodiments of the above aspects, the antibody is formulated to be administered at a flat dose of 900 mg. In some embodiments of the above aspects, the antibody is formulated to be administered at a flat dose of 1000 mg. In some embodiments of the above aspects, the antibody is formulated to be administered at a flat dose of 1100 mg. In some embodiments of the above aspects, the antibody is formulated to be administered at a flat dose of 1200 mg. In some embodiments of the above aspects, the antibody is formulated to be administered at a flat dose of 1300 mg. In some embodiments of the above aspects, the antibody is formulated to be administered at a flat dose of 1400 mg. In some embodiments of the above aspects, the antibody is formulated to be administered at a flat dose of 1500 mg. In some embodiments of the above aspects, the antibody is formulated to be administered at a flat dose of 1600 mg. In some embodiments of the above aspects, the antibody is formulated to be administered at a flat dose of 1700 mg. In some embodiments of the above aspects, the antibody is formulated to be administered at a flat dose of 1800 mg. In some embodiments of the above aspects, the antibody is formulated to be administered at a flat dose of 1900 mg. In some embodiments of the above aspects, the antibody is formulated to be administered at a flat dose of 2000 mg.

[0123] In some embodiments of any of the above aspects, the antibody is administered at a frequency of Q4W at a dose of 20 mg/kg. In some embodiments of any of the above aspects, the antibody is formulated to be administered at a frequency of Q4W at a dose of 20 mg/kg. In some embodiments of any of the above aspects, the antibody is administered at a frequency of Q4W at a dose of 1200 mg. In some embodiments of any of the above aspects, the antibody is formulated to be administered at a frequency of Q4W at a dose of 1200 mg. In some embodiments of any of the above aspects, the antibody is administered at a frequency of once per month at a dose of 20 mg/kg. In some embodiments of any of the above aspects, the antibody is formulated to be administered at a frequency of once per month at a dose of 20 mg/kg. In some embodiments of any of the above aspects, the antibody is administered at a frequency of once per month at a dose of 1200 mg. In some embodiments of any of the above aspects, the antibody is formulated to be administered at a frequency of once per month at a dose of 1200 mg. [0124] In any of the above aspects, the antibody is administered in a loading dose followed by a maintenance dose. In some embodiments of any of the above aspects, the loading dose is administered until a serum concentration of TNX-1500 > 750 pg/ml is obtained. In some embodiments of any of the above aspects, the loading dose is 20 mg/kg on days 0, 2, 5, 7 and weekly until a serum concentration of TNX-1500 > 750 pg/ml is obtained. In some embodiments of any of the above aspects, the loading dose is 30 mg/kg. In some embodiments of any of the above aspects, the loading dose is 20 mg/kg. In some embodiments of any of the above aspects, the loading dose is 30 mg/kg twice per week (BIW). In some embodiments of any of the above aspects, the loading dose is 20 mg/kg twice per week. In some embodiments of any of the above aspects, the loading dose is 20 mg/kg on days 0, 2, 5, 7 and weekly for one to six weeks. In some embodiments of any of the above aspects, the loading dose is 30 mg/kg on days 0, 2, 5, 7 and weekly for one to six weeks. In some embodiments of any of the above aspects, the loading dose is 20 mg/kg on days 0, 2, 5, 7 and weekly for one week. In some embodiments of any of the above aspects, the loading dose is 30 mg/kg biweekly for two weeks. In some embodiments of any of the above aspects, the loading dose is 20 mg/kg on days 0, 2, 5, 7 and weekly for two weeks. In some embodiments of any of the above aspects, the loading dose is 20 mg/kg on days 0, 2, 5, 7 and weekly for three weeks. In some embodiments of any of the above aspects, the loading dose is 20 mg/kg on days 0, 2, 5, 7 and weekly for four weeks. In some embodiments of any of the above aspects, the loading dose is 20 mg/kg on days 0, 2, 5, 7 and weekly for five weeks. In some embodiments of any of the above aspects, the loading dose is 20 mg/kg on days 0, 2, 5, 7 and weekly for six weeks. In some embodiments of any of the above aspects, the maintenance dose is 20 mg/kg. In some embodiments of any of the above aspects, the maintenance dose is 20 mg/kg at a frequency of Q1W. In some embodiments of any of the above aspects, the maintenance dose is 20 mg/kg at a frequency of Q4W. In some embodiments of any of the above aspects, the maintenance dose is 20 mg/kg at a frequency of once per month. In some embodiments, the loading dose is 30 mg/kg twice a week, and the maintenance dose is 20 mg/kg Q1W. In some embodiments, the loading dose is 30 mg/kg twice a week for two weeks, and the maintenance dose is 20 mg/kg Q1W.

[0125] In some embodiments of any of the above aspects, the loading dose is 20 mg/kg on days 0, 2, 5, 7 and weekly until a serum concentration of TNX-1500 > 750 pg/ml is obtained, and the maintenance dose is 20 mg/kg at a frequency of Q4W. In some embodiments of any of the above aspects, the loading dose is 20 mg/kg on days 0, 2, 5, 7 and weekly for one to six weeks, and the maintenance dose is 20 mg/kg at a frequency of Q4W. In some embodiments of any of the above aspects, the loading dose is 20 mg/kg on days 0, 2, 5, 7 and weekly for one week, and the maintenance dose is 20 mg/kg at a frequency of Q4W. In some embodiments of any of the above aspects, the loading dose is 20 mg/kg on days 0, 2, 5, 7 and weekly for two weeks, and the maintenance dose is 20 mg/kg at a frequency of Q4W. In some embodiments of any of the above aspects, the loading dose is 20 mg/kg on days 0, 2, 5, 7 and weekly for three weeks, and the maintenance dose is 20 mg/kg at a frequency of Q4W. In some embodiments of any of the above aspects, the loading dose is 20 mg/kg on days 0, 2, 5, 7 and weekly for four weeks, and the maintenance dose is 20 mg/kg at a frequency of Q4W. In some embodiments of any of the above aspects, the loading dose is 20 mg/kg on days 0, 2, 5, 7 and weekly for five weeks, and the maintenance dose is 20 mg/kg at a frequency of Q4W. In some embodiments of any of the above aspects, the loading dose is 20 mg/kg on days 0, 2, 5, 7 and weekly for six weeks, and the maintenance dose is 20 mg/kg at a frequency of Q4W.

[0126] In some embodiments of any of the above aspects, the loading dose is 20 mg/kg on days 0, 2, 5, 7 and weekly until a serum concentration of TNX-1500 > 750 pg/ml is obtained, and the maintenance dose is 20 mg/kg at a frequency of once per month. In some embodiments of any of the above aspects, the loading dose is 20 mg/kg on days 0, 2, 5, 7 and weekly for one to six weeks, and the maintenance dose is 20 mg/kg at a frequency of once per month. In some embodiments of any of the above aspects, the loading dose is 20 mg/kg on days 0, 2, 5, 7 and weekly for one week, and the maintenance dose is 20 mg/kg at a frequency of once per month. In some embodiments of any of the above aspects, the loading dose is 20 mg/kg on days 0, 2, 5, 7 and weekly for two weeks, and the maintenance dose is 20 mg/kg at a frequency of once per month. In some embodiments of any of the above aspects, the loading dose is 20 mg/kg on days 0, 2, 5, 7 and weekly for three weeks, and the maintenance dose is 20 mg/kg at a frequency of once per month. In some embodiments of any of the above aspects, the loading dose is 20 mg/kg on days 0, 2, 5, 7 and weekly for four weeks, and the maintenance dose is 20 mg/kg at a frequency of once per month. In some embodiments of any of the above aspects, the loading dose is 20 mg/kg on days 0, 2, 5, 7 and weekly for five weeks, and the maintenance dose is 20 mg/kg at a frequency of once per month. In some embodiments of any of the above aspects, the loading dose is 20 mg/kg on days 0, 2, 5, 7 and weekly for six weeks, and the maintenance dose is 20 mg/kg at a frequency of once per month.

[0127] In some embodiments of any of the above aspects, the loading dose is 1200 mg on days 0, 2, 5, 7 and weekly until a serum concentration of TNX-1500 > 750 pg/ml is obtained. In some embodiments of any of the above aspects, the loading dose is 1200 mg on days 0, 2, 5, 7 and weekly for one to six weeks. In some embodiments of any of the above aspects, the loading dose is 1200 mg on days 0, 2, 5, 7 and weekly for one week. In some embodiments of any of the above aspects, the loading dose is 1200 mg on days 0, 2, 5, 7 and weekly for two weeks. In some embodiments of any of the above aspects, the loading dose is 1200 mg on days 0, 2, 5, 7 and weekly for three weeks. In some embodiments of any of the above aspects, the loading dose is 1200 mg on days 0, 2, 5, 7 and weekly for four weeks. In some embodiments of any of the above aspects, the loading dose is 1200 mg on days 0, 2, 5, 7 and weekly for five weeks. In some embodiments of any of the above aspects, the loading dose is 1200 mg on days 0, 2, 5, 7 and weekly for six weeks. In some embodiments of any of the above aspects, the maintenance dose is 1200 mg at a frequency of Q4W. In some embodiments of any of the above aspects, the maintenance dose is 1200 mg at a frequency of once per month.

[0128] In some embodiments of any of the above aspects, the loading dose is 1200 mg on days 0, 2, 5, 7 and weekly until a serum concentration of TNX-1500 > 750 pg/ml is obtained, and the maintenance dose is 1200 mg at a frequency of Q4W. In some embodiments of any of the above aspects, the loading dose is 1200 mg on days 0, 2, 5, 7 and weekly for one to six weeks, and the maintenance dose is 1200 mg at a frequency of Q4W. In some embodiments of any of the above aspects, the loading dose is 1200 mg on days 0, 2, 5, 7 and weekly for one week, and the maintenance dose is 1200 mg at a frequency of Q4W. In some embodiments of any of the above aspects, the loading dose is 1200 mg on days 0, 2, 5, 7 and weekly for two weeks, and the maintenance dose is 1200 mg at a frequency of Q4W. In some embodiments of any of the above aspects, the loading dose is 1200 mg on days 0, 2, 5, 7 and weekly for three weeks, and the maintenance dose is 1200 mg at a frequency of Q4W. In some embodiments of any of the above aspects, the loading dose is 1200 mg on days 0, 2, 5, 7 and weekly for four weeks, and the maintenance dose is 1200 mg at a frequency of Q4W. In some embodiments of any of the above aspects, the loading dose is 1200 mg on days 0, 2, 5, 7 and weekly for five weeks, and the maintenance dose is 1200 mg at a frequency of Q4W. In some embodiments of any of the above aspects, the loading dose is 1200 mg on days 0, 2, 5, 7 and weekly for six weeks, and the maintenance dose is 1200 mg at a frequency of Q4W.

[0129] In some embodiments of any of the above aspects, the loading dose is 1200 mg on days 0, 2, 5, 7 and weekly until a serum concentration of TNX-1500 > 750 pg/ml is obtained, and the maintenance dose is 1200 mg at a frequency of once per month. In some embodiments of any of the above aspects, the loading dose is 1200 mg on days 0, 2, 5, 7 and weekly for one to six weeks, and the maintenance dose is 1200 mg at a frequency of once per month. In some embodiments of any of the above aspects, the loading dose is 1200 mg on days 0, 2, 5, 7 and weekly for one week, and the maintenance dose is 1200 mg at a frequency of once per month. In some embodiments of any of the above aspects, the loading dose is 1200 mg on days 0, 2, 5, 7 and weekly for two weeks, and the maintenance dose is 1200 mg at a frequency of once per month. In some embodiments of any of the above aspects, the loading dose is 1200 mg on days 0, 2, 5, 7 and weekly for three weeks, and the maintenance dose is 1200 mg at a frequency of once per month. In some embodiments of any of the above aspects, the loading dose is 1200 mg on days 0, 2, 5, 7 and weekly for four weeks, and the maintenance dose is 1200 mg at a frequency of once per month. In some embodiments of any of the above aspects, the loading dose is 1200 mg on days 0, 2, 5, 7 and weekly for five weeks, and the maintenance dose is 1200 mg at a frequency of once per month. In some embodiments of any of the above aspects, the loading dose is 1200 mg on days 0, 2, 5, 7 and weekly for six weeks, and the maintenance dose is 1200 mg at a frequency of once per month.

