Combinations of antibodies and bispecific antibodies that specifically bind to TRAIL or FasL

Abstract

Antibodies that specifically bind to TRAIL, bispecific antibodies that specifically bind to TRAIL and FasL, and pharmaceutical compositions comprising antibodies that specifically bind to TRAIL and antibodies that specifically bind to FasL and / or bispecific antibodies, as well as methods for preparing and using the same.

Description

[Technical Field]

[0001] Cross-Citation of Related Applications This application claims priority to PCT application No. PCT / CN2022 / 126336, filed October 20, 2022, and entitled "Combination of antibodies and bispecific antibodies that specifically bind to TRAIL or FasL," the entire contents of which are incorporated herein by reference.

[0002] Citation to Electronic Sequence Listing The contents of the electronic sequence listing (file name: CN_20220714_SEQLIST.xml, date of recording: 2023.09.14, size: 219KB) are incorporated by reference in their entirety into this application.

[0003] The present application relates to antibodies that specifically bind to TRAIL, bispecific antibodies that specifically bind to TRAIL and FasL, and pharmaceutical compositions comprising antibodies that specifically bind to TRAIL and antibodies that specifically bind to FasL and / or bispecific antibodies, as well as methods for preparing and using the same. [Background technology]

[0004] Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is cleaved from the cell surface by type II transmembrane proteins of the TNF superfamily, cysteine ​​proteases, and matrix metalloproteinase 2 (MMP-2), resulting in a soluble form that retains proapoptotic activity (Wiley, SR et al., Immunity vol. 3, 6 (1995): 673-82; Mariani, SM, and PH Krammer, European Journal of Immunology vol. 28, 3 (1998): 973-82). TRAIL constitutive expression is present in multiple tissues but is primarily expressed in natural killer (NK) cells and macrophages (Wang, S., Current Medicinal Chemistry vol. 17, 29 (2010): 3309-17).

[0005] TRAIL has five distinct receptors: TRAIL-R1, TRAIL-R2, DcR1, DcR2, and osteoprotegerin. Among these, TRAIL-R1 (also known as DR4) and TRAIL-R2 (also known as DR5) contain a cytoplasmic domain called the death domain, which can induce cytotoxic signals after receptor binding with homologous ligands. DcR1 does not contain a death domain, DcR2 contains an incomplete death domain, and osteoprotegerin is a soluble TRAIL receptor. These three receptors act as decoy receptors, blocking the binding of TRAIL to its pro-apoptotic receptors or interfering with death receptor-mediated death signals, thereby preventing apoptosis (Walczak, H, and PH Krammer. Experimental Cell Research Vol. 256, 1 (2000): 58-66). DR4 is generally expressed in most human tissues, including the spleen, thymus, liver, peripheral blood leukocytes, activated T cells, and small intestine. DR5 expression is widespread in normal and tumor tissues, but is particularly abundant in the spleen, peripheral blood leukocytes, and activated lymphocytes (Wang, S. Current medicinal chemistry vol. 17, 29 (2010): 3309-17.).

[0006] After binding to the death receptors DR4 or DR5, TRAIL induces receptor trimerization and recruits Fas-associated protein (FADD) and membrane-proximal caspases (caspase 8 or 10) to form a receptor complex called the death-inducing signaling complex (DISC). Caspases are synthesized as inactive zymogens and then recruit and form the DISC, which then induces their own activation. Activated caspases then directly activate downstream effector caspases (caspases 3, 6, and 7) by cleaving them. Activated caspase 3 can cleave multiple cellular proteins, further inducing apoptosis (Ashkenazi, A, and V.M. Dixit. Science (New York, NY) vol. 281, 5381 (1998): 1305-8). In type I cells, a relatively large number of DISCs are internalized and assembled into a complex, generating enough caspase 8 (or 10) to signal and promote cell death. Conversely, in type II cells, the DISC forms more slowly and inefficiently. Therefore, activation of caspase-8 in type II cells is insufficient to activate apoptosis. Apoptosis is initiated through mitochondrial caspase-8-mediated cleavage of the BH3-interacting domain death agonist (Bid), resulting in a truncated form of Bid (tBid), which then induces activation of Bax and Bak in mitochondria. Activated Bax and Bak promote loss of mitochondrial membrane potential and release of cytochrome c, leading to further apoptosis (Barnhart, Bryan C et al. Seminars in Immunology vol. 15, 3 (2003): 185-93; Kohlhaas, Susan L et al. The Journal of Biological Chemistry vol. 282, 17 (2007): 12831-41).

[0007] In addition to inducing cell death, TRAIL signaling can also promote cell growth, survival, and proliferation by activating nuclear factor-κB (NF-κB), MAP kinase (MAPK), and Akt (Lin, Y et al. Molecular and cellular biology vol. 20, 18 (2000): 6638-45; Lee, Tae-Jin et al. Biochemical and biophysical research communications vol. 351, 4 (2006): 1024-30). For example, TRAIL can initiate the formation of a cytoplasmic complex containing FADD, TNF receptor-associated factor 2 (TRAF2), and NF-κB essential modulator (NEMO), which may lead to the activation of other signaling pathways, including NF-κB and MAPK activation, as well as the production of proinflammatory cytokines and chemokines.

[0008] Fas ligand (FasL) is also a type II transmembrane protein of the TNF superfamily and shares 28% homology with TRAIL (Rossin, Aurelie et al. Cancers vol. 11, 5 639. 8 May 2019, doi:10.3390 / cancers11050639). After binding to its death receptor, FasL initiates a cascade similar to that of TRAIL, recruiting FADD and caspase 8 or caspase 10 to form a receptor complex and signaling to promote cell death. In type II cells, a mitochondrial-dependent pathway involving Bid cleavage and cytochrome C release is also activated to induce apoptosis (Yin, Xiao-Ming, and Wen-Xing Ding. Current molecular medicine vol. 3, 6(2003):491-508).

[0009] Studies have shown that FASL and TRAIL, as ligands for death receptors, are involved in the development and progression of several diseases. According to a study by Yin et al., death receptor-induced liver apoptosis contributes to the progression of several liver diseases, including viral hepatitis, inflammatory hepatitis, Wilson's disease, alcoholic liver disease, endotoxemia-induced liver failure, and ischemia / reperfusion-induced liver injury (Yin, Xiao-Ming, and Wen-Xing Ding. Current Molecular Medicine vol. 3, 6 (2003): 491-508). According to a study by Ochi et al., administration of anti-TRAIL antibody alone partially suppresses hepatic NK cell-mediated hepatotoxicity, while administration in combination with anti-FasL monoclonal antibody and perforin inhibitors completely suppresses hepatotoxicity (Ochi, Makoto et al. Hepatology (Baltimore, Md.) vol. 39, 5 (2004): 1321-31). According to a study by Zhang et al., in the case of host-versus-graft disease after kidney transplantation, TRAIL and FasL are involved in cell-mediated cytotoxicity through death domain-mediated apoptosis signaling (Zhang, Yun et al., Immunology Letters, vol. 152, 1 (2013): 1-7). According to a study by Tasew et al., FasL- and TRAIL-expressing cells are present in the dermis of patients with ulcerative cutaneous leishmaniasis (CL), and suppression of FasL and TRAIL can reduce leishmaniasis-induced skin ulcers (Tasew, Geremew et al., PLoS Neglected Tropical Diseases, vol. 4, 10e844, 12 Oct. 2010). Therefore, the development of novel antibodies that bind to TRAIL or FasL, or bispecific antibodies that simultaneously bind to TRAIL and FasL, and pharmaceutical compositions containing antibodies that bind to TRAIL and / or FasL are important in the pharmaceutical field.