[0130] In some embodiments of any of the above aspects, the loading dose is 1800 mg. In some embodiments of any of the above aspects, the loading dose is 1800 mg on Day 1 followed by maintenance doses administered Q4W starting at Week 4. In some embodiments of any of the above aspects, the loading dose is 1800 mg on Day 1 followed by maintenance doses administered monthly starting at one month after the loading dose. In some embodiments of any of the above aspects, the maintenance dose is 1200 mg at a frequency of Q4W. In some embodiments of any of the above aspects, the maintenance dose is 1200 mg at a frequency of once per month. In some embodiments of any of the above aspects, the loading dose is 1800 mg on Day 1 followed by maintenance doses of 1200 mg administered Q4W starting at Week 4. In some embodiments of any of the above aspects, the loading dose is 1800 mg on Day 1 followed by maintenance doses of 1200 mg administered monthly starting at one month after the loading dose. [0131] In any of the above aspects, the transplant recipient may be human. In some embodiments of the above aspects, the transplant is a xenotransplant. The xenotransplant may be from a non-human donor. In some embodiments, the non-human donor is selected from a group consisting of a pig, a mini-swine, and a non-human primate. Optionally, the non-human donor is a pig or mini-swine that has been engineered to decrease or eliminate expression of one or more genes. In some embodiments, the one or more decreased or eliminated genes include, but are not limited to, porcine endogenous retroviruses (PERV), a-1,3- galactosyltransferase (GGTA1), cytidine monophosphate-N-acetylneuraminic acid hydroxylase (CMAH), pi,4-N-acetylgalactosaminyltransferase (P4GalNT2), and MHC class I. Optionally, the one or more decreased or eliminated genes comprise PERV. The PERV may be PERV A, a PERV B, or a PERV C. The expression of all PERV genes may be eliminated in the pig or mini-swine. The expression of the one or more genes may be decreased or eliminated using CRISPR/Cas9 gene editing.

[0132] In some embodiments, the non-human donor may be engineered to express one or more human proteins. Examples of one or more human proteins include, but are not limited to, complement regulatory protein, human a-galactosidase, a coagulation regulatory protein, a human anti-inflammatory protein, and human CTLA-4-Ig or a combination thereof. The one or more human proteins may be expressed in all tissues of the non-human donor. In some embodiments, the one or more human proteins are expressed in a tissue-specific manner in the non-human donor. Examples of complement regulatory protein include, but are not limited to, human decay-accelerating factor (CD55), membrane cofactor protein (CD46) and CD59. Examples of coagulation regulatory proteins include, but are not limited to, thrombomodulin, endothelial protein C receptor, tissue factor pathway inhibitor, CD39, and CD73. Examples of human anti-inflammatory proteins include, but are not limited to, hemeoxygenase-1 (HO-1) and A20.

[0133] In any of the above aspects, the transplant rejection may be an acute or a chronic humoral rejection of a grafted cell, tissue, or organ. In any of the above aspects, the transplant rejection may be an acute or chronic graft rejection in a graft recipient of an allogeneic transplant or xenotransplant. The methods disclosed herein may promote a long-term graft survival of the grafted cell, tissue, or organ. Optionally, the long-term graft survival is at least 6 months post-transplant, at least lyear post-transplant or at least 5 years post-transplant. [0134] In any of the above aspects, the transplant rejection may be associated with the transplantation of hematopoietic cells or bone marrow, an allogeneic transplant of pancreatic islet cells, graft vs host disease, or a solid organ transplant. In some embodiments of the any of the above aspects, the transplant rejection is associated with the transplantation of hematopoietic cells. In some embodiments of the any of the above aspects, the transplant rejection is associated with the transplantation of bone marrow. In some embodiments of the any of the above aspects, the transplant rejection is associated with an allogeneic transplant of pancreatic islet cells. In some embodiments of the any of the above aspects, the transplant rejection is associated with graft vs host disease. In some embodiments of the any of the above aspects, the transplant rejection is associated with a solid organ transplant.

[0135] In any of the above aspects, the transplant rejection may be associated with a solid organ transplant selected from the group consisting of a heart transplant, a kidney transplant, a liver transplant, a lung transplant, a pancreas transplant, an intestines transplant, a kidneypancreas transplant, a heart-lung transplant, a kidney-heart transplant, a kidney -heart-pancreas transplant, a heart-liver transplant, a heart-liver-kidney transplant, a heart-lung-kidney transplant, a heart-lung-liver transplant, a lung-kidney transplant, a lung-liver transplant, a liver-intestines-pancreas transplant, an intestines-pancreas transplant, a liver-kidney- intestines-pancreas transplant, and a kidney-intestines transplant. In some embodiments of any of the above aspects, the transplant rejection is associated with a heart transplant. In some embodiments of any of the above aspects, the transplant rejection is associated with a kidney transplant. In some embodiments of any of the above aspects, the transplant rejection is associated with a liver transplant. In some embodiments of any of the above aspects, the transplant rejection is associated with a lung transplant. In some embodiments of any of the above aspects, the transplant rejection is associated with a pancreas transplant. In some embodiments of any of the above aspects, the transplant rejection is associated with an intestines transplant. In some embodiments of any of the above aspects, the transplant rejection is associated with a kidney-pancreas transplant. In some embodiments of any of the above aspects, the transplant rejection is associated with a heart-lung transplant. In some embodiments of any of the above aspects, the transplant rejection is associated with a kidneyheart transplant. In some embodiments of any of the above aspects, the transplant rejection is associated with a kidney-heart-pancreas transplant. In some embodiments of any of the above aspects, the transplant rejection is associated with a heart-liver transplant. In some embodiments of any of the above aspects, the transplant rejection is associated with a heartliver-kidney transplant. In some embodiments of any of the above aspects, the transplant rejection is associated with a heart-lung-kidney transplant. In some embodiments of any of the above aspects, the transplant rejection is associated with a heart-lung-liver transplant. In some embodiments of any of the above aspects, the transplant rejection is associated with a lungkidney transplant. In some embodiments of any of the above aspects, the transplant rejection is associated with a lung-liver transplant. In some embodiments of any of the above aspects, the transplant rejection is associated with a liver-intestines-pancreas transplant. In some embodiments of any of the above aspects, the transplant rejection is associated with an intestines-pancreas transplant. In some embodiments of any of the above aspects, the transplant rejection is associated with a liver-kidney-intestines-pancreas transplant. In some embodiments of any of the above aspects, the transplant rejection is associated with a kidneyintestines transplant.

[0136] In some embodiments of any of the above aspects, the administration of the antiCD 154 antibody modulates the immune system of the transplant recipient. Modulation of the transplant recipient’s immune system can be demonstrated by blockade of anti -Keyhole Limpet Hemocyanin (anti-KLH) antibody production. The blockade may be of the primary anti-KLH antibody response, the secondary anti-KLH antibody response, or both. Modulation of the transplant recipient’s immune system can be demonstrated by decreased levels of soluble CD 154 in the transplant recipient’s blood.

[0137] In some embodiments of any of the above aspects, the method comprises administering to said mammal a therapeutically effective amount of an anti-CD154 antibody disclosed herein in combination with one or more additional agents. In some embodiments of any of the above aspects, the anti-CD154 antibody disclosed herein is formulated to be administered in combination with one or more additional agents. Optionally, the one or more additional agents is selected from the group consisting of anti -thrombotic drugs, anti-platelet drugs and non-steroidal anti-inflammatory drugs (NSAIDs). The anti-CD154 antibody may be administered simultaneously with the one or more additional agents. The anti-CD154 antibody may be formulated to be administered simultaneously with the one or more additional agents. In some embodiments, the anti-CD154 antibody is administered sequentially with the one or more additional agents. In some embodiments, the anti-CD154 antibody is formulated to be administered sequentially with the one or more additional agents. Optionally, the anti-CD154 antibody is administered prior to the one or more additional agents. Optionally, the anti-CD 154 antibody is formulated to be administered prior to the one or more additional agents. The antiCD 154 antibody may be administered subsequent to the one or more additional agents. The anti-CD 154 antibody may be formulated to be administered subsequent to the one or more additional agents. In some embodiments, the anti-CD 154 antibody is administered in the same composition as the one or more additional agents. In some embodiments, the anti-CD 154 antibody in the same composition as the one or more additional agents. Optionally, the anti- CD 154 antibody and the one or more additional agents are in separate compositions. In some embodiments, the one or more additional agents comprises a conventional immunosuppressive agent. Non-limiting examples of conventional immunosuppressive agents include mycophenolate mofetil (MMF), rapamycin, and tacrolimus. In some embodiments, the conventional immunosuppressive agent is mycophenolate mofetil (MMF). In some embodiments, the conventional immunosuppressive agent is rapamycin. In some embodiments, the conventional immunosuppressive agent is tacrolimus.

[0138] Non-limiting examples of anti -thrombotic drugs include but are not limited to a glycoprotein Ilb/IIIa receptor antagonist, a direct or indirect factor Xa inhibitor and an anticoagulant. Non-limiting examples of anticoagulants include, but are not limited to, heparin, warfarin, rivaroxaban (XARELTO®), ximelgatran (EXANTA®), dabigatran (PRADAXA®), apixaban (ELIQUIS®), edoxaban (S AV AYS A®), enoxaparin (LOVENOX®), and fondaparinux (ARIXTRA®). Non-limiting examples of anti -thrombotic drugs include, but are not limited to, those disclosed in US Patent Nos. 4,782,069; 5,332,822; 5,492,895; 5,612,363, 5,691,364 5,693,641; 5,721,214; 5,726,173; 5,753,635; 5,846,970; 5,849,759; 5,889,005;

6,107,280; 6,140,351; 6,150,329; 6,180,627; 6,200,976; 6,242,432; 6,248,770; 6,271,215;

6,280,731; 6,287,794; 6,300,330; 6,300,342; 6,333,338; 6,395,731; 6,417,203; 6,432,955;

6,444,672; 6,451,832; 6,458,793; 6,486,129; 6,500,803; 6,583,173; 6,599,881; 6,723,723;

6,730,672; 6,753,331; 6,774,110; 6,797,710; and 6,924,296, incorporated in their entirety for all purposes. Non-limiting examples of glycoprotein Ilb/IIIa receptor antagonists include, but are not limited to, abciximab (REOPRO®), rivaroxaban (XARELTO®), apixaban (ELIQUIS®), edoxaban (SAVAYSA®), idrabiotaparinux, tirofiban (AGGRASTAT®), and eptifibatide (INTEGRILIN®). The direct or indirect factor Xa inhibitors include, but are not limited to, apixaban (ELIQUIS®), idrabiotaparinux, fondaparinux (ARIXTRA®), and rivaroxaban (XARELTO®). [0139] Non-limiting examples of anti-platelet drugs include, but are not limited to, TXA2 pathway inhibitors, the adenosine diphosphate (ADP) pathway inhibitors, thrombin inhibitors, Protease activated receptor-1 (PAR-1) inhibitors and phosphodiesterase (PDE) inhibitors. Non-limiting examples of ADP pathway inhibitors include, but are not limited, to clopidogrel (PLAVIX®, ticlopidine (TICLID®), prasugrel (EFFIENT®), ticagrelor (BRILINTA®), cangrelor (KENGREAL®) and elinogrel. Non-limiting examples of PDE inhibitors include dipyridamole (PERSANTINE®) and cilostazol (PLETAL®).

[0140] Non-limiting examples of NSAIDs include, but are not limited to, acetylsalicylic acid, celecoxib (CELEBREX®), diclofenac (VOLTAREN®, PENNSAID®, SOLARAZE®, ZIPSOR®, CATAFLAM®, ZORVOLEX®), diflunisal (DOLOBID®), etodolac (LODINE SR®, ECCOXOLAC®), ibuprofen (BRUFEN®, ADVIL®, MOTRIN®), indomethacin (INDOCIN®), ketoprofen (ORUDIS®), ketorolac (TORADOL®, ACULAR®, SPRIX®), nabumetone (RELAFEN®), naproxen (AFLAXEN®, ALEVE®, ANAPROX®, NAPRELAN®), oxaprozin (DAYPRO®, DAYRUN®, DURAPROX®), piroxicam (FELDENE®), salsalate (MONO-GESIC®, SALFLEX®, DISALCID®, SALSITAB®), sulindac (CLINORIL®), tolmetin (TOLECTIN®), prasugrel (EFFIENT®), ticagrelor (BRILINTA®) and cangrelor (KENGREAL®).

Method of treating an immune-related disease

[0141] A fourth aspect of the present disclosure provides a method of treating an immune- related disease in a subject in need thereof. In some embodiments, the method comprises administering to the subject an effective amount of an anti-CD154 antibody disclosed herein. Optionally, a therapeutically effective amount of the anti-CD154 antibody is administered. In some embodiments, the anti-CD154 antibody is administered in a pharmaceutical composition disclosed herein.

[0142] A fifth aspect of the present disclosure provides an anti-CD154 antibody of the disclosure for use in treating an immune-related disease in a subject in need thereof. Optionally, a therapeutically effective amount of the anti-CD154 antibody is used. In some embodiments, the anti-CD154 is formulated in a pharmaceutical composition disclosed herein. [0143] A sixth aspect of the present disclosure provides the use of an anti-CD154 antibody of the disclosure for in the manufacture of a medicament for treating an immune-related disease in a subject in need thereof. Optionally, a therapeutically effective amount of the anti-CD154 antibody is used. In some embodiments, the anti-CD154 is formulated in a pharmaceutical composition disclosed herein.

[0144] In some embodiments of the above aspects, the anti-CD154 is administered in a single dose. In some embodiments of the above aspects, the anti-CD154 is formulated to be administered in a single dose. Optionally, in any of the above aspects, the anti-CD154 antibody is administered in multiple doses. Optionally, in any of the above aspects the anti-CD154 antibody is formulated to be administered in multiple doses.

[0145] In any of the above aspects, the anti-CD154 antibody may be administered on a schedule such as once daily (Q1D), once every two days (Q2D), once every three days (Q3D), once weekly (Q1W), once every two weeks (Q2W), once every three weeks (Q3W), once every four weeks (Q4W), once every five weeks (Q5W), once every six weeks (Q6W), once every month (Q1M), once every two months (Q2M), or once every three months (Q3M). In some embodiments of the above aspects, the anti-CD154 antibody is administered once daily (Q1D). In some embodiments of the above aspects, the anti-CD154 antibody is administered once every two days (Q2D). In some embodiments of the above aspects, the anti-CD154 antibody is administered once every three days (Q3D). In some embodiments of the above aspects, the anti-CD154 antibody is administered once weekly (Q1W). In some embodiments of the above aspects, the anti-CD154 antibody is administered once every two weeks (Q2W). In some embodiments of the above aspects, the anti-CD154 antibody is administered once every three weeks (Q3W). In some embodiments of the above aspects, the anti-CD154 antibody is administered once every four weeks (Q4W). In some embodiments of the above aspects, the anti-CD154 antibody is administered once every five weeks (Q5W). In some embodiments of the above aspects, the anti-CD154 antibody is administered once every six weeks (Q6W). In some embodiments of the above aspects, the anti-CD154 antibody is administered once every month (Q1M). In some embodiments of the above aspects, the anti-CD154 antibody is administered once every two months (Q2M). In some embodiments of the above aspects, the anti-CD154 antibody is administered once every three months (Q3M).

[0146] In any of the above aspects, the anti-CD154 antibody may be formulated to be administered on a schedule such as once daily (Q1D), once every two days (Q2D), once every three days (Q3D), once weekly (Q1W), once every two weeks (Q2W), once every three weeks (Q3W), once every four weeks (Q4W), once every five weeks (Q5W), once every six weeks (Q6W), once every month (Q1M), once every two months (Q2M), or once every three months (Q3M). In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered once daily (Q1D). In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered once every two days (Q2D). In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered once every three days (Q3D). In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered once weekly (Q1W). In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered once every two weeks (Q2W). In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered once every three weeks (Q3W). In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered once every four weeks (Q4W). In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered once every five weeks (Q5W). In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered once every six weeks (Q6W). In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered once every month (Q1M). In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered once every two months (Q2M). In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered once every three months (Q3M).

[0147] In any of the above aspects, the anti-CD154 antibody may be administered at a dose of 5-50 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is administered at a dose of about 5 to about 50 mg/kg. In any of the above aspects, the anti- CD154 antibody may be administered at a dose of 5-30 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is administered at a dose of about 5 to about 30 mg/kg. Optionally, in any of the above aspects, the anti-CD154 antibody is administered at a dose of 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg or 50 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is administered at a dose of about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg or about 50 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is administered at a dose of about 5 mg/kg. In some embodiments of the above aspects, the antiCD 154 antibody is administered at a dose of about 10 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is administered at a dose of about 15 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is administered at a dose of about 20 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is administered at a dose of about 25 mg/kg. In some embodiments of the above aspects, the anti- CD154 antibody is administered at a dose of about 30 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is administered at a dose of about 35 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is administered at a dose of about 40 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is administered at a dose of about 45 mg/kg In some embodiments of the above aspects, the antiCD 154 antibody is administered at a dose of about 50 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is administered at a dose of 5 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is administered at a dose of 10 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is administered at a dose of 15 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is administered at a dose of 20 mg/kg. In some embodiments of the above aspects, the antiCD 154 antibody is administered at a dose of 25 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is administered at a dose of 30 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is administered at a dose of 35 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is administered at a dose of 40 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is administered at a dose of 45 mg/kg In some embodiments of the above aspects, the anti-CD154 antibody is administered at a dose of 50 mg/kg. In some embodiments of the above aspects, the antiCD 154 antibody is administered systemically. In any of the above aspects, the anti-CD154 antibody may be administered intravenously.

[0148] In any of the above aspects, the anti-CD154 antibody may be formulated to be administered at a dose of 5-50 mg/kg. In some embodiments of the above aspects, the antiCD 154 antibody is formulated to be administered at a dose of about 5 to about 50 mg/kg. In any of the above aspects, the anti-CD154 antibody may be formulated to be administered at a dose of 5-30 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered at a dose of about 5 to about 30 mg/kg. Optionally, in any of the above aspects, the anti-CD154 antibody is formulated to be administered at a dose of 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg or 50 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered at a dose of about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg or about 50 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered at a dose of about 5 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered at a dose of about 10 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered at a dose of about 15 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered at a dose of about 20 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered at a dose of about 25 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered at a dose of about 30 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered at a dose of about 35 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered at a dose of about 40 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered at a dose of about 45 mg/kg In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered at a dose of about 50 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered at a dose of 5 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered at a dose of 10 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered at a dose of 15 mg/kg. In some embodiments of the above aspects, the antiCD 154 antibody is formulated to be administered at a dose of 20 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered at a dose of 25 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered at a dose of 30 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered at a dose of 35 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered at a dose of 40 mg/kg. In some embodiments of the above aspects, the antiCD 154 antibody is formulated to be administered at a dose of 45 mg/kg In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered at a dose of 50 mg/kg. In some embodiments of the above aspects, the anti-CD154 antibody is formulated to be administered systemically. In any of the above aspects, the anti-CD154 antibody may be formulated to be administered intravenously.

[0149] In some embodiments of the above aspects, the antibody is administered at a flat dose selected from the group consisting of 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg, and 2000 mg. In some embodiments of the above aspects, the antibody is administered at a flat dose of 200 mg. In some embodiments of the above aspects, the antibody is administered at a flat dose of 300 mg. In some embodiments of the above aspects, the antibody is administered at a flat dose of 400 mg. In some embodiments of the above aspects, the antibody is administered at a flat dose of 500 mg. In some embodiments of the above aspects, the antibody is administered at a flat dose of 600 mg. In some embodiments of the above aspects, the antibody is administered at a flat dose of 700 mg. In some embodiments of the above aspects, the antibody is administered at a flat dose of 800 mg. In some embodiments of the above aspects, the antibody is administered at a flat dose of 900 mg. In some embodiments of the above aspects, the antibody is administered at a flat dose of 1000 mg. In some embodiments of the above aspects, the antibody is administered at a flat dose of 1100 mg. In some embodiments of the above aspects, the antibody is administered at a flat dose of 1200 mg of the above aspects. In some embodiments of the above aspects, the antibody is administered at a flat dose of 1300 mg. In some embodiments of the above aspects, the antibody is administered at a flat dose of 1400 mg. In some embodiments of the above aspects, the antibody is administered at a flat dose of 1500 mg. In some embodiments of the above aspects, the antibody is administered at a flat dose of 1600 mg. In some embodiments of the above aspects, the antibody is administered at a flat dose of 1700 mg. In some embodiments of the above aspects, the antibody is administered at a flat dose of 1800 mg of the above aspects. In some embodiments, the antibody is administered at a flat dose of 1900 mg of the above aspects. In some embodiments of the above aspects, the antibody is administered at a flat dose of 2000 mg. [0150] In some embodiments of the above aspects, the antibody is formulated to be administered at a flat dose selected from the group consisting of 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg, and 2000 mg. In some embodiments of the above aspects, the antibody is formulated to be administered at a flat dose of 200 mg. In some embodiments of the above aspects, the antibody is formulated to be administered at a flat dose of 300 mg. In some embodiments of the above aspects, the antibody is formulated to be administered at a flat dose of 400 mg. In some embodiments of the above aspects, the antibody is formulated to be administered at a flat dose of 500 mg. In some embodiments of the above aspects, the antibody is formulated to be administered at a flat dose of 600 mg. In some embodiments of the above aspects, the antibody is formulated to be administered at a flat dose of 700 mg. In some embodiments of the above aspects, the antibody is formulated to be administered at a flat dose of 800 mg. In some embodiments of the above aspects, the antibody is formulated to be administered at a flat dose of 900 mg. In some embodiments of the above aspects, the antibody is formulated to be administered at a flat dose of 1000 mg. In some embodiments of the above aspects, the antibody is formulated to be administered at a flat dose of 1100 mg. In some embodiments of the above aspects, the antibody is formulated to be administered at a flat dose of 1200 mg. In some embodiments of the above aspects, the antibody is formulated to be administered at a flat dose of 1300 mg. In some embodiments of the above aspects, the antibody is formulated to be administered at a flat dose of 1400 mg. In some embodiments of the above aspects, the antibody is formulated to be administered at a flat dose of 1500 mg. In some embodiments of the above aspects, the antibody is formulated to be administered at a flat dose of 1600 mg. In some embodiments of the above aspects, the antibody is formulated to be administered at a flat dose of 1700 mg. In some embodiments of the above aspects, the antibody is formulated to be administered at a flat dose of 1800 mg. In some embodiments of the above aspects, the antibody is formulated to be administered at a flat dose of 1900 mg. In some embodiments of the above aspects, the antibody is formulated to be administered at a flat dose of 2000 mg.

[0151] In some embodiments of any of the above aspects, the antibody is administered at a frequency of Q4W at a dose of 20 mg/kg. In some embodiments of any of the above aspects, the antibody is formulated to be administered at a frequency of Q4W at a dose of 20 mg/kg. In some embodiments of any of the above aspects, the antibody is administered at a frequency of Q4W at a dose of 1200 mg. In some embodiments of any of the above aspects, the antibody is formulated to be administered at a frequency of Q4W at a dose of 1200 mg. In some embodiments of any of the above aspects, the antibody is administered at a frequency of once per month at a dose of 20 mg/kg. In some embodiments of any of the above aspects, the antibody is formulated to be administered at a frequency of once per month at a dose of 20 mg/kg. In some embodiments of any of the above aspects, the antibody is administered at a frequency of once per month at a dose of 1200 mg. In some embodiments of any of the above aspects, the antibody is formulated to be administered at a frequency of once per month at a dose of 1200 mg.

[0152] In any of the above aspects, the antibody is administered in a loading dose followed by a maintenance dose. In some embodiments of any of the above aspects, the loading dose is administered until a serum concentration of TNX-1500 > 750 pg/ml is obtained. In some embodiments of any of the above aspects, the loading dose is 20 mg/kg on days 0, 2, 5, 7 and weekly until a serum concentration of TNX-1500 > 750 pg/ml is obtained. In some embodiments of any of the above aspects, the loading dose is 30 mg/kg. In some embodiments of any of the above aspects, the loading dose is 20 mg/kg. In some embodiments of any of the above aspects, the loading dose is 30 mg/kg twice per week. In some embodiments of any of the above aspects, the loading dose is 20 mg/kg twice per week. In some embodiments of any of the above aspects, the loading dose is 20 mg/kg on days 0, 2, 5, 7 and weekly for one to six weeks. In some embodiments of any of the above aspects, the loading dose is 30 mg/kg on days 0, 2, 5, 7 and weekly for one to six weeks. In some embodiments of any of the above aspects, the loading dose is 20 mg/kg on days 0, 2, 5, 7 and weekly for one week. In some embodiments of any of the above aspects, the loading dose is 20 mg/kg on days 0, 2, 5, 7 and weekly for two weeks. In some embodiments of any of the above aspects, the loading dose is 30 mg/kg biweekly for two weeks. In some embodiments of any of the above aspects, the loading dose is 20 mg/kg on days 0, 2, 5, 7 and weekly for three weeks. In some embodiments of any of the above aspects, the loading dose is 20 mg/kg on days 0, 2, 5, 7 and weekly for four weeks. In some embodiments of any of the above aspects, the loading dose is 20 mg/kg on days 0, 2, 5, 7 and weekly for five weeks. In some embodiments of any of the above aspects, the loading dose is 20 mg/kg on days 0, 2, 5, 7 and weekly for six weeks. In some embodiments of any of the above aspects, the maintenance dose is 20 mg/kg. In some embodiments of any of the above aspects, the maintenance dose is 20 mg/kg at a frequency of Q1W. In some embodiments of any of the above aspects, the maintenance dose is 20 mg/kg at a frequency of Q4W. In some embodiments of any of the above aspects, the maintenance dose is 20 mg/kg at a frequency of once per month. In some embodiments, the loading dose is 30 mg/kg twice a week, and the maintenance dose is 20 mg/kg Q1W. In some embodiments, the loading dose is 30 mg/kg twice a week for two weeks, and the maintenance dose is 20 mg/kg Q1W.