[0010] Currently, inhibitors of FasL or TRAIL have been reported. For example, Chinese Patent CN108290950B discloses the anti-FasL antibody 119-4A (reference antibody in the Examples section of this application) and its use, and Chinese Patent CN108997503B discloses the fusion protein sDR5-Fc, which has the function of blocking the TRAIL-DR5 signal pathway (reference antibody in the Examples section of this application). However, monoclonal antibodies targeting TRAIL and bispecific antibody drugs simultaneously targeting TRAIL and FasL are not yet commercially available. Therefore, there is an urgent need to develop monoclonal antibodies targeting TRAIL and bispecific antibody drugs simultaneously targeting TRAIL and FasL.

[0011] The contents of all publications, patents, patent applications and published patent applications mentioned in this application are hereby incorporated by reference in their entirety. Summary of the Invention

[0012] In one aspect, the present application provides an isolated antibody or antigen-binding fragment capable of specifically binding to TRAIL. H and V L and an isolated antibody or antigen-binding fragment that specifically binds to TRAIL, the antibody or antigen-binding fragment comprising: H is the V shown in the amino acid sequence SEQ ID NO:13 H wherein the V comprises HC-CDR1, HC-CDR2 and HC-CDR3; L is the V shown in the amino acid sequence SEQ ID NO:22 L comprises LC-CDR1, LC-CDR2 and LC-CDR3.

[0013] In some embodiments, V H or the above V H and mutants of V L or the above V L and a variant of V Hcomprises an HC-CDR1 comprising the amino acid sequence SEQ ID NO:1, an HC-CDR2 comprising the amino acid sequence SEQ ID NO:3, and an HC-CDR3 comprising the amino acid sequence SEQ ID NO:5, H The variant of V contains at most about five amino acid substitutions in its HC-CDRs, L comprises an LC-CDR1 comprising the amino acid sequence SEQ ID NO:7, an LC-CDR2 comprising the amino acid sequence SEQ ID NO:9, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO:11, L The variant contains at most about five amino acid substitutions in its LC-CDRs.

[0014] In some embodiments, a V includes an amino acid sequence set forth in any one of SEQ ID NOs: 13-14 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 13-14. H and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 22 to 27 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 22 to 27. L The present invention provides an isolated antibody or antigen-binding fragment that specifically binds to TRAIL, comprising:

[0015] In some embodiments, (i) a V comprising the amino acid sequence SEQ ID NO:13 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO:13. H and V, including the amino acid sequence SEQ ID NO:22 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:22. L (ii) V comprising the amino acid sequence SEQ ID NO:14 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:14 H and V, including the amino acid sequence SEQ ID NO:23 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:23.L (iii) V comprising the amino acid sequence SEQ ID NO:14 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:14 H and V, including the amino acid sequence SEQ ID NO:24 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:24. L (iv) V comprising the amino acid sequence SEQ ID NO:14 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:14 H and V, including the amino acid sequence SEQ ID NO: 25 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 25. L (v) V comprising the amino acid sequence SEQ ID NO:14 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:14 H and V, including the amino acid sequence SEQ ID NO:26 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:26. L or (vi) V comprising the amino acid sequence SEQ ID NO:14 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:14. H and V, including the amino acid sequence SEQ ID NO:27 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:27. L The present invention provides an isolated antibody or antigen-binding fragment that specifically binds to TRAIL, comprising:

[0016] In some embodiments, the present application provides H and V L and an isolated antibody or antigen-binding fragment that specifically binds to TRAIL, the antibody or antigen-binding fragment comprising: H is the V shown in the amino acid sequence SEQ ID NO:15 H wherein the V comprises HC-CDR1, HC-CDR2 and HC-CDR3; L is the V shown in the amino acid sequence SEQ ID NO:28L comprises LC-CDR1, LC-CDR2 and LC-CDR3.

[0017] In some embodiments, V H or the above V H and mutants of V L or the above V L and a variant of V H comprises an HC-CDR1 comprising the amino acid sequence SEQ ID NO:2, an HC-CDR2 comprising the amino acid sequence SEQ ID NO:4, and an HC-CDR3 comprising the amino acid sequence SEQ ID NO:6, H The variant of V contains at most about five amino acid substitutions in its HC-CDRs, L comprises an LC-CDR1 comprising the amino acid sequence SEQ ID NO:8, an LC-CDR2 comprising the amino acid sequence SEQ ID NO:10, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO:12, L The variant contains at most about five amino acid substitutions in its LC-CDRs.

[0018] In some embodiments, a V includes an amino acid sequence set forth in any one of SEQ ID NOs: 15-21 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 15-21. H and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 28 to 32 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 28 to 32. L The present invention provides an isolated antibody or antigen-binding fragment that specifically binds to TRAIL, comprising:

[0019] In some embodiments, (i) a V comprising the amino acid sequence SEQ ID NO:15 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO:15. Hand V, including the amino acid sequence SEQ ID NO:28 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:28. L (ii) V comprising the amino acid sequence SEQ ID NO:16 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:16 H and V, including the amino acid sequence SEQ ID NO:29 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:29. L (iii) V comprising the amino acid sequence SEQ ID NO:17 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:17 H and V, including the amino acid sequence SEQ ID NO:29 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:29. L (iv) V comprising the amino acid sequence SEQ ID NO:18 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:18 H and V, including the amino acid sequence SEQ ID NO:29 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:29. L (v) V comprising the amino acid sequence SEQ ID NO:19 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:19 H and V, including the amino acid sequence SEQ ID NO:29 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:29. L (vi) V comprising the amino acid sequence SEQ ID NO:20 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:20 H and V, including the amino acid sequence SEQ ID NO:29 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:29. L(vii) V comprising the amino acid sequence SEQ ID NO:16 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:16 H and V, including the amino acid sequence SEQ ID NO: 30 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 30. L (viii) V comprising the amino acid sequence SEQ ID NO:17 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:17. H and V, including the amino acid sequence SEQ ID NO: 30 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 30. L (ix) V comprising the amino acid sequence SEQ ID NO:18 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:18 H and V, including the amino acid sequence SEQ ID NO: 30 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 30. L (x) V comprising the amino acid sequence SEQ ID NO:19 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:19 H and V, including the amino acid sequence SEQ ID NO: 30 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 30. L (xi) V comprising the amino acid sequence SEQ ID NO:20 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:20 H and V, including the amino acid sequence SEQ ID NO: 30 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 30. L (xii) V comprising the amino acid sequence SEQ ID NO:16 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:16 Hand V, including the amino acid sequence SEQ ID NO: 31 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 31. L (xiii) V comprising the amino acid sequence SEQ ID NO:17 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:17. H and V, including the amino acid sequence SEQ ID NO: 31 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 31. L (xiv) V comprising the amino acid sequence SEQ ID NO:18 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:18. H and V, including the amino acid sequence SEQ ID NO: 31 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 31. L (xv) V comprising the amino acid sequence SEQ ID NO:19 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:19 H and V, including the amino acid sequence SEQ ID NO: 31 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 31. L (xvi) V comprising the amino acid sequence SEQ ID NO:20 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:20 H and V, including the amino acid sequence SEQ ID NO: 31 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 31. L or (xvii) V comprising the amino acid sequence SEQ ID NO:21 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO:21. H and V, including the amino acid sequence SEQ ID NO: 32 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 32. L The present invention provides an isolated antibody or antigen-binding fragment that specifically binds to TRAIL, comprising:

[0020] In some embodiments, an isolated antibody or antigen-binding fragment that specifically binds to TRAIL is provided, which specifically binds to TRAIL competitively with any of the isolated antibodies described above. In some embodiments, an isolated antibody or antigen-binding fragment that specifically binds to TRAIL is provided, which specifically binds to the same epitope as any of the isolated antibodies described above.