[0153] In some embodiments of any of the above aspects, the loading dose is 20 mg/kg on days 0, 2, 5, 7 and weekly until a serum concentration of TNX-1500 > 750 pg/ml is obtained, and the maintenance dose is 20 mg/kg at a frequency of Q4W. In some embodiments of any of the above aspects, the loading dose is 20 mg/kg on days 0, 2, 5, 7 and weekly for one to six weeks, and the maintenance dose is 20 mg/kg at a frequency of Q4W. In some embodiments of any of the above aspects, the loading dose is 20 mg/kg on days 0, 2, 5, 7 and weekly for one week, and the maintenance dose is 20 mg/kg at a frequency of Q4W. In some embodiments of any of the above aspects, the loading dose is 20 mg/kg on days 0, 2, 5, 7 and weekly for two weeks, and the maintenance dose is 20 mg/kg at a frequency of Q4W. In some embodiments of any of the above aspects, the loading dose is 20 mg/kg on days 0, 2, 5, 7 and weekly for three weeks, and the maintenance dose is 20 mg/kg at a frequency of Q4W. In some embodiments of any of the above aspects, the loading dose is 20 mg/kg on days 0, 2, 5, 7 and weekly for four weeks, and the maintenance dose is 20 mg/kg at a frequency of Q4W. In some embodiments of any of the above aspects, the loading dose is 20 mg/kg on days 0, 2, 5, 7 and weekly for five weeks, and the maintenance dose is 20 mg/kg at a frequency of Q4W. In some embodiments of any of the above aspects, the loading dose is 20 mg/kg on days 0, 2, 5, 7 and weekly for six weeks, and the maintenance dose is 20 mg/kg at a frequency of Q4W.

[0154] In some embodiments of any of the above aspects, the loading dose is 20 mg/kg on days 0, 2, 5, 7 and weekly until a serum concentration of TNX-1500 > 750 pg/ml is obtained, and the maintenance dose is 20 mg/kg at a frequency of once per month. In some embodiments of any of the above aspects, the loading dose is 20 mg/kg on days 0, 2, 5, 7 and weekly for one to six weeks, and the maintenance dose is 20 mg/kg at a frequency of once per month. In some embodiments of any of the above aspects, the loading dose is 20 mg/kg on days 0, 2, 5, 7 and weekly for one week, and the maintenance dose is 20 mg/kg at a frequency of once per month. In some embodiments of any of the above aspects, the loading dose is 20 mg/kg on days 0, 2, 5, 7 and weekly for two weeks, and the maintenance dose is 20 mg/kg at a frequency of once per month. In some embodiments of any of the above aspects, the loading dose is 20 mg/kg on days 0, 2, 5, 7 and weekly for three weeks, and the maintenance dose is 20 mg/kg at a frequency of once per month. In some embodiments of any of the above aspects, the loading dose is 20 mg/kg on days 0, 2, 5, 7 and weekly for four weeks, and the maintenance dose is 20 mg/kg at a frequency of once per month. In some embodiments of any of the above aspects, the loading dose is 20 mg/kg on days 0, 2, 5, 7 and weekly for five weeks, and the maintenance dose is 20 mg/kg at a frequency of once per month. In some embodiments of any of the above aspects, the loading dose is 20 mg/kg on days 0, 2, 5, 7 and weekly for six weeks, and the maintenance dose is 20 mg/kg at a frequency of once per month.

[0155] In some embodiments of any of the above aspects, the loading dose is 1200 mg on days 0, 2, 5, 7 and weekly until a serum concentration of TNX-1500 > 750 pg/ml is obtained. In some embodiments of any of the above aspects, the loading dose is 1200 mg on days 0, 2, 5, 7 and weekly for one to six weeks. In some embodiments of any of the above aspects, the loading dose is 1200 mg on days 0, 2, 5, 7 and weekly for one week. In some embodiments of any of the above aspects, the loading dose is 1200 mg on days 0, 2, 5, 7 and weekly for two weeks. In some embodiments of any of the above aspects, the loading dose is 1200 mg on days 0, 2, 5, 7 and weekly for three weeks. In some embodiments of any of the above aspects, the loading dose is 1200 mg on days 0, 2, 5, 7 and weekly for four weeks. In some embodiments of any of the above aspects, the loading dose is 1200 mg on days 0, 2, 5, 7 and weekly for five weeks. In some embodiments of any of the above aspects, the loading dose is 1200 mg on days 0, 2, 5, 7 and weekly for six weeks. In some embodiments of any of the above aspects, the maintenance dose is 1200 mg at a frequency of Q4W. In some embodiments of any of the above aspects, the maintenance dose is 1200 mg at a frequency of once per month.

[0156] In some embodiments of any of the above aspects, the loading dose is 1200 mg on days 0, 2, 5, 7 and weekly until a serum concentration of TNX-1500 > 750 pg/ml is obtained, and the maintenance dose is 1200 mg at a frequency of Q4W. In some embodiments of any of the above aspects, the loading dose is 1200 mg on days 0, 2, 5, 7 and weekly for one to six weeks, and the maintenance dose is 1200 mg at a frequency of Q4W. In some embodiments of any of the above aspects, the loading dose is 1200 mg on days 0, 2, 5, 7 and weekly for one week, and the maintenance dose is 1200 mg at a frequency of Q4W. In some embodiments of any of the above aspects, the loading dose is 1200 mg on days 0, 2, 5, 7 and weekly for two weeks, and the maintenance dose is 1200 mg at a frequency of Q4W. In some embodiments of any of the above aspects, the loading dose is 1200 mg on days 0, 2, 5, 7 and weekly for three weeks, and the maintenance dose is 1200 mg at a frequency of Q4W. In some embodiments of any of the above aspects, the loading dose is 1200 mg on days 0, 2, 5, 7 and weekly for four weeks, and the maintenance dose is 1200 mg at a frequency of Q4W. In some embodiments of any of the above aspects, the loading dose is 1200 mg on days 0, 2, 5, 7 and weekly for five weeks, and the maintenance dose is 1200 mg at a frequency of Q4W. In some embodiments of any of the above aspects, the loading dose is 1200 mg on days 0, 2, 5, 7 and weekly for six weeks, and the maintenance dose is 1200 mg at a frequency of Q4W.

[0157] In some embodiments of any of the above aspects, the loading dose is 1200 mg on days 0, 2, 5, 7 and weekly until a serum concentration of TNX-1500 > 750 pg/ml is obtained, and the maintenance dose is 1200 mg at a frequency of once per month. In some embodiments of any of the above aspects, the loading dose is 1200 mg on days 0, 2, 5, 7 and weekly for one to six weeks, and the maintenance dose is 1200 mg at a frequency of once per month. In some embodiments of any of the above aspects, the loading dose is 1200 mg on days 0, 2, 5, 7 and weekly for one week, and the maintenance dose is 1200 mg at a frequency of once per month. In some embodiments of any of the above aspects, the loading dose is 1200 mg on days 0, 2, 5, 7 and weekly for two weeks, and the maintenance dose is 1200 mg at a frequency of once per month. In some embodiments of any of the above aspects, the loading dose is 1200 mg on days 0, 2, 5, 7 and weekly for three weeks, and the maintenance dose is 1200 mg at a frequency of once per month. In some embodiments of any of the above aspects, the loading dose is 1200 mg on days 0, 2, 5, 7 and weekly for four weeks, and the maintenance dose is 1200 mg at a frequency of once per month. In some embodiments of any of the above aspects, the loading dose is 1200 mg on days 0, 2, 5, 7 and weekly for five weeks, and the maintenance dose is 1200 mg at a frequency of once per month. In some embodiments of any of the above aspects, the loading dose is 1200 mg on days 0, 2, 5, 7 and weekly for six weeks, and the maintenance dose is 1200 mg at a frequency of once per month.

[0158] In some embodiments of any of the above aspects, the subject is human. In some embodiments of any of the above aspects, the immune related disease is selected from the group consisting of Amyotrophic Lateral Sclerosis, Inflammatory Bowel Disease (e.g., Ulcerative Colitis), Irritable Bowel Syndrome, Idiopathic Thrombocytopenic Purpura, Systemic Lupus Erythematosus, Lupus Nephritis, Multiple Sclerosis e.g., Relapsing Remitting Multiple Sclerosis or Secondary Progressive Multiple Sclerosis), Psoriasis, Rheumatoid Arthritis, Systemic Scleroderma, Interstitial Lung Disease, Atopic Dermatitis, Antiphospholipid Syndrome, Sarcoidosis, Myositis, Pneumocystis, Type 1 Diabetes, Sjogren syndrome, and Graft versus host disease. In some embodiments of any of the above aspects, the immune related disease is selected from the group consisting of Systemic Lupus Erythematosus, Multiple Sclerosis, Type 1 Diabetes, and Sjogren syndrome. In some embodiments of any of the above aspects, the immune related disease is Amyotrophic Lateral Sclerosis. In some embodiments of any of the above aspects, the immune related disease is Inflammatory Bowel Disease. In some embodiments, the Inflammatory Bowel Disease is Ulcerative Colitis. In some embodiments of any of the above aspects, the immune related disease is Irritable Bowel Syndrome. In some embodiments of any of the above aspects, the immune related disease is Idiopathic Thrombocytopenic Purpura. In some embodiments of any of the above aspects, the immune related disease is Systemic Lupus Erythematosus. In some embodiments of any of the above aspects, the immune related disease is Lupus Nephritis. In some embodiments of any of the above aspects, the immune related disease is Multiple Sclerosis. In some embodiments the Multiple Sclerosis is Relapsing Remitting Multiple Sclerosis. In some the embodiments, the Multiple Sclerosis is Secondary Progressive Multiple Sclerosis. In some embodiments, the Multiple Sclerosis is Relapsing Remitting Multiple Sclerosis or Secondary Progressive Multiple Sclerosis. In some embodiments of any of the above aspects, the immune related disease is Psoriasis. In some embodiments of any of the above aspects, the immune related disease is Rheumatoid Arthritis. In some embodiments of any of the above aspects, the immune related disease is Systemic Scleroderma. In some embodiments of any of the above aspects, the immune related disease is Interstitial Lung Disease. In some embodiments of any of the above aspects, the immune related disease is Atopic Dermatitis. In some embodiments of any of the above aspects, the immune related disease is Antiphospholipid Syndrome. In some embodiments of any of the above aspects, the immune related disease is Sarcoidosis. In some embodiments of any of the above aspects, the immune related disease is Myositis. In some embodiments of any of the above aspects, the immune related disease is Pneumocystis. In some embodiments of any of the above aspects, the immune related disease is Type 1 Diabetes. In some embodiments of any of the above aspects, the immune related disease is Sjogren syndrome. In some embodiments of any of the above aspects, the immune related disease is Graft versus host disease.

[0159] In some embodiments of any of the above aspects, the administration of the antiCD 154 antibody modulates the immune system of the subject. Modulation of the subject’s immune system can be demonstrated by blockade of anti-Keyhole Limpet Hemocyanin (anti- KLH) antibody production. The blockade may be of the primary anti-KLH antibody response, the secondary anti-KLH antibody response, or both. Modulation of the subject’s immune system can be demonstrated by decreased levels of soluble CD 154 in the subject’s blood.

[0160] In some embodiments of any of the above aspects, the method comprises administering to said mammal a therapeutically effective amount of an anti-CD154 antibody disclosed herein in combination with one or more additional agents. In some embodiments of any of the above aspects, the anti-CD154 antibody disclosed herein is formulated to be administered in combination with one or more additional agents. Optionally, the one or more additional agents is selected from the group consisting of anti -thrombotic drugs, anti-platelet drugs and non-steroidal anti-inflammatory drugs (NSAIDs). The anti-CD154 antibody may be administered simultaneously with the one or more additional agents. The anti-CD154 antibody may be formulated to be administered simultaneously with the one or more additional agents. In some embodiments, the anti-CD154 antibody is administered sequentially with the one or more additional agents. In some embodiments, the anti-CD154 antibody is formulated to be administered sequentially with the one or more additional agents. Optionally, the anti-CD154 antibody is administered prior to the one or more additional agents. Optionally, the anti-CD 154 antibody is formulated to be administered prior to the one or more additional agents. The antiCD 154 antibody may be administered subsequent to the one or more additional agents. The anti-CD 154 antibody may be formulated to be administered subsequent to the one or more additional agents. In some embodiments, the anti-CD 154 antibody is administered in the same composition as the one or more additional agents. In some embodiments, the anti-CD 154 antibody in the same composition as the one or more additional agents. Optionally, the anti- CD 154 antibody and the one or more additional agents are in separate compositions. In some embodiments, the one or more additional agents comprises a conventional immunosuppressive agent. Non-limiting examples of conventional immunosuppressive agents include mycophenolate mofetil (MMF), rapamycin, and tacrolimus. In some embodiments, the conventional immunosuppressive agent is mycophenolate mofetil (MMF). In some embodiments, the conventional immunosuppressive agent is rapamycin. In some embodiments, the conventional immunosuppressive agent is tacrolimus.

[0161] Non-limiting examples of anti -thrombotic drugs include but are not limited to a glycoprotein Hb/IIIa receptor antagonist, a direct or indirect factor Xa inhibitor and an anticoagulant. Non-limiting examples of anticoagulants include, but are not limited to, heparin, warfarin, rivaroxaban (XARELTO®), ximelgatran (EXANTA®), dabigatran (PRADAXA®), apixaban (ELIQUIS®), edoxaban (S AV AYS A®), enoxaparin (LOVENOX®), and fondaparinux (ARIXTRA®). Non-limiting examples of anti -thrombotic drugs include, but are not limited to, those disclosed in US Patent Nos. 4,782,069; 5,332,822; 5,492,895; 5,612,363, 5,691,364 5,693,641; 5,721,214; 5,726,173; 5,753,635; 5,846,970; 5,849,759; 5,889,005;

6,730,672; 6,753,331; 6,774,110; 6,797,710; and 6,924,296, incorporated in their entirety for all purposes. Non-limiting examples of glycoprotein Ilb/IIIa receptor antagonists include, but are not limited to, abciximab (REOPRO®), rivaroxaban (XARELTO®), apixaban (ELIQUIS®), edoxaban (SAVAYSA®), idrabiotaparinux, tirofiban (AGGRASTAT®), and eptifibatide (INTEGRILIN®). The direct or indirect factor Xa inhibitors include, but are not limited to, apixaban (ELIQUIS®), idrabiotaparinux, fondaparinux (ARIXTRA®), and rivaroxaban (XARELTO®).

[0162] Non-limiting examples of anti-platelet drugs include, but are not limited to, TXA2 pathway inhibitors, the adenosine diphosphate (ADP) pathway inhibitors, thrombin inhibitors, Protease activated receptor-1 (PAR-1) inhibitors and phosphodiesterase (PDE) inhibitors. Non-limiting examples of ADP pathway inhibitors include, but are not limited, to clopidogrel (PLAVIX®, ticlopidine (TICLID®), prasugrel (EFFIENT®), ticagrelor (BRILINTA®), cangrelor (KENGREAL®) and elinogrel. Non-limiting examples of PDE inhibitors include dipyridamole (PERSANTINE®) and cilostazol (PLETAL®).

[0163] Non-limiting examples of NSAIDs include, but are not limited to, acetylsalicylic acid, celecoxib (CELEBREX®), diclofenac (VOLTAREN®, PENNSAID®, SOLARAZE®, ZIPSOR®, CATAFLAM®, ZORVOLEX®), diflunisal (DOLOBID®), etodolac (LODINE SR®, ECCOXOLAC®), ibuprofen (BRUFEN®, ADVIL®, MOTRIN®), indomethacin (INDOCIN®), ketoprofen (ORUDIS®), ketorolac (TORADOL®, ACULAR®, SPRIX®), nabumetone (RELAFEN®), naproxen (AFLAXEN®, ALEVE®, ANAPROX®, NAPRELAN®), oxaprozin (DAYPRO®, DAYRUN®, DURAPROX®), piroxicam (FELDENE®), salsalate (MONO-GESIC®, SALFLEX®, DISALCID®, SALSITAB®), sulindac (CLINORIL®), tolmetin (TOLECTIN®), prasugrel (EFFIENT®), ticagrelor (BRILINTA®) and cangrelor (KENGREAL®).

EXEMPLARY EMBODIMENTS

[0164] Particular embodiments of the disclosure are set forth in the following numbered embodiments:

1. A method of treating or preventing a transplant rejection comprising administrating to a transplant recipient a therapeutically effective amount of an anti-CD154 antibody, wherein the antibody comprises a humanized variable domain, wherein the variable domain comprises a heavy chain variable region (VH) and a light chain variable region (VL), and wherein the VH is operably linked to a human Fc region derived from IgG4 and comprising S228P and L235A amino acid modifications; wherein the VH comprises

(a) a heavy chain CDR1 having the amino acid sequence of SEQ ID NO: 3,

(b) a heavy chain CDR2 having the amino acid sequence of SEQ ID NO: 4, and

(c) a heavy chain CDR3 having the amino acid sequence of SEQ ID NO: 5; and wherein the VL comprises

(a) a light chain CDR1 having the amino acid sequence of SEQ ID NO: 6,

(b) a light chain CDR2 having the amino acid sequence of SEQ ID NO: 7, and

(c) a light chain CDR3 having the amino acid sequence of SEQ ID NO: 8.

2. An anti-CD154 antibody for use in treating or preventing a transplant rejection in a transplant recipient wherein the antibody comprises a humanized variable domain, wherein the variable domain comprises a heavy chain variable region (VH) and a light chain variable region (VL), and wherein the VH is operably linked to a human Fc region derived from IgG4 and comprising S228P and L235A amino acid modifications; wherein the VH comprises

(a) a heavy chain CDR1 having the amino acid sequence of SEQ ID NO: 3,

(b) a heavy chain CDR2 having the amino acid sequence of SEQ ID NO: 4, and

(a) a light chain CDR1 having the amino acid sequence of SEQ ID NO: 6, (b) a light chain CDR2 having the amino acid sequence of SEQ ID NO: 7, and

(c) a light chain CDR3 having the amino acid sequence of SEQ ID NO: 8.

3. Use of an anti-CD154 antibody in the manufacture of a pharmaceutical composition for treating or preventing a transplant rejection in a transplant recipient, wherein the antibody comprises a humanized variable domain, wherein the variable domain comprises a heavy chain variable region (VH) and a light chain variable region (VL), and wherein the VH is operably linked to a human Fc region derived from IgG4 and comprising S228P and L235A amino acid modifications; wherein the VH comprises

(a) a heavy chain CDR1 having the amino acid sequence of SEQ ID NO: 3,

(b) a heavy chain CDR2 having the amino acid sequence of SEQ ID NO: 4, and

(a) a light chain CDR1 having the amino acid sequence of SEQ ID NO: 6,

(b) a light chain CDR2 having the amino acid sequence of SEQ ID NO: 7, and

(c) a light chain CDR3 having the amino acid sequence of SEQ ID NO: 8.

4. The method of embodiment 1, the anti-CD154 antibody for use of embodiment 2 or the use of embodiment 3, wherein the transplant is an allogeneic transplant, autologous transplant or a xenogeneic transplant.

5. The method of embodiment 1 or 4, the anti-CD154 antibody for use of embodiment 2 or 4, or the use of embodiment 3 or 4, wherein the transplant rejection is associated with a hematopoietic cell or bone marrow transplant, an allogeneic transplant of pancreatic islet cells, graft vs host disease, or a solid organ transplant.

6. The method, anti-CD154 antibody for use, or use of embodiment 5, wherein the solid organ transplant is selected from the group consisting of a heart transplant, a kidney transplant, a liver transplant, a lung transplant, a pancreas transplant, a kidney-pancreas transplant, a heartlung transplant, kidney-heart transplant, a kidney-heart-pancreas transplant, a heart-liver transplant, a heart-liver-kidney transplant, a heart-lung-kidney transplant, a heart-lung-liver transplant, a lung-kidney transplant, a lung-liver transplant, a liver-intestines-pancreas transplant, an intestines-pancreas transplant, a liver-kidney-intestines-pancreas transplant, and a kidney-intestines transplant.

7. A method of treating an immune-related disease comprising administrating to a subject in need of treatment a therapeutically effective amount of an anti-CD 154 antibody, wherein the antibody comprises a humanized variable domain, wherein the variable domain comprises a heavy chain variable region (VH) and a light chain variable region (VL), and wherein the VH is operably linked to a human Fc region derived from IgG4 and comprising S228P and L235A amino acid modifications; wherein the VH comprises

(a) a heavy chain CDR1 having the amino acid sequence of SEQ ID NO: 3,

(b) a heavy chain CDR2 having the amino acid sequence of SEQ ID NO: 4, and

(a) a light chain CDR1 having the amino acid sequence of SEQ ID NO: 6,

(b) a light chain CDR2 having the amino acid sequence of SEQ ID NO: 7, and

(c) a light chain CDR3 having the amino acid sequence of SEQ ID NO: 8.

8. An anti-CD154 antibody for use in treating an immune-related disease in a subject in need thereof, wherein the antibody comprises a humanized variable domain, wherein the variable domain comprises a heavy chain variable region (VH) and a light chain variable region (VL), and wherein the VH is operably linked to a human Fc region derived from IgG4 and comprising S228P and L235A amino acid modifications; wherein the VH comprises

(a) a heavy chain CDR1 having the amino acid sequence of SEQ ID NO: 3,

(b) a heavy chain CDR2 having the amino acid sequence of SEQ ID NO: 4, and

(a) a light chain CDR1 having the amino acid sequence of SEQ ID NO: 6,

(b) a light chain CDR2 having the amino acid sequence of SEQ ID NO: 7, and

(c) a light chain CDR3 having the amino acid sequence of SEQ ID NO: 8. 9. Use of an anti-CD154 antibody in the manufacture of a pharmaceutical composition for treating immune-related disease in a subject in need thereof, wherein the antibody comprises a humanized variable domain, wherein the variable domain comprises a heavy chain variable region (VH) and a light chain variable region (VL), and wherein the VH is operably linked to a human Fc region derived from IgG4 and comprising S228P and L235A amino acid modifications; wherein the VH comprises

(a) a heavy chain CDR1 having the amino acid sequence of SEQ ID NO: 3,

(b) a heavy chain CDR2 having the amino acid sequence of SEQ ID NO: 4, and

(a) a light chain CDR1 having the amino acid sequence of SEQ ID NO: 6,

(b) a light chain CDR2 having the amino acid sequence of SEQ ID NO: 7, and

(c) a light chain CDR3 having the amino acid sequence of SEQ ID NO: 8.

10. The method of embodiment 7, the anti-CD154 antibody for use of embodiment 8, or the use of embodiment 9, wherein the immune related disease is selected from the group consisting of Amyotrophic Lateral Sclerosis, Inflammatory Bowel Disease, Irritable Bowel Syndrome, Idiopathic Thrombocytopenic Purpura, Systemic Lupus Erythematosus, Lupus Nephritis, Multiple Sclerosis, Relapsing Remitting Multiple Sclerosis, Secondary Progressive Multiple Sclerosis, Psoriasis, Rheumatoid Arthritis, Systemic Scleroderma, Interstitial Lung Disease, Atopic Dermatitis, Antiphospholipid Syndrome, Sarcoidosis, Myositis, Ulcerative Colitis, Pneumocystis, Type 1 Diabetes, Sjogren syndrome, and Graft versus host disease.

11. The method, the anti-CD154 antibody for use, or use of embodiment 10, wherein the immune related disease is selected from the group consisting of Systemic Lupus Erythematosus, Multiple Sclerosis, Type 1 Diabetes, and Sjogren syndrome.

12. The method of any one of embodiments 1, 7 and 10-11, the anti-CD154 antibody for use of any one of embodiments 2, 8 and 10-11, or the use of any one of embodiments 3 and 9-11, wherein the antibody comprises the Fc region comprises the amino acid sequence of SEQ ID NOs: 1 or 2. 13. The method of any one of embodiments 1, 7, and 10-12, the anti-CD154 antibody for use of any one of embodiments 2, 8 and 10-12, or the use of any one of embodiments 3 and 9-12, wherein the heavy chain comprises a constant region comprising the amino acid sequence of SEQ ID NO: 12 or 13.