[0021] In some embodiments, any of the isolated antibodies that specifically bind to TRAIL comprises an Fc region. In some embodiments, the isolated antibody that specifically binds to TRAIL is a full-length IgG antibody. In some embodiments, the isolated antibody that specifically binds to TRAIL is a full-length IgG1, IgG2, IgG3, or IgG4 antibody. In some embodiments, the isolated antibody that specifically binds to TRAIL is a chimeric, fully human, or humanized antibody. In some embodiments, the isolated antibody that specifically binds to TRAIL is an antigen-binding fragment selected from Fab, Fab', F(ab)'2, Fab'-SH, single-chain Fv (scFv), Fv fragment, dAb, Fd, nanobody, double-chain antibody (diabody), and linear antibody.

[0022] In some embodiments, a nucleic acid molecule encoding any of the above antibodies or antigen-binding fragments that specifically bind to TRAIL is provided. In some embodiments, a vector comprising any of the above nucleic acid molecules is provided. In some embodiments, a host cell is provided that comprises any of the above antibodies or antigen-binding fragments that specifically bind to TRAIL, any of the above nucleic acid molecules, or any of the above vectors. In some embodiments, a method is provided for preparing an antibody or antigen-binding fragment that specifically binds to TRAIL, comprising: a) culturing any of the above host cells under conditions that effectively express the antibody or antigen-binding fragment that specifically binds to TRAIL; and b) obtaining the expressed antibody from the host cell.

[0023] In some embodiments, pharmaceutical compositions, reagent kits, and articles of manufacture comprising any of the above antibodies or antigen-binding fragments that specifically bind to TRAIL are provided.

[0024] In some embodiments, there is provided a method for treating a disease or condition in an individual in need thereof, comprising administering to the individual an effective amount of any of the above-mentioned antibodies or antigen-binding fragments that specifically bind to TRAIL, or a pharmaceutical composition comprising the same. In some embodiments, there is provided the use of any of the above-mentioned antibodies or antigen-binding fragments that specifically bind to TRAIL in the preparation of a pharmaceutical composition for treating a disease or condition in an individual in need thereof. In some embodiments, there is provided the use of any of the above-mentioned antibodies or antigen-binding fragments that specifically bind to TRAIL, or a pharmaceutical composition comprising the same, in the preparation of a medicament for treating a disease or condition in an individual in need thereof. In some embodiments, the disease or condition is related to the TRAIL signaling pathway and includes inflammatory diseases, autoimmune diseases, transplant-related diseases, liver diseases, neurodegenerative diseases, or cancer. In some embodiments, the disease or condition is selected from the group consisting of transplant rejection, graft-versus-host disease, liver damage, pulmonary arterial hypertension, Alzheimer's disease, systemic inflammatory response syndrome, sepsis, multiple organ dysfunction syndrome, trauma, multiple sclerosis, idiopathic pulmonary fibrosis, osteoarthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, acute lung injury, acute respiratory distress syndrome, myocardial infarction, myocardial disease, ischemia-reperfusion injury, diabetes, brain injury, spinal cord injury, acute viral hepatitis B, acute viral hepatitis C, chronic hepatitis C, chronic hepatitis B, alcoholic hepatitis, non-alcoholic steatohepatitis, cirrhosis, drug-induced liver injury / liver failure, autoimmune hepatitis, chronic kidney disease, acute kidney disease, diabetic nephropathy, and cancer.

[0025] In another aspect, the present application provides a bispecific antibody that specifically binds to TRAIL and FasL, and a pharmaceutical composition comprising the bispecific antibody that specifically binds to TRAIL and FasL. In some examples, the present application provides a method for preventing and / or treating a disease associated with the TRAIL and / or FasL signaling pathway using the bispecific antibody or a pharmaceutical composition thereof. In other examples, the present application provides use of the bispecific antibody or a pharmaceutical composition thereof in the preparation of a medicament for preventing and / or treating a disease associated with the TRAIL and / or FasL signaling pathway.

[0026] In some embodiments, the present application provides a bispecific antibody comprising a first antigen-binding domain that specifically binds to TRAIL and a second antigen-binding domain that specifically binds to FasL, wherein the first antigen-binding domain comprises: (i) a VHC-CDR1 comprising the amino acid sequence SEQ ID NO:1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO:3, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO:5; H and V comprising an LC-CDR1 comprising the amino acid sequence SEQ ID NO:7, an LC-CDR2 comprising the amino acid sequence SEQ ID NO:9, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO:11. L or (ii) a V comprising an HC-CDR1 comprising the amino acid sequence SEQ ID NO:2, an HC-CDR2 comprising the amino acid sequence SEQ ID NO:4, and an HC-CDR3 comprising the amino acid sequence SEQ ID NO:6. H and V comprising an LC-CDR1 having the amino acid sequence SEQ ID NO:8, an LC-CDR2 having the amino acid sequence SEQ ID NO:10, and an LC-CDR3 having the amino acid sequence SEQ ID NO:12. L or (iii) a V comprising an HC-CDR1 comprising the amino acid sequence SEQ ID NO:2, an HC-CDR2 comprising the amino acid sequence SEQ ID NO:161, and an HC-CDR3 comprising the amino acid sequence SEQ ID NO:6. Hand V comprising an LC-CDR1 having the amino acid sequence SEQ ID NO:8, an LC-CDR2 having the amino acid sequence SEQ ID NO:10, and an LC-CDR3 having the amino acid sequence SEQ ID NO:12. L In some embodiments, the second antigen-binding domain comprises (i) a V-CDR1 comprising an HC-CDR1 having the amino acid sequence SEQ ID NO:51, an HC-CDR2 having the amino acid sequence SEQ ID NO:53, and an HC-CDR3 having the amino acid sequence SEQ ID NO:55. H and V comprising an LC-CDR1 having the amino acid sequence SEQ ID NO: 57, an LC-CDR2 having the amino acid sequence SEQ ID NO: 59, and an LC-CDR3 having the amino acid sequence SEQ ID NO: 61. L or (ii) a V comprising an HC-CDR1 comprising the amino acid sequence SEQ ID NO: 52, an HC-CDR2 comprising the amino acid sequence SEQ ID NO: 54, and an HC-CDR3 comprising the amino acid sequence SEQ ID NO: 56. H and V comprising an LC-CDR1 having the amino acid sequence SEQ ID NO: 58, an LC-CDR2 having the amino acid sequence SEQ ID NO: 60, and an LC-CDR3 having the amino acid sequence SEQ ID NO: 62. L or (iii) a V comprising an HC-CDR1 comprising the amino acid sequence SEQ ID NO: 52, an HC-CDR2 comprising the amino acid sequence SEQ ID NO: 54, and an HC-CDR3 comprising the amino acid sequence SEQ ID NO: 56. H and a V comprising an LC-CDR1 having the amino acid sequence SEQ ID NO: 162, an LC-CDR2 having the amino acid sequence SEQ ID NO: 60, and an LC-CDR3 having the amino acid sequence SEQ ID NO: 62. L , including.