14. The method of any one of embodiments 1, 7 and 10-13, the anti-CD154 antibody for use of any one of embodiments 2, 8 and 10-13, or the use of any one of embodiments 3 and 9-13, wherein the VH comprises the amino acid sequence of SEQ ID NO: 9.

15. The method of any one of embodiments 1, 7 and 10-14, the anti-CD154 antibody for use of any one of embodiments 2, 8 and 10-14, or the use of any one of embodiments 3 and 9-14, wherein the VL comprises the amino acid sequence of SEQ ID NO: 10.

16. The method of any one of embodiments 1, 7 and 10-15, the anti-CD154 antibody for use of any one of embodiments 2, 8 and 10-15, or the use of any one of embodiments 3 and 9-15, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 14 or 15.

17. The method of any one of embodiments 1, 7 and 10-16, the anti-CD154 antibody for use of any one of embodiments 2, 8 and 10-16, or the use of any one of embodiments 3 and 9-16, wherein the light chain comprises the amino acid sequence of SEQ ID NO: 16.

18. The method of any one of embodiments 1, 7 and 10-17, the anti-CD154 antibody for use of any one of embodiments 2, 8 and 10-17, or the use of any one of embodiments 3 and 9-17, wherein the light chain comprising the amino acid sequence of SEQ ID NO: 16 and a heavy chain comprising an amino acid sequence of SEQ ID NO: 14 or 15.

19. The method of any one of embodiments 1, 7 and 10-18, the anti-CD154 antibody for use of any one of embodiments 2, 8 and 10-18, or the use of any one of embodiments 3 and 9-18, wherein the antibody is administered at or formulated to be administered a dose selected from the group consisting of 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30mg/kg, 35mg/kg, 40 mg/kg, 45mg/kg, and 50 mg/kg.

20. The method, anti-CD154 antibody for use, or use of embodiment 19, wherein the antibody is administered at or formulated to be administered at a dose is 20 mg/kg.

21. The method of any one of embodiments 1, 7 and 10-18, the anti-CD154 antibody for use of any one of embodiments 2, 8 and 10-18, or the use of any one of embodiments 3 and 9-18, wherein the antibody is administered at or formulated to be administered at a flat dose selected from the group consisting of 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg, and 2000 mg.

22. The method, anti-CD154 antibody for use, or use of embodiment 21, wherein the antibody is administered at or formulated to be administered at a dose is 1200 mg.

23. The method of any one of embodiments 1, 7 and 10-22, the anti-CD154 antibody for use of any one of embodiments 2, 8 and 10-22, or the use of any one of embodiments 3 and 9-22, wherein the antibody is administered at or formulated to be administered at a frequency selected from the group consisting of Q1W, Q2W, Q3W, Q4W, Q5W and Q6W.

24. The method, anti-CD154 antibody for use, or use of embodiment 23, wherein the antibody is administered at or formulated to be administered at a frequency of Q4W.

25. The method of any one of embodiments 1, 7 and 10-22, the anti-CD154 antibody for use of any one of embodiments 2, 8 and 10-22, or the use of any one of embodiments 3 and 9-22, wherein the antibody is administered at or formulated to be administered at a frequency once per month.

26. The method of any one of embodiments 1, 7 and 10-18, the anti-CD154 antibody for use of any one of embodiments 2, 8 and 10-18, or the use of any one of embodiments 3 and 9-18, wherein the antibody is administered at or formulated to be administered at a frequency of Q4W at a dose of 20 mg/kg.

27. The method of any one of embodiments 1, 7 and 10-18, the anti-CD154 antibody for use of any one of embodiments 2, 8 and 10-18, or the use of any one of embodiments 3 and 9-18, wherein the antibody is administered at or formulated to be administered at a frequency of Q4W at a dose of 1200 mg.

28. The method of any one of embodiments 1, 7 and 10-18, the anti-CD154 antibody for use of any one of embodiments 2, 8 and 10-18, or the use of any one of embodiments 3 and 9-18, wherein the antibody is administered at or formulated to be administered at a frequency of once per month at a dose of 20 mg/kg.

29. The method of any one of embodiments 1, 7 and 10-18, the anti-CD154 antibody for use of any one of embodiments 2, 8 and 10-18, or the use of any one of embodiments 3 and 9-18, wherein the antibody is administered at or formulated to be administered at a frequency of once per month at a dose of 1200 mg.

30. The method of any one of embodiments 1, 7 and 10-18, the anti-CD154 antibody for use of any one of embodiments 2, 8 and 10-18, or the use of any one of embodiments 3 and 9-18, wherein the antibody is administered at or formulated to be administered at a loading dose followed by a maintenance dose.

31. The method, anti-CD154 antibody for use, or use of embodiment 30, wherein the loading dose is administered until a serum concentration of TNX-1500 > 750 pg/ml is obtained.

32. The method, anti-CD154 antibody for use, or use of embodiment 30 or 31, wherein the loading dose is 20 mg/kg on days 0, 2, 5, 7 and weekly until a serum concentration of TNX-1500 > 750 pg/ml is obtained.

33. The method, anti-CD154 antibody for use, or use of any one of embodiments 30-32, wherein the loading dose is 20 mg/kg on days 0, 2, 5, 7 and weekly for one to six weeks.

34. The method, anti-CD154 antibody for use, or use of any one of embodiments 30-33, wherein the maintenance dose is 1200 mg at a frequency of Q4W.

35. The method, anti-CD154 antibody for use, or use of any one of embodiments 30-33, wherein the maintenance dose is 1200 mg at a frequency of once per month.

36. The method of any one of embodiments 1, 7 and 10-35, the anti-CD154 antibody for use of any one of embodiments 2, 8 and 10-35, or the use of any one of embodiments 3 and 9-35, wherein the antibody is administered or formulated as a pharmaceutical composition comprising the antibody and a pharmaceutically acceptable carrier.

37. The method of any one of embodiments 1, 7 and 10-36, the anti-CD154 antibody for use of any one of embodiments 2, 8 and 10-36, or the use of any one of embodiments 3 and 9-36, wherein the antibody is administered intravenously.

EXAMPLES

[0165] The following examples are offered for illustrative purposes only and do not limit the scope of the present disclosure or paragraphs in any way. Indeed, various modifications of the disclosure in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description and fall within the scope of the paragraphs. Example 1. Immunosuppressive effect of TNX- 1500 in non-human primates

[0166] To evaluate immunosuppressive effects of TNX-1500, TNX-1500 monotherapy was tested in MHC mismatched kidney transplantation. Specifically, six non-human primate recipients received TNX-1500 (Tonix Pharmaceuticals), 20 mg/kg intravenously (IV) on days 0, 2, 5, and 12 and then weekly for 6 months. An additional six recipients received 20 mg/kg IV on days 0, 2, 5, and 12 and then weekly for the first 6 weeks, after which the dosing was reduced to 20 mg/kg IV every 2 weeks with daily mycophenolate mofetil (MMF, Roche Inc; 20 mg/kg orally twice a day) was initiated on day 0 and continued until end of study (EOS) (day 180). stTNX/Mono and loTNX/MMF were compared with historical data of the immunosuppressive effect of conventional immunosuppression and no immunosuppressant. In this instance, historical reference experiments with conventional immunosuppression (Conv IS) was taken over 10 years from 37 recipients. Those recipients underwent kidney transplant with a conventional triple drug immunosuppressive regimen consisting of tacrolimus intramuscularly (Astellas Pharma Inc; 2-4 mg/kg intramuscularly daily, titrated to maintain trough levels of 10-15 ng/mL), MMF, and prednisone (100 mg on day 0, tapered to 1 mg by 2 weeks) until day 120; recipients with surviving renal allografts then underwent conditioning and donor bone marrow transplantation (DBMT) in a 1 of several delayed tolerance protocols. For the group that received no immunosuppressive, no medication was given to an additional 5 transplant recipients. In the six recipients treated with ‘standarddose’ TNX-1500 monotherapy (stTNX/Mono), five of six recipients survived >180 days (6 months) with excellent renal function (Fig. 1 A); one renal allograft failed due to T Cell mediated rejection on day 28 (Fig. 2A). Serum TNX-1500 levels plateaued at 800-1500 mg/ml by 30-60 days post-transplantation and the levels of the recipient that rejected its allograft were not different from those in recipients without rejection (Fig. IB).

Histopathology in the 5 allografts surviving at end of the study showed no evidence of rejection (Fig. 2B), and no C4d deposition (Fig. 2C) without donor specific antibody (DS A) production (Table 2).

[0167] To seek the possibility of reducing the dose of TNX-1500, the efficacy of TNX- 1500 in combination with MMF (loTNX/MMF group) was evaluated. In the loTNX/MMF group, TNX-1500 was administered at 20 mg/kg weekly until 6 weeks followed by treatment every other week until EOS. Interestingly, the results were less favorable by combining MMF. Despite daily MMF, 2 recipients developed rejection on days 48 and 36, although they were still receiving TNX-1500 weekly (Fig. 1C). The histopathology of these kidneys showed TCMR types 3 (Fig. 2D) and 2, respectively (Table 2). The recipient with TCMR type 3 also developed DSA with C4d deposition (Fig. 2E). TNX-1500 levels in these 2 recipients were between 500 and 800 pg/mL (Fig. ID), not significantly different from recipients in stTNX/mono (Fig. IB) or loTNX/MMF animals without rejection episodes (Fig. ID). An additional loTNX/MMF recipient was euthanized on day 111 (Fig. 1C) because of a gastrointestinal complication (ileus) as a side effect of MMF. No renal allograft rejection was identified during autopsy. The remaining 3 recipients did well until day 180 (Fig. 1C), without rejection or DSA. [0168] The graft survival rates of these 2 TNX groups were significantly higher than our historical results with no immunosuppression (Fig. 3, P < 0.001). Although not statistically significant (P = 0.2), 83% graft survival at EOS (day 180) with stTNX/mono compared favorably with conventional triple drug immunosuppression (i.e., Conv IS), with 57% survival (day 120) (Fig. 3). Overall survival with loTNX/MMF was statistically similar to the graft survival rates with Conv IS. Of note, PTLD was observed in 3 recipients in Conv IS, whereas no PTLD was observed in the current experience with TNX-1500. The risk of developing PTLD appeared significantly lower in TNX-1500 (stTNX/mono + loTNX/MMF) vs Conv IS (P < 0.0001).

Table 2

MHC Renal allograft Biopsy#l Biopsy #2 Biopsy #3

Group ID _disparity survival (d) (D50-70) (D100-120) (D170-180) ^DSA

Ml 0420 5/10 >180 No rej, C4dO No rej, C4dO No rej, C4d0 Negative

M10521 Full >180 No rej, C4dO NP No rej, C4d0 Negative

M3120 Full >180 No rej, C4dO No rej, C4dO No rej, C4d0 Negative stTNX/mono

M3920 Full 28 CMR 3, C4d0 Negative

M6420 Full >180 No rej, C4dO Borderline No rej, C4d0 Negative

Ml 021 Full >180 No rej, C4dO No rej, C4dO No rej, C4d0 Negative

M8021 Full >111 No rej, C4dO No rej, C4dO Negative

M5321 5/10 48 TCMR 3 Positive

M521 Full >180 No rej, C4dO No rej, C4dO No rej, C4d0 Negative loTNX/MMF

M1421 7/10 36 TCMR 2A Negative

Ml 1321 Full >180 No rej, C4dO NP No rej, C4d0 Negative

M8221 Full >180 No rej,C4dO NP No rej, C4d0 Negative

Example 2, Pharmacokinetics and Pharmacodynamics of TNX-1500 in Humans

[0169] Healthy human subjects were given TNX-1500 solution infused intravenously (IV) over a period of one hour to achieve doses of 3, 10, and or 30 mg/kg. A total of 26 participants were enrolled in three Cohorts (Cohort 1 : n=4 at 3 mg/kg, n=2 placebo; Cohort 3 : n=8 at 10 mg/kg, n=2 placebo; Cohort 3: n=8 at 30 mg/kg, n=2 placebo). A total of 24 participants completed the study and two discontinued early (one placebo participant was lost to follow-up and one participant who received 30 mg/kg TNX-1500 withdrew consent). Participants were observed in the clinic on day one and followed with periodic clinic visits for 120 days.