[0027] In some embodiments, the present application provides a bispecific antibody comprising a first antigen-binding domain that specifically binds to TRAIL and a second antigen-binding domain that specifically binds to FasL, wherein the second antigen-binding domain comprises: (i) a V-CDR1 comprising an HC-CDR1 having the amino acid sequence SEQ ID NO:51, an HC-CDR2 having the amino acid sequence SEQ ID NO:53, and an HC-CDR3 having the amino acid sequence SEQ ID NO:55; H and V comprising an LC-CDR1 having the amino acid sequence SEQ ID NO: 57, an LC-CDR2 having the amino acid sequence SEQ ID NO: 59, and an LC-CDR3 having the amino acid sequence SEQ ID NO: 61. L or (ii) a V comprising an HC-CDR1 comprising the amino acid sequence SEQ ID NO: 52, an HC-CDR2 comprising the amino acid sequence SEQ ID NO: 54, and an HC-CDR3 comprising the amino acid sequence SEQ ID NO: 56. H and V comprising an LC-CDR1 having the amino acid sequence SEQ ID NO: 58, an LC-CDR2 having the amino acid sequence SEQ ID NO: 60, and an LC-CDR3 having the amino acid sequence SEQ ID NO: 62. L or (iii) a V comprising an HC-CDR1 comprising the amino acid sequence SEQ ID NO: 52, an HC-CDR2 comprising the amino acid sequence SEQ ID NO: 54, and an HC-CDR3 comprising the amino acid sequence SEQ ID NO: 56. H and a V comprising an LC-CDR1 having the amino acid sequence SEQ ID NO: 162, an LC-CDR2 having the amino acid sequence SEQ ID NO: 60, and an LC-CDR3 having the amino acid sequence SEQ ID NO: 62. L , including.

[0028] In some embodiments, the first antigen-binding domain of any of the bispecific antibodies described herein comprises: (i) V H and V L and V H is the V shown in the amino acid sequence SEQ ID NO:13 H wherein V comprises an HCDR1, an HCDR2, and an HCDR3; Lis the V shown in the amino acid sequence SEQ ID NO:22 L or (ii) V H and V L and V H is the V shown in the amino acid sequence SEQ ID NO:15 H wherein V comprises an HCDR1, an HCDR2, and an HCDR3; L is the V shown in the amino acid sequence SEQ ID NO:28 L or (iii) V H and V L and V H is the V shown in the amino acid sequence SEQ ID NO:164 H wherein V comprises an HCDR1, an HCDR2, and an HCDR3; L is the amino acid sequence shown in SEQ ID NO:168 L or (iv) V H and V L and V H is the amino acid sequence shown in SEQ ID NO:166 H wherein V comprises an HCDR1, an HCDR2, and an HCDR3; L is the V shown in the amino acid sequence SEQ ID NO:170 L includes LCDR1, LCDR2 and LCDR3.

[0029] In some embodiments, according to any of the bispecific antibodies described herein, the first antigen-binding domain comprises a V domain comprising an amino acid sequence set forth in any one of SEQ ID NOs: 13-20, 33-40, 164, and 166, or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 13-20, 33-40, 164, and 166. Hand V comprising an amino acid sequence set forth in any one of SEQ ID NOs: 22-31, 41-50, 168, and 170, or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 22-31, 41-50, 168, and 170. L , including.

[0030] In some embodiments, according to any of the bispecific antibodies described herein, the first antigen-binding domain comprises (i) a V domain comprising the amino acid sequence set forth in any one of SEQ ID NOs: 13 and 33, or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 13 and 33. H and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 22 and 41 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 22 and 41. L (ii) a V comprising an amino acid sequence set forth in any one of SEQ ID NOs: 14 and 34 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 14 and 34. H and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 23 and 42 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 23 and 42. L (iii) V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 14 and 34 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 14 and 34. H and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 24 and 43 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 24 and 43. L(iv) V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 14 and 34 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 14 and 34. H and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 25 and 44 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 25 and 44. L (v) V comprising an amino acid sequence set forth in any one of SEQ ID NOs: 14 and 34 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 14 and 34. H and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 26 and 45 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 26 and 45. L (vi) V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 14 and 34 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 14 and 34. H and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 27 and 46 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 27 and 46. L (vii) V comprising an amino acid sequence set forth in any one of SEQ ID NOs: 15 and 35 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 15 and 35. H and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 28 and 47 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 28 and 47. L(viii) V comprising an amino acid sequence set forth in any one of SEQ ID NOs: 16 and 36 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 16 and 36. H and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 29 and 48 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 29 and 48. L (ix) a V comprising an amino acid sequence set forth in any one of SEQ ID NOs: 17 and 37 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 17 and 37. H and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 29 and 48 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 29 and 48. L (x) a V comprising an amino acid sequence set forth in any one of SEQ ID NOs: 18 and 38 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 18 and 38 H and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 29 and 48 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 29 and 48. L (xi) V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 19 and 39 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 19 and 39. H and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 29 and 48 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 29 and 48. L(xii) V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 20 and 40 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 20 and 40. H and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 29 and 48 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 29 and 48. L (xiii) V comprising an amino acid sequence set forth in any one of SEQ ID NOs: 16 and 36 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 16 and 36. H and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 30 and 49 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 30 and 49. L (xiv) V comprising an amino acid sequence set forth in any one of SEQ ID NOs: 17 and 37 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 17 and 37. H and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 30 and 49 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 30 and 49. L (xv) V comprising an amino acid sequence set forth in any one of SEQ ID NOs: 18 and 38 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 18 and 38. H and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 30 and 49 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 30 and 49. L(xvi) V comprising an amino acid sequence set forth in any one of SEQ ID NOs: 19 and 39 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 19 and 39. H and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 30 and 49 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 30 and 49. L (xvii) V comprising an amino acid sequence set forth in any one of SEQ ID NOs: 20 and 40 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 20 and 40. H and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 30 and 49 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 30 and 49. L (xviii) V comprising an amino acid sequence set forth in any one of SEQ ID NOs: 16 and 36 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 16 and 36. H and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 31 and 50 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 31 and 50. L (xix) a V comprising an amino acid sequence set forth in any one of SEQ ID NOs: 17 and 37 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 17 and 37. H and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 31 and 50 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 31 and 50. L(xx) a V comprising an amino acid sequence set forth in any one of SEQ ID NOs: 18 and 38 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 18 and 38 H and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 31 and 50 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 31 and 50. L (xxi) V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 19 and 39 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 19 and 39. H and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 31 and 50 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 31 and 50. L (xxii) V comprising an amino acid sequence set forth in any one of SEQ ID NOs: 20 and 40 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 16 and 36. H and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 31 and 50 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 31 and 50. L (xxiii) V comprising the amino acid sequence set forth in SEQ ID NO: 164 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in SEQ ID NO: 164. H and V comprising the amino acid sequence set forth in SEQ ID NO: 168 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in SEQ ID NO: 168. L or (xxiv) the amino acid sequence set forth in SEQ ID NO:166 or a sequence at least as similar to the amino acid sequence set forth in SEQ ID NO:166. V, including its variants with at least about 80% sequence identity Hand V comprising the amino acid sequence set forth in SEQ ID NO: 170 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in SEQ ID NO: 170. L , including.

[0031] In some embodiments, according to any of the bispecific antibodies described herein, the second antigen-binding domain comprises: (i) V H and V L and V H is the V shown in the amino acid sequence SEQ ID NO:63 H wherein V comprises an HCDR1, an HCDR2, and an HCDR3; L is the V shown in the amino acid sequence SEQ ID NO:73 L or (ii) V H and V L and V H is the V shown in the amino acid sequence SEQ ID NO:66 H wherein V comprises an HCDR1, an HCDR2, and an HCDR3; L is V shown in the amino acid sequence SEQ ID NO:76 L or (iii) V H and V L and V H is the V shown in the amino acid sequence SEQ ID NO:163 H wherein V comprises an HCDR1, an HCDR2, and an HCDR3; L is the V shown in the amino acid sequence SEQ ID NO:167 L or (iv) V H and V L and V H is the V shown in the amino acid sequence SEQ ID NO:165 H wherein V comprises an HCDR1, an HCDR2, and an HCDR3; L is the V shown in the amino acid sequence SEQ ID NO:169 L includes LCDR1, LCDR2 and LCDR3.