[0170] Serum concentrations of TNX-1500 were serially monitored in the three cohorts to compare the three different doses. The mean (±SD) TNX-1500 serum concentration-time profiles by cohort and dose(Cohort, dose in mg/kg) in a linear-linear scale (Figure 4) and log- linear scale (Figure 5) were taken. Mean TNX-1500 serum concentration was measured hourly by cohort and dose: cohort 1 at a dose of 3 mg/kg (see Figures 6A and 6B), cohort 2 at a dose lOmg/kg (see Figures 7A and 7B), and cohort 3 at a dose of 30 mg/kg (see Figures 8A and 8B). TNX-1500 PK parameters including Cmax, AUCo-t, AUCo-00, ti/2 , and T_max were also measured (Figures 9, 10, 11 A and 1 IB) and each parameter was normalized (Figures 11 A and 1 IB) and compared with dose (Figures 12-14). These values were then normalized (Figures 9, 10, 11 A and 1 IB). These data demonstrate that the half-life of TNX-1500 in humans was found to be around 36 days. Subjects that received placebo did not have positive concentration of TNX-1500. Serum concentrations of TNX-1500 increased with the dose, in terms of exposure the average trend does not imply PK linearity but only three doses have been tested. For most of subjects the Cmax was reached more than one hour (median tmax for all tested doses= 2.50 h) after the end of infusion. Monthly dosing of TNX-1500 is supported by the data.

[0171] To determine efficacy, Keyhole Limpet Hemocyanin (KLH) was administered to evaluate the immune modulation potency of TNX-1500. Briefly, participants received an antigen challenge with KLH (Immucothel®) administered subcutaneously (SC) on Day 2 and Day 29 of the study. Samples for anti-KLH antibody (Ab) were obtained on Days 1 (prechallenge), 8, 15, 29, 36, 50, 64, 78, and 120. TNX-1500 at 10 mg/kg and 30 mg/kg, on average, blocked both the primary and secondary anti-KLH Ab responses, evidenced by the mean Ab level at all sampled timepoints (i.e., through Day 120) being below the lower limit of quantitation (400 pg/L) of the assay. TNX-1500 at 3 mg/kg blocked the primary response to KLH Day 2 challenge and reduced the peak secondary response to KLH Day 29 challenge by approximately two thirds relative to the peak response to placebo (see Figure 15).

[0172] Serum levels of soluble CD 154 were also measured. A summary of soluble CD 154 in all subjects at day one, 1 hour post-dose, 2 hours post-dose, 3 hours post-dose, 4 hours post-dose, 8 hours post-dose, day 2, day 3, day 8, day 29, day 50 and day 120 can be found in Figure 16. All three doses of TNX-1500 were able to decrease soluble CD154 levels through the end of study (z.e., Day 120).

Tolerability

[0173] TNX-1500 was generally well-tolerated with a favorable safety and tolerability profile. The only treatment-emergent adverse event (TEAE) occurring in > 3 participants among all TNX-1500 groups was Aphthous ulcer, occurring in one participant each in the 3 mg/kg, 10 mg/kg, and 30 mg/kg groups; all were rated as mild, possibly related, and resolved in 2-10 days. There were no TEAEs assessed as related to KLH administration. No TEAEs led to study discontinuation and there were no serious adverse events. There were no thromboembolic events, which were prespecified as TEAEs of special interest.

Example 3 , Use of TNX- 1500 for treating Renal Transplant in Non-Human Primates

[0174] To evaluate the efficacy of an optimized immunosuppressive regimen, including a higher dose of anti-CD154mAb (TNX-1500), in prolonging graft survival in pig-to-baboon kidney xenotransplantation (KTx), baboons (n=9) received kidneys from gene-edited pigs (n=7, triple-knockout or double-knockout with growth hormone-receptor-knockout and 6 human transgenes: human CD46, human CD55, human Tracheobronchomalacia (TBM), human Endothelial protein C receptor (EPCR), human Heme oxygenase- 1 (HOI), and human CD47). Group A baboons (n=3) received induction treatment with anti-thymocyte globulin, anti-CD20 monoclonal antibody, and Cl -esterase inhibitor, followed by maintenance treatment with 20 mg/kg TNX-1500, rapamycin, +/- methylprednisolone, and +/- IL-6R blockade. Group B (n=6) received the identical regimen except for an increased TNX-1500 dose (30 mg/kg). All animals were CMV-negative.

[0175] Group A baboons survived 59, 86, and 120 days, with antibody-mediated rejection (AMR) at graft failure. Group B had prolonged graft survival: >1 year (n=2), >6 months (n=2), and >3 months (n=2). One experienced antibody mediated rejection after reduction of immunosuppressive therapy (day 439); five were euthanized with functioning grafts due to complications: gastric ulcer bleeding (day 100), weight loss/diarrhea (day 117), arterial thrombosis (day 203), electrolyte imbalance (day 225), and pneumonia (following greatly increased immunosuppressive therapy) (day 405). Accordingly, an optimized TNX- 1500- based regimen prevented AMR and prolonged xenograft survival.

Example 4, Use of TNX-1500 for treating Renal Transplant in humans

[0176] A trial to evaluate the efficacy of TNX-1500 to treat kidney transplant recipients will be conducted. In this prophetic example, seven (7) adult transplant recipients will receive kidney transplants from either living or deceased donors. The conditioning regimen used in this protocol is an ordered series of procedures and treatments including: thymic irradiation, chemotherapy, antibody administration (TNX-1500 and rituximab) prior to hematopoietic stem cell (HSC) transplant. The conditioning regimen requires six days leading up to the day of transplantation, which is designated as study Day 0. Negative numbers in descending order designate days pre-transplant, while positive numbers in ascending order designate days posttransplant.

[0177] Briefly, recipients of previous living or deceased donor’s kidney transplants that were maintained on conventional immunosuppression (I.S.), receive a conditioning regimen that includes rituximab on study day -6, fludarabine 15 mg/m2/day on days -5 to -3 (3 doses), CP (30 mg/kg/day) on days -5 and -4, followed by local thymic irradiation (7 Gy) on day -1 and TNX-1500 (Fc-modified anti-CD154 mAb) on days, -2, -1, 0 and +1. Donor HSCs are infused on study day 0. Methylprednisolone 250mg/day starts on day 0 and tapered off by day 20. Prophylaxis is provided for hemorrhagic cystitis, Pneumocystis carinii pneumonia (PCP), fungal infection, cytomegalovirus (CMV), and perioperative infection. All patients who require any blood transfusion receive only leukocyte-depleted and irradiated blood products for a period of at least 12 months following HSC transplant. The recipients undergo renal allograft biopsy at 6 months after HSC transplant. If the I.S. withdrawal criteria are met, I.S. is slowly tapered off by 9-12 months.

Administration and Dosing

[0178] TNX-1500 is supplied as a clear to slightly opalescent, colorless to slightly brownish, preservative-free, solution for infusion. The bulk TNX-1500 solution is sterilized by filtration and aseptically filled into depyrogenized, glass vials with rubber stoppers). TNX-1500 vials are to be stored refrigerated (2-8°C). Participants receive TNX-1500 20 mg/kg/dose on days 0, 2, 5 7 and weekly until it reaches therapeutic levels >750 ug/ml. TNX-1500 administration should be timed and possible drug-related adverse events (AEs) can be identified/managed. Further, this will allow for premedication to be administered prior to start of the 1 hour infusion and should be a reasonable approach for the other conditioning agents as well. The dose of TNX-1500 is prepared by and administered by the investigator or his/her designee who is properly trained in the handling and aseptic preparation of IV infusions. The subject’s admission weight is used when calculating each infusion administration.

[0179] Upon confirmation of subject dose, the product is prepared from vial(s), using aseptic technique and administration to the subject via IV infusion using a syringe and infusion pump. Detailed instructions on the storage, preparation and infusion of TNX-1500 is referenced in the Global Pharmacy Manual (40mg/ml) provided by the manufacturer and can be referenced prior to administration of product to any study subject.

Pretreatment

[0180] Prior to each infusion of TNX-1500, baseline body temperature and any unusual symptoms, reported by the subject, is recorded. Premedication then includes 650-1000 mg acetaminophen (Tylenol®) and an Hl -antagonist (antihistamine, e.g. 25 mg diphenhydramine) to minimize infusion reactions. Before the first infusion of TNX-1500, 8 mg/kg (maximum 500 mg) of methylprednisolone (MP) is administered IV. Premedication occurs at least 1 hour and no more than 5 hours prior to the start of infusion.

Administration and Dosing

[0181] The first dose of TNX-1500 (Day 0) is administered over 1 hour using a syringe pump. The second and subsequent 20 mg/kg doses of TNX-1500 are administered over 1 hour using a syringe pump. The infusion is administered using a peripheral vein, or a central line, if the latter is in place. Since the compatibility with other intravenously administered medications is not known, TNX- 1500 should not be infused through a common intravenous line used for other medications, unless the line is flushed prior to and after administration of TNX-1500.

Management of drug reactions

[0182] Potentially severe “First dose reactions” may occur upon the initial administration of TNX-1500. Although acetaminophen and diphenhydramine are given prophylactically further doses of acetaminophen (650 mg PO or PR) and diphenhydramine (50 mg PO or i.v.) may be administered if fever or chills occur. Corticosteroids (250 mg i.v. of methylprednisolone) may also be administered if a severe reaction occurs. All symptoms of drug reactions and treatment for drug reactions must be recorded on the appropriate case report forms.

Analysis of Safety

[0183] Recipients are monitored for acute or chronic side effects of TNX-1500, including “first dose effects,” that may be associated with the antibody TNX-1500. The incidence of CMV and other opportunistic infections is assessed at 3, 6, 12, 24,36 and 48 months posttransplant. Participants who have to discontinue any of the procedures due to adverse events are important in assessing the safety of the conditioning regimen. Analysis of Efficacy

[0184] The primary endpoint for this study is estimated from the Kaplan Meier survival curve and associated point-wise 95% confidence interval. The analysis intent to treat, with individuals who experience irreversible rejection counted as treatment failures. Graft and subject survival is assessed using time to event methods, with Kaplan-Meier estimates survival estimates and associated point- wise 95% confidence intervals provided for graft and subject survival at 3, 6, 12, 24 and 36 month time points.

[0185] The number of participants treated with corticosteroids after the first 20 days or experiencing 1 or more episodes of acute or chronic renal allograft rejection will be reported, and rejection episodes will be characterized as to whether anti -lymphocyte therapy was required. Changes in serum creatinine levels from the participant's established baseline will be analyzed to assess renal function using statistical methods that account for correlation between repeated measures.

Example 5, Use of TNX-1500 for treatment of heart transplants in non-human primate

[0186] To test the use of TNX-1500 for the treatment of allotransplant and determine thromboembolism risk, non-human primates were given allogeneic heart transplants and given an expanded series of weekly doses of TNX-1500 therapy: TNX-1500 alone or TNX- 1500 in combination with mycophenolate mofetil (MMF; TNX-1500/MMF), Rapamycin (Rapa; TNX-1500/Rapa), or Tacrolimus (Tac; TNX-1500/Tac). Briefly, after allogeneic heart transplant, TNX-1500 was administered at 30 mg/kg twice a week (BIW) for two weeks and then administered 20 mg/kg week through the end of the study (Day 180) and separated into 4 treatment groups: TNX-1500 alone (n=19); TNX-1500/MMF(200 mg/d PO of MMF; n=4); TNX-1500/Rapa (Rapa target trough 5-10 ng/ml; n=13); or TNX-1500/Tac (Tac target trough 3-5 ng/ml; n=7). A schematic of the study design can be found in Figure 17.

[0187] Rejection occurred in 3 of 19 grafts in non-human primate treated with TNX-1500 alone. All grafts in the non-human primates in the TNX-1500/MMF, TNX-1500/Rapa and TNX-1500/Tac survived for 2.5-3 months after treatment cessation except those censored with beating grafts, usually due to parvovirus-associated anemia. (See, Figure 18 A). On protocol biopsies or explant at day 180, both TNX/Rapa (p=0.30 vs TNX-1500 alone) and TNX-1500/Rac (p=0.13 vs TNX-1500 alone) were associated with lower mean International Society for Heart and Lung Transplantation (ISHLT) acute rejection scores than either TNX- 1500 alone or TNX-1500/MMF (p=0.03 when all data sets analyzed in one-way ANOVA). (See Figure 18B). Cardiac allograft vasculopathy (CAV) scores were lowest around day 90 and day 180 with TNX-1500/Rapa relative to other groups (p=0.13, 0.54 vs TNX-1500 alone at day 90 and day 180) (p=0.50, 0.30 when all data sets analyzed in one-way ANOVA). (See Figure 18C) There was no significant difference in the absolute number of regulatory T cells (Treg) or the ratio of effector T cells/Treg between groups. No microvascular thrombosis or macroscopic thromboemboli were observed in this series.

[0188] TNX- 1500 demonstrated robust efficacy to prevent graft rej ection during treatment in NHP, both alone and in combination with conventional immunosuppressive agents.