[0032] In some embodiments, according to any of the bispecific antibodies described herein, the second antigen-binding domain comprises a V domain comprising an amino acid sequence set forth in any one of SEQ ID NOs: 63-72, 80-88, 163, and 165, or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 63-72, 80-88, 163, and 165. H and V comprising an amino acid sequence set forth in any one of SEQ ID NOs: 73-79, 89-95, 167 and 169, or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 73-79, 89-95, 167 and 169. L , including.

[0033] In some embodiments, according to any of the bispecific antibodies described herein, the second antigen-binding domain comprises (i) a V domain comprising the amino acid sequence set forth in any one of SEQ ID NOs: 63 and 80, or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 63 and 80. H and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 73 and 89 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 73 and 89. L (ii) a V comprising an amino acid sequence set forth in any one of SEQ ID NOs: 64 and 81 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 64 and 81. H and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 74 and 90 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 74 and 90. L(iii) V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 65 and 81 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 65 and 81. H and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 74 and 90 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 74 and 90. L (iv) V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 64 and 81 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 64 and 81. H and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 75 and 91 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 75 and 91. L (v) V comprising an amino acid sequence set forth in any one of SEQ ID NOs: 65 and 81 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 65 and 81. H and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 75 and 91 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 75 and 91. L (vi) V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 66 and 82 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 66 and 82. H and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 76 and 92 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 76 and 92. L(vii) V comprising an amino acid sequence set forth in any one of SEQ ID NOs: 67 and 83 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 67 and 83. H and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 77 and 93 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 77 and 93. L (viii) V comprising an amino acid sequence set forth in any one of SEQ ID NOs: 68 and 84 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 68 and 84. H and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 77 and 93 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 77 and 93. L (ix) a V comprising an amino acid sequence set forth in any one of SEQ ID NOs: 69 and 85 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 69 and 85. H and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 77 and 93 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 77 and 93. L (x) a V comprising an amino acid sequence set forth in any one of SEQ ID NOs: 70 and 86 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 70 and 86. H and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 77 and 93 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 77 and 93. L(xi) V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 71 and 87 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 71 and 87. H and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 77 and 93 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 77 and 93. L (xii) V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 72 and 88 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 72 and 88. H and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 77 and 93 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 77 and 93. L (xiii) V comprising an amino acid sequence set forth in any one of SEQ ID NOs: 67 and 83 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 67 and 83. H and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 78 and 94 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 78 and 94. L (xiv) V comprising an amino acid sequence set forth in any one of SEQ ID NOs: 68 and 84 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 68 and 84. H and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 78 and 94 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 78 and 94. L(xv) V comprising an amino acid sequence set forth in any one of SEQ ID NOs: 69 and 85 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 69 and 85. H and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 78 and 94 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 78 and 94. L (xvi) V comprising an amino acid sequence set forth in any one of SEQ ID NOs: 70 and 86 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 70 and 86. H and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 78 and 94 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 78 and 94. L (xvii) V comprising an amino acid sequence set forth in any one of SEQ ID NOs: 71 and 87 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 71 and 87. H and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 78 and 94 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 78 and 94. L (xviii) V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 72 and 88 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 72 and 88. H and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 78 and 94 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 78 and 94. L(xix) V comprising an amino acid sequence set forth in any one of SEQ ID NOs: 67 and 83 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 67 and 83. H and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 79 and 95 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 79 and 95. L (xx) V comprising an amino acid sequence set forth in any one of SEQ ID NOs: 68 and 84 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 68 and 84. H and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 79 and 95 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 79 and 95. L (xxi) V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 69 and 85 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 69 and 85. H and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 79 and 95 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 79 and 95. L (xxii) V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 70 and 86 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 70 and 86. H and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 79 and 95 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 79 and 95. L(xxiii) V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 71 and 87 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 71 and 87. H and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 79 and 95 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 79 and 95. L , (xxiv) SEQ ID N or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 72 and 88. H and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 79 and 95 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 79 and 95. L (xxv) V comprising the amino acid sequence set forth in SEQ ID NO: 163 or a variant thereof having at least about 80% sequence identity with the amino acid sequence of SEQ ID NO: 163. H and V comprising the amino acid sequence set forth in SEQ ID NO: 167 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in SEQ ID NO: 167. L or (xxvi) V comprising the amino acid sequence set forth in SEQ ID NO: 165 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO: 165. H and V comprising the amino acid sequence set forth in SEQ ID NO: 169 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in SEQ ID NO: 169. L , including.

[0034] In some embodiments, according to any of the bispecific antibodies described herein, the first antigen-binding domain comprises a VHC-CDR1 comprising the amino acid sequence SEQ ID NO:1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO:3, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO:5. H and V comprising an LC-CDR1 comprising the amino acid sequence SEQ ID NO:7, an LC-CDR2 comprising the amino acid sequence SEQ ID NO:9, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO:11. L and the second antigen-binding domain comprises a VHC-CDR1 comprising the amino acid sequence SEQ ID NO: 51, a HC-CDR2 comprising the amino acid sequence SEQ ID NO: 53, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO: 55. H and V comprising an LC-CDR1 having the amino acid sequence SEQ ID NO: 57, an LC-CDR2 having the amino acid sequence SEQ ID NO: 59, and an LC-CDR3 having the amino acid sequence SEQ ID NO: 61. L Includes:

[0035] In some embodiments, according to any of the bispecific antibodies described herein, the first antigen-binding domain comprises a VHC-CDR1 comprising the amino acid sequence SEQ ID NO:1, a HC-CDR2 comprising the amino acid sequence SEQ ID NO:3, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO:5. H and V comprising an LC-CDR1 comprising the amino acid sequence SEQ ID NO:7, an LC-CDR2 comprising the amino acid sequence SEQ ID NO:9, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO:11. L and the second antigen-binding domain comprises a VHC-CDR1 comprising the amino acid sequence SEQ ID NO: 52, a HC-CDR2 comprising the amino acid sequence SEQ ID NO: 54, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO: 56. Hand V comprising an LC-CDR1 having the amino acid sequence SEQ ID NO: 58, an LC-CDR2 having the amino acid sequence SEQ ID NO: 60, and an LC-CDR3 having the amino acid sequence SEQ ID NO: 62. L Includes:

[0036] In some embodiments, according to any of the bispecific antibodies described herein, the first antigen-binding domain comprises a VHC-CDR1 comprising the amino acid sequence SEQ ID NO:2, a HC-CDR2 comprising the amino acid sequence SEQ ID NO:4, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO:6. H and V comprising an LC-CDR1 having the amino acid sequence SEQ ID NO:8, an LC-CDR2 having the amino acid sequence SEQ ID NO:10, and an LC-CDR3 having the amino acid sequence SEQ ID NO:12. L and the second antigen-binding domain comprises a VHC-CDR1 comprising the amino acid sequence SEQ ID NO: 51, a HC-CDR2 comprising the amino acid sequence SEQ ID NO: 53, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO: 55. H and V comprising an LC-CDR1 having the amino acid sequence SEQ ID NO: 57, an LC-CDR2 having the amino acid sequence SEQ ID NO: 59, and an LC-CDR3 having the amino acid sequence SEQ ID NO: 61. L Includes:

[0037] In some embodiments, according to any of the bispecific antibodies described herein, the second antigen-binding domain comprises a VHC-CDR1 comprising the amino acid sequence SEQ ID NO:2, a HC-CDR2 comprising the amino acid sequence SEQ ID NO:4, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO:6. H and V comprising an LC-CDR1 comprising the amino acid sequence SEQ ID NO:8, an LC-CDR2 comprising the amino acid sequence SEQ ID NO:10, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO:12. Land the second antigen-binding domain comprises a VHC-CDR1 comprising the amino acid sequence SEQ ID NO: 52, a HC-CDR2 comprising the amino acid sequence SEQ ID NO: 54, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO: 56. H and V comprising an LC-CDR1 having the amino acid sequence SEQ ID NO: 58, an LC-CDR2 having the amino acid sequence SEQ ID NO: 60, and an LC-CDR3 having the amino acid sequence SEQ ID NO: 62. L Includes:

[0038] In some embodiments, according to any of the bispecific antibodies described herein, the first antigen-binding domain comprises a VHC-CDR1 comprising the amino acid sequence SEQ ID NO:2, a HC-CDR2 comprising the amino acid sequence SEQ ID NO:161, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO:6. H and V comprising an LC-CDR1 having the amino acid sequence SEQ ID NO:8, an LC-CDR2 having the amino acid sequence SEQ ID NO:10, and an LC-CDR3 having the amino acid sequence SEQ ID NO:12. L and the second antigen-binding domain comprises a VHC-CDR1 comprising the amino acid sequence SEQ ID NO: 52, a HC-CDR2 comprising the amino acid sequence SEQ ID NO: 54, and a HC-CDR3 comprising the amino acid sequence SEQ ID NO: 56. H and a V comprising an LC-CDR1 having the amino acid sequence SEQ ID NO: 162, an LC-CDR2 having the amino acid sequence SEQ ID NO: 60, and an LC-CDR3 having the amino acid sequence SEQ ID NO: 62. L Includes:

[0039] In some embodiments, according to any of the bispecific antibodies described herein, the first antigen-binding domain comprises a V domain comprising the amino acid sequence set forth in any one of SEQ ID NOs: 14 and 34, or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 14 and 34. Hand V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 23 and 42 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 23 and 42. L and the second antigen-binding domain comprises a V comprising an amino acid sequence set forth in any one of SEQ ID NOs: 64 and 81 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 64 and 81. H and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 74 and 90 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 74 and 90. L Includes:

[0040] In some embodiments, according to any of the bispecific antibodies described herein, the first antigen-binding domain comprises a V domain comprising the amino acid sequence set forth in any one of SEQ ID NOs: 14 and 34, or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 14 and 34. H and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 24 and 43 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 24 and 43. L and the second antigen-binding domain comprises a V comprising an amino acid sequence set forth in any one of SEQ ID NOs: 64 and 81 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 64 and 81. H and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 74 and 90 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 74 and 90. L Includes:

[0041] In some embodiments, according to any of the bispecific antibodies described herein, the first antigen-binding domain comprises a V domain comprising the amino acid sequence set forth in any one of SEQ ID NOs: 15 and 35, or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 15 and 35. H and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 28 and 47 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 28 and 47. L and the second antigen-binding domain comprises a V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 66 and 82 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 66 and 82. H and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 76 and 92 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 76 and 92. L Includes:

[0042] In some embodiments, according to any of the bispecific antibodies described herein, the first antigen-binding domain comprises a V domain comprising the amino acid sequence set forth in any one of SEQ ID NOs: 16 and 36, or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 16 and 36. H and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 31 and 50 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 31 and 50. L and the second antigen-binding domain comprises a V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 66 and 82 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 66 and 82. Hand V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 76 and 92 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 76 and 92. L Includes:

[0043] In some embodiments, according to any of the bispecific antibodies described herein, the first antigen-binding domain comprises a V domain comprising the amino acid sequence set forth in any one of SEQ ID NOs: 16 and 36, or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 16 and 36. H and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 31 and 50 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 31 and 50. L and the second antigen-binding domain comprises a V comprising an amino acid sequence set forth in any one of SEQ ID NOs: 69 and 85 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 69 and 85. H and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 79 and 95 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 79 and 95. L Includes:

[0044] In some embodiments, according to any of the bispecific antibodies described herein, the first antigen-binding domain comprises a VHQ domain comprising the amino acid sequence set forth in SEQ ID NO:164 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO:164. H and V comprising the amino acid sequence set forth in SEQ ID NO: 168 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in SEQ ID NO: 168. Land the second antigen-binding domain comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 163 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO: 163. H and V comprising the amino acid sequence set forth in SEQ ID NO: 167 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in SEQ ID NO: 167. L Includes:

[0045] In some embodiments, according to any of the bispecific antibodies described herein, the first antigen-binding domain comprises a VHQ domain comprising the amino acid sequence set forth in SEQ ID NO:166 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO:166. H and V comprising the amino acid sequence set forth in SEQ ID NO: 170 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in SEQ ID NO: 170. L and the second antigen-binding domain comprises a V comprising the amino acid sequence set forth in SEQ ID NO: 165 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in SEQ ID NO: 165. H and V comprising the amino acid sequence set forth in SEQ ID NO: 169 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in SEQ ID NO: 169. L Includes:

[0046] In some embodiments, the bispecific antibodies described herein comprise an Fc. In other embodiments, the Fc described herein is selected from the group consisting of IgG1, IgG2, IgG3, IgG4, IgA, IgM, IgE, and IgD Fcs. In some embodiments, the Fc comprises an Fc variant. In some embodiments, the Fc is glycosylated. In some embodiments, the Fc is deglycosylated. In some embodiments, the Fc has reduced fucosylation or is afucosylated. In some embodiments, the Fc variant comprises a substitution at one or more of positions 228, 239, 282, 289, 297, 312, 324, 330, 335, 337, 339, 356, 359, 361, 383, 384, 398, 400, 440, 422, and 442 (EU numbering). In some embodiments, the Fc variant comprises a substitution at position 297. In some embodiments, the substitution at position 297 is 297Q.

[0047] In some embodiments, the bispecific antibody has a DVD-Ig structure. In some embodiments, the bispecific antibody comprises four polypeptide chains, of which: Both polypeptide chains are V from N-terminus to C-terminus H 1-LV H 2-C H 1 structure, except that V H 1 is a heavy chain variable region that specifically binds to TRAIL, and V H 2 is a heavy chain variable region that specifically binds to FasL, L is a linker peptide, and C H 1 is heavy chain constant region C H 1 domain, provided that the polypeptide chain is C H 2 and C H further comprising an Fc comprising three domains, The other two polypeptide chains are both V L 1-LV L 2-C L structure, where V L 1 is a light chain variable region that specifically binds to TRAIL, and VL 2 is a light chain variable region that specifically binds to FasL, L is a linker peptide, and C L is the light chain constant region, Of these, V H 1 and V L 1 constitutes an antigen-binding domain (Fv) that can specifically bind to TRAIL, and V H 2-C H 1 and V L 2-C L constitutes an antigen-binding domain (Fab) capable of specifically binding to FasL.

[0048] In some other embodiments, the bispecific antibody comprises four polypeptide chains, including: Both polypeptide chains are V H 1-LV H 2-C H 1 structure, except that V H 1 is a heavy chain variable region that specifically binds to FasL, and V H 2 is a heavy chain variable region that specifically binds to TRAIL, L is a linker peptide, and C H 1 is heavy chain constant region C H 1 domain, provided that the polypeptide chain is C H 2 and C H further comprising an Fc comprising three domains, The other two polypeptide chains are both V L 1-LV L 2-C L structure, where V L 1 is a light chain variable region that specifically binds to FasL, and V L 2 is a light chain variable region that specifically binds to TRAIL, L is a linker peptide, and C L is the light chain constant region, Of these, V H 1 and V L 1 constitutes the antigen-binding domain (Fv) that can specifically bind to FasL, and V H 2-C H 1 and V L 2-C Lconstitutes an antigen-binding domain (Fab) that can specifically bind to TRAIL.