Notably, TNX-1500/Rapa provided superior protection from CAV scores in the later posttreatment intervals. The absence of thromboembolic events predicts safety in clinical translation.

Example 6, Use of TNX-1500 for treating Multiple Sclerosis

[0189] A trial to evaluate the efficacy of TNX-1500 to treat multiple sclerosis will be conducted. In this prophetic example, participants are randomly assigned to receive TNX-1500 intravenously (IV) every 4 weeks (Q4W). Subjects receive an initial loading dose of 1800 mg on Day 1 followed by 1200 mg maintenance doses at weeks 4 and 8. Controls receive matching placebo administrations in a blinded fashion.

[0190] Efficacy relative to placebo is assessed at week 12 by evaluating inhibition of the formation of new active brain lesions (new GdE T1 lesions) and volume and count of new or enlarging T2 lesions as measured by MRI. The study also characterizes safety and tolerability of TNX-1500 in participants with multiple sclerosis and activation of the CD40/CD40L signaling pathway by analysis of the levels of expression of genes in whole blood or in subsets of PBMC in order to study treatment effects.

Claims

(a) a heavy chain CDR1 having the amino acid sequence of SEQ ID NO: 3,

(b) a heavy chain CDR2 having the amino acid sequence of SEQ ID NO: 4, and

(a) a light chain CDR1 having the amino acid sequence of SEQ ID NO: 6,

(b) a light chain CDR2 having the amino acid sequence of SEQ ID NO: 7, and

(c) a light chain CDR3 having the amino acid sequence of SEQ ID NO: 8.

(a) a heavy chain CDR1 having the amino acid sequence of SEQ ID NO: 3,

(b) a heavy chain CDR2 having the amino acid sequence of SEQ ID NO: 4, and

(a) a light chain CDR1 having the amino acid sequence of SEQ ID NO: 6,

(b) a light chain CDR2 having the amino acid sequence of SEQ ID NO: 7, and

(c) a light chain CDR3 having the amino acid sequence of SEQ ID NO: 8.

(a) a heavy chain CDR1 having the amino acid sequence of SEQ ID NO: 3,

(b) a heavy chain CDR2 having the amino acid sequence of SEQ ID NO: 4, and

(a) a light chain CDR1 having the amino acid sequence of SEQ ID NO: 6,

(b) a light chain CDR2 having the amino acid sequence of SEQ ID NO: 7, and

(c) a light chain CDR3 having the amino acid sequence of SEQ ID NO: 8.

4. The method of claim 1, the anti-CD154 antibody for use of claim 2 or the use of claim 3, wherein the transplant is an allogeneic transplant, autologous transplant or a xenogeneic transplant.

5. The method of claim 1 or 4, the anti-CD154 antibody for use of claim 2 or 4, or the use of claim 3 or 4, wherein the transplant rejection is associated with a hematopoietic cell or bone marrow transplant, an allogeneic transplant of pancreatic islet cells, graft vs host disease, or a solid organ transplant.

6. The method, anti-CD154 antibody for use, or use of claim 5, wherein the solid organ transplant is selected from the group consisting of a heart transplant, a kidney transplant, a liver transplant, a lung transplant, a pancreas transplant, a kidney-pancreas transplant, a heart-lung transplant, kidney-heart transplant, a kidney -heart-pancreas transplant, a heart-liver transplant, a heart-liver-kidney transplant, a heart-lung-kidney transplant, a heart-lung-liver transplant, a lung-kidney transplant, a lung-liver transplant, a liver-intestines-pancreas transplant, an intestines-pancreas transplant, a liver-kidney-intestines-pancreas transplant, and a kidneyintestines transplant.

(a) a heavy chain CDR1 having the amino acid sequence of SEQ ID NO: 3,

(b) a heavy chain CDR2 having the amino acid sequence of SEQ ID NO: 4, and

(a) a light chain CDR1 having the amino acid sequence of SEQ ID NO: 6,

(b) a light chain CDR2 having the amino acid sequence of SEQ ID NO: 7, and

(c) a light chain CDR3 having the amino acid sequence of SEQ ID NO: 8.

(a) a heavy chain CDR1 having the amino acid sequence of SEQ ID NO: 3,

(b) a heavy chain CDR2 having the amino acid sequence of SEQ ID NO: 4, and

(a) a light chain CDR1 having the amino acid sequence of SEQ ID NO: 6,

(b) a light chain CDR2 having the amino acid sequence of SEQ ID NO: 7, and

(c) a light chain CDR3 having the amino acid sequence of SEQ ID NO: 8.

9. Use of an anti-CD154 antibody in the manufacture of a pharmaceutical composition for treating immune-related disease in a subject in need thereof, wherein the antibody comprises a humanized variable domain, wherein the variable domain comprises a heavy chain variable region (VH) and a light chain variable region (VL), and wherein the VH is operably linked to a human Fc region derived from IgG4 and comprising S228P and L235A amino acid modifications; wherein the VH comprises

(a) a heavy chain CDR1 having the amino acid sequence of SEQ ID NO: 3, (b) a heavy chain CDR2 having the amino acid sequence of SEQ ID NO: 4, and

(a) a light chain CDR1 having the amino acid sequence of SEQ ID NO: 6,

(b) a light chain CDR2 having the amino acid sequence of SEQ ID NO: 7, and

(c) a light chain CDR3 having the amino acid sequence of SEQ ID NO: 8.

10. The method of claim 7, the anti-CD154 antibody for use of claim 8, or the use of claim 9, wherein the immune related disease is selected from the group consisting of Amyotrophic Lateral Sclerosis, Inflammatory Bowel Disease, Irritable Bowel Syndrome, Idiopathic Thrombocytopenic Purpura, Systemic Lupus Erythematosus, Lupus Nephritis, Multiple Sclerosis, Relapsing Remitting Multiple Sclerosis, Secondary Progressive Multiple Sclerosis, Psoriasis, Rheumatoid Arthritis, Systemic Scleroderma, Interstitial Lung Disease, Atopic Dermatitis, Antiphospholipid Syndrome, Sarcoidosis, Myositis, Ulcerative Colitis, Pneumocystis, Type 1 Diabetes, Sjogren syndrome, and Graft versus host disease.

11. The method, the anti-CD154 antibody for use, or use of claim 10, wherein the immune related disease is selected from the group consisting of Systemic Lupus Erythematosus, Multiple Sclerosis, Type 1 Diabetes, and Sjogren syndrome.

12. The method of any one of claims 1, 7 and 10-11, the anti-CD154 antibody for use of any one of claims 2, 8 and 10-11, or the use of any one of claims 3 and 9-11, wherein the antibody comprises the Fc region comprises the amino acid sequence of SEQ ID NOs: 1 or 2.

13. The method of any one of claims 1, 7, and 10-12, the anti-CD154 antibody for use of any one of claims 2, 8 and 10-12, or the use of any one of claims 3 and 9-12, wherein the heavy chain comprises a constant region comprising the amino acid sequence of SEQ ID NO: 12 or 13.

14. The method of any one of claims 1, 7 and 10-13, the anti-CD154 antibody for use of any one of claims 2, 8 and 10-13, or the use of any one of claims 3 and 9-13, wherein the VH comprises the amino acid sequence of SEQ ID NO: 9.

15. The method of any one of claims 1, 7 and 10-14, the anti-CD154 antibody for use of any one of claims 2, 8 and 10-14, or the use of any one of claims 3 and 9-14, wherein the VL comprises the amino acid sequence of SEQ ID NO: 10.

16. The method of any one of claims 1, 7 and 10-15, the anti-CD154 antibody for use of any one of claims 2, 8 and 10-15, or the use of any one of claims 3 and 9-15, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 14 or 15.

17. The method of any one of claims 1, 7 and 10-16, the anti-CD154 antibody for use of any one of claims 2, 8 and 10-16, or the use of any one of claims 3 and 9-16, wherein the light chain comprises the amino acid sequence of SEQ ID NO: 16.

18. The method of any one of claims 1, 7 and 10-17, the anti-CD154 antibody for use of any one of claims 2, 8 and 10-17, or the use of any one of claims 3 and 9-17, wherein the light chain comprising the amino acid sequence of SEQ ID NO: 16 and a heavy chain comprising an amino acid sequence of SEQ ID NO: 14 or 15.

19. The method of any one of claims 1, 7 and 10-18, the anti-CD154 antibody for use of any one of claims 2, 8 and 10-18, or the use of any one of claims 3 and 9-18, wherein the antibody is administered at or formulated to be administered a dose selected from the group consisting of 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30mg/kg, 35mg/kg, 40 mg/kg, 45 mg/kg, and 50 mg/kg.

20. The method, anti-CD154 antibody for use, or use of claim 19, wherein the antibody is administered at or formulated to be administered at a dose is 20 mg/kg.

21. The method of any one of claims 1, 7 and 10-18, the anti-CD154 antibody for use of any one of claims 2, 8 and 10-18, or the use of any one of claims 3 and 9-18, wherein the antibody is administered at or formulated to be administered at a flat dose selected from the group consisting of 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg, and 2000 mg.

22. The method, anti-CD154 antibody for use, or use of claim 21, wherein the antibody is administered at or formulated to be administered at a dose is 1200 mg.

23. The method of any one of claims 1, 7 and 10-22, the anti-CD154 antibody for use of any one of claims 2, 8 and 10-22, or the use of any one of claims 3 and 9-22, wherein the antibody is administered at or formulated to be administered at a frequency selected from the group consisting of Q1W, Q2W, Q3W, Q4W, Q5W and Q6W.

24. The method, anti-CD154 antibody for use, or use of claim 23, wherein the antibody is administered at or formulated to be administered at a frequency of Q4W.

25. The method of any one of claims 1, 7 and 10-22, the anti-CD154 antibody for use of any one of claims 2, 8 and 10-22, or the use of any one of claims 3 and 9-22, wherein the antibody is administered at or formulated to be administered at a frequency once per month.

26. The method of any one of claims 1, 7 and 10-18, the anti-CD154 antibody for use of any one of claims 2, 8 and 10-18, or the use of any one of claims 3 and 9-18, wherein the antibody is administered at or formulated to be administered at a frequency of Q4W at a dose of 20 mg/kg.

27. The method of any one of claims 1, 7 and 10-18, the anti-CD154 antibody for use of any one of claims 2, 8 and 10-18, or the use of any one of claims 3 and 9-18, wherein the antibody is administered at or formulated to be administered at a frequency of Q4W at a dose of 1200 mg.

28. The method of any one of claims 1, 7 and 10-18, the anti-CD154 antibody for use of any one of claims 2, 8 and 10-18, or the use of any one of claims 3 and 9-18, wherein the antibody is administered at or formulated to be administered at a frequency of once per month at a dose of 20 mg/kg.

29. The method of any one of claims 1, 7 and 10-18, the anti-CD154 antibody for use of any one of claims 2, 8 and 10-18, or the use of any one of claims 3 and 9-18, wherein the antibody is administered at or formulated to be administered at a frequency of once per month at a dose of 1200 mg.

30. The method of any one of claims 1, 7 and 10-18, the anti-CD154 antibody for use of any one of claims 2, 8 and 10-18, or the use of any one of claims 3 and 9-18, wherein the antibody is administered at or formulated to be administered at a loading dose followed by a maintenance dose.

31. The method, anti-CD154 antibody for use, or use of claim 30, wherein the loading dose is administered until a serum concentration of TNX-1500 > 750 pg/ml is obtained.

32. The method, anti-CD154 antibody for use, or use of claim 30 or 31, wherein the loading dose is 20 mg/kg on days 0, 2, 5, 7 and weekly until a serum concentration of TNX-1500 > 750 pg/ml is obtained.

33. The method, anti-CD154 antibody for use, or use of any one of claims 30-32, wherein the loading dose is 20 mg/kg on days 0, 2, 5, 7 and weekly for one to six weeks.

34. The method, anti-CD154 antibody for use, or use of any one of claims 30-33, wherein the maintenance dose is 1200 mg at a frequency of Q4W.

35. The method, anti-CD154 antibody for use, or use of any one of claims 30-33, wherein the maintenance dose is 1200 mg at a frequency of once per month.

36. The method of any one of claims 1, 7 and 10-35, the anti-CD154 antibody for use of any one of claims 2, 8 and 10-35, or the use of any one of claims 3 and 9-35, wherein the antibody is administered or formulated as a pharmaceutical composition comprising the antibody and a pharmaceutically acceptable carrier.

37. The method of any one of claims 1, 7 and 10-36, the anti-CD154 antibody for use of any one of claims 2, 8 and 10-36, or the use of any one of claims 3 and 9-36, wherein the antibody is administered intravenously.