[0049] In some embodiments, the bispecific antibody described in the present application is selected from the group consisting of: (a) the amino acid sequence SEQ ID NO:104 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:104, and / or the amino acid sequence SEQ ID NO:105 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:105; (b) the amino acid sequence SEQ ID NO:104 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:104, and / or the amino acid sequence SEQ ID NO:106 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:106; (c) the amino acid sequence SEQ ID NO:107 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:107, and / or the amino acid sequence SEQ ID NO:108 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:108; (d) the amino acid sequence SEQ ID NO:107 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:107, and / or the amino acid sequence SEQ ID NO:109 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:109; (e) the amino acid sequence SEQ ID NO:110 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:110, and / or the amino acid sequence SEQ ID NO:111 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:111; or (f) the amino acid sequence SEQ ID NO:172 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:172, and / or the amino acid sequence SEQ ID NO:174 or the amino acid sequence SEQ ID NO:175. and variants thereof having at least about 80% sequence identity with NO:174.

[0050] In some embodiments, the bispecific antibody described in the present application is selected from the group consisting of: (a) the amino acid sequence SEQ ID NO:131 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:131, and / or the amino acid sequence SEQ ID NO:105 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:105; (b) the amino acid sequence SEQ ID NO:131 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:131, and / or the amino acid sequence SEQ ID NO:106 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:106; (c) the amino acid sequence SEQ ID NO:132 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:132, and / or the amino acid sequence SEQ ID NO:108 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:132. (d) the amino acid sequence SEQ ID NO:132 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:132, and / or the amino acid sequence SEQ ID NO:109 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:109; (e) the amino acid sequence SEQ ID NO:133 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:133, and / or the amino acid sequence SEQ ID NO:111 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:111; or (f) the amino acid sequence SEQ ID NO:176 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:176, and / or the amino acid sequence SEQ ID NO:174 or the amino acid sequence SEQ ID NO:175. It includes variants thereof having at least about 80% sequence identity with NO:174.

[0051] In some other embodiments, the bispecific antibodies described herein have a Bs4Ab structure. In some embodiments, the bispecific antibodies comprise four polypeptide chains, including: Two polypeptide chains, V from N-terminus to C-terminus H 1-C H 1-L1-V H 2-L3-V L 2 structure or V H 1-C H 1-L1-V L 2-L3-V H 2 structure, except for V H 1 is a heavy chain variable region that specifically binds to TRAIL, and V H 2 is a heavy chain variable region that specifically binds to FasL, and V L 2 is a light chain variable region that specifically binds to FasL, L1 and L3 are linker peptides, and C H 1 is heavy chain constant region C H 1 domain, provided that the polypeptide chain is C H 2 and C H further comprising an Fc comprising three domains, and The other two polypeptide chains are V from N-terminus to C-terminus L 1-C L structure, where V L 1 is a light chain variable region that specifically binds to TRAIL, and C L is the light chain constant region.

[0052] Of these, V H 1-C H 1 and V L 1-C L constitutes the antigen-binding domain (Fab) that specifically binds to TRAIL, and V H 2-L3-V L 2 or V L 2-L3-V H 2 constitutes an antigen-binding domain (scFv) that specifically binds to FasL.

[0053] In some embodiments, the bispecific antibody comprises four polypeptide chains, including: Two polypeptide chains, V from N-terminus to C-terminus H 1-C H 1-L1-V H 2-L3-V L 2 structure or V H 1-C H 1-L1-V L 2-L3-V H 2 structure, except for V H 1 is a heavy chain variable region that specifically binds to FasL, and V H 2 is a heavy chain variable region that specifically binds to TRAIL, and V L 2 is a light chain variable region that specifically binds to TRAIL, L1 and L3 are linker peptides, and C H 1 is heavy chain constant region C H 1 domain, provided that the polypeptide chain is C H 2 and C H further comprising an Fc comprising three domains, and The other two polypeptide chains are V from N-terminus to C-terminus L 1-C L structure, but V L 1 is a light chain variable region that specifically binds to FasL, and C L is the light chain constant region.

[0054] Of these, V H 1-C H 1 and V L 1-C L constitutes the antigen-binding domain (Fab) that specifically binds to FasL, and V H 2-L3-V L 2 or V L 2-L3-V H 2 constitutes an antigen-binding domain (scFv) that specifically binds to TRAIL.

[0055] In some embodiments, the bispecific antibody is selected from the group consisting of: (a) the amino acid sequence SEQ ID NO:112 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:112, and / or the amino acid sequence SEQ ID NO:113 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:113; (b) the amino acid sequence SEQ ID NO:114 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:114, and / or the amino acid sequence SEQ ID NO:115 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:115; (c) the amino acid sequence SEQ ID NO:116 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:116, and / or the amino acid sequence SEQ ID NO:119 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:119; (d) the amino acid sequence SEQ ID NO:117 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:117 and / or the amino acid sequence SEQ ID NO:119 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:119; (e) the amino acid sequence SEQ ID NO:118 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:118 and / or the amino acid sequence SEQ ID NO:119 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:119; (f) the amino acid sequence SEQ ID NO:120 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:120 and / or the amino acid sequence SEQ ID NO:121 or a variant thereof (g) the amino acid sequence SEQ ID NO:120 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:120, and / or the amino acid sequence SEQ ID NO:121.(h) the amino acid sequence SEQ ID NO:122 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:122, (i) the amino acid sequence SEQ ID NO:123 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:123, and / or the amino acid sequence SEQ ID NO:124 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:124, or (ii) the amino acid sequence SEQ ID NO:171 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:171, and / or the amino acid sequence SEQ ID NO:173 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:173.

[0056] In some embodiments, the bispecific antibody is selected from the group consisting of: (a) the amino acid sequence SEQ ID NO:134 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:134, and / or the amino acid sequence SEQ ID NO:113 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:113; (b) the amino acid sequence SEQ ID NO:135 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:135, and / or the amino acid sequence SEQ ID NO:113 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:113; (c) the amino acid sequence SEQ ID NO:136 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:136, and / or the amino acid sequence SEQ ID NO:115 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:136. (d) the amino acid sequence SEQ ID NO:137 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:137 and / or the amino acid sequence SEQ ID NO:115 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:115; (e) the amino acid sequence SEQ ID NO:138 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:138 and / or the amino acid sequence SEQ ID NO:119 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:119; (f) the amino acid sequence SEQ ID NO:139 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:139 and / or the amino acid sequence SEQ ID NO:119 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:139. (g) the amino acid sequence SEQ ID NO:140 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:140, and / or the amino acid sequence SEQ ID NO:140.(h) the amino acid sequence SEQ ID NO:141 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:141 and / or the amino acid sequence SEQ ID NO:121 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:121; (i) the amino acid sequence SEQ ID NO:141 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:141 and / or the amino acid sequence SEQ ID NO:122 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:122; (j) the amino acid sequence SEQ ID NO:142 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:142 and / or the amino acid sequence SEQ ID NO:124 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:142. or (k) the amino acid sequence SEQ ID NO:175 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:175, and / or the amino acid sequence SEQ ID NO:173 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:173.

[0057] In some embodiments, the bispecific antibodies described herein have a Hetero H, CrossMab structure. In some embodiments, the bispecific antibodies comprise four polypeptide chains, of which: A single polypeptide chain is V from the N-terminus to the C-terminus H 1-C H 1 structure, except that V H 1 is a heavy chain variable region that specifically binds to TRAIL, and C H 1 is heavy chain constant region C H 1 domain, provided that the polypeptide chain is C H 2 and C H further comprising an Fc comprising three domains, and A single polypeptide chain is V from the N-terminus to the C-terminus L 1-C L Including, but V L 1 is a light chain variable region that specifically binds to TRAIL, and C L is the light chain constant region, and A single polypeptide chain is V from the N-terminus to the C-terminus H 2-C L Including, but V H 2 is a heavy chain variable region that specifically binds to FasL, and C L is a light chain constant region, provided that said polypeptide chain is C H 2 and C H further comprising an Fc comprising three domains, and A single polypeptide chain is V from the N-terminus to the C-terminus L 2-C H 1, but V L 2 is a light chain variable region that specifically binds to FasL, and C H 1 is heavy chain constant region C H It is one domain.

[0058] Of these, V H 1-C H 1 and V L 1-C L constitutes the antigen-binding domain (Fab) that specifically binds to TRAIL, and V H 2-C L and V L 2-C H 1 constitutes an antigen-binding domain (scFv) that specifically binds to FasL.

[0059] In some embodiments, the bispecific antibody comprises four polypeptide chains, including: A single polypeptide chain is V from the N-terminus to the C-terminus H 1-C H 1 structure, except that V H 1 is a heavy chain variable region that specifically binds to FasL, and C H 1 is heavy chain constant region C H 1 domain, provided that the polypeptide chain is CH 2 and C H further comprising an Fc comprising three domains, and A single polypeptide chain is V from the N-terminus to the C-terminus L 1-C L Including, but V L 1 is a light chain variable region that specifically binds to FasL, and C L is the light chain constant region, and A single polypeptide chain is V from the N-terminus to the C-terminus H 2-C L Including, but V H 2 is a heavy chain variable region that specifically binds to TRAIL, and C L is a light chain constant region, provided that said polypeptide chain is C H 2 and C H further comprising an Fc comprising three domains, and A single polypeptide chain is V from the N-terminus to the C-terminus L 2-C H 1, but V L 2 is a light chain variable region that specifically binds to TRAIL, and C H 1 is heavy chain constant region C H It is one domain.

[0060] Of these, V H 1-C H 1 and V L 1-C L constitutes the antigen-binding domain (Fab) that specifically binds to FasL, and V H 2-C L and V L 2-C H 1 constitutes an antigen-binding domain (scFv) that specifically binds to TRAIL.

[0061] In some embodiments, the bispecific antibody is selected from the group consisting of (a) the amino acid sequence SEQ ID NO:125 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:125, and / or the amino acid sequence SEQ ID NO:126 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:126, and / or the amino acid sequence SEQ ID NO:127 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:127, and / or the amino acid sequence SEQ ID NO:129 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:129, or (b) the amino acid sequence SEQ ID NO:125 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:125, and / or the amino acid sequence SEQ ID NO:130 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:130. The amino acid sequence of SEQ ID NO:129 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:129 is preferably SEQ ID NO:130, and / or the amino acid sequence of SEQ ID NO:128 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:128 is preferably SEQ ID NO:130, and / or the amino acid sequence of SEQ ID NO:129 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:129 is preferably SEQ ID NO:130.

[0062] In some embodiments, the bispecific antibody is selected from the group consisting of (a) the amino acid sequence SEQ ID NO:143 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:143, and / or the amino acid sequence SEQ ID NO:126 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:126, and / or the amino acid sequence SEQ ID NO:144 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:144, and / or the amino acid sequence SEQ ID NO:129 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:129, or (b) the amino acid sequence SEQ ID NO:145 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:145, and / or the amino acid sequence SEQ ID NO:130 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:130. and / or the amino acid sequence SEQ ID NO:146 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:146, and / or the amino acid sequence SEQ ID NO:129 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:129.

[0063] In some embodiments, there is provided a method of treating a disease or condition in an individual in need thereof, comprising administering to the individual an effective amount of any of the bispecific antibodies described above, or a pharmaceutical composition comprising the same. In some embodiments, there is provided a use of any of the bispecific antibodies described above in the preparation of a pharmaceutical composition for treating a disease or condition in an individual in need thereof. In some embodiments, there is provided a use of any of the bispecific antibodies described above, or a pharmaceutical composition comprising the same, in the preparation of a medicament for treating a disease or condition. In some embodiments, the disease or condition comprises an inflammatory disease, an autoimmune disease, a transplant-related disease, a liver disease, a neurodegenerative disease, or cancer associated with the TRAIL and / or FasL signaling pathway. In some embodiments, the disease or condition is selected from the group consisting of transplant rejection, graft-versus-host disease, liver injury, systemic inflammatory response syndrome, sepsis, multiple organ dysfunction syndrome, trauma, multiple sclerosis, idiopathic pulmonary fibrosis, osteoarthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, acute lung injury, acute respiratory distress syndrome, myocardial infarction, myocardial disease, ischemia-reperfusion injury, diabetes, brain injury, spinal cord injury, acute viral hepatitis B, acute viral hepatitis C, chronic hepatitis C, chronic hepatitis B, alcoholic hepatitis, non-alcoholic steatohepatitis, cirrhosis, drug-induced liver injury / liver failure, autoimmune hepatitis, chronic kidney disease, acute kidney disease, diabetic nephropathy, and cancer.

[0064] In some embodiments, the application provides an isolated nucleic acid molecule encoding any of the bispecific antibodies. In some embodiments, the application provides a vector comprising any of the nucleic acid molecules. In some embodiments, the application provides a host cell comprising any of the bispecific antibodies, any of the nucleic acid molecules, or any of the vectors. In some embodiments, the application provides a method for preparing a bispecific antibody that specifically binds TRAIL and FasL, comprising: a) culturing any of the host cells under conditions effective to express the bispecific antibody that specifically binds TRAIL and FasL; and b) obtaining the expressed bispecific antibody from the host cell.

[0065] Additionally provided are pharmaceutical compositions, reagent kits and articles of manufacture comprising the bispecific antibodies, nucleic acid molecules, vectors, or host cells.

[0066] In one aspect, the present application provides a pharmaceutical composition comprising (i) an antibody or antigen-binding fragment that specifically binds to TRAIL, and (ii) an antibody or antigen-binding fragment that specifically binds to FasL.

[0067] In one aspect, the present application provides a method for treating and / or preventing a disease or condition in an individual in need thereof, comprising administering to the individual an effective amount of (i) an antibody or antigen-binding fragment that specifically binds to TRAIL and (ii) an antibody or antigen-binding fragment that specifically binds to FasL, or a pharmaceutical composition comprising the antibody or antigen-binding fragment that specifically binds to TRAIL and the antibody or antigen-binding fragment that specifically binds to FasL.

[0068] In another aspect, the present application provides the use of an antibody or antigen-binding fragment that specifically binds TRAIL and an antibody or antigen-binding fragment that specifically binds FasL in the preparation of a pharmaceutical composition for treating a disease or condition in an individual in need thereof.In another aspect, the present application provides the use of a pharmaceutical composition comprising an antibody or antigen-binding fragment that specifically binds TRAIL and an antibody or antigen-binding fragment that specifically binds FasL, or an antibody or antigen-binding fragment that specifically binds TRAIL and an antibody or antigen-binding fragment that specifically binds FasL, in the preparation of a medicament for treating a disease or condition in an individual in need thereof.

[0069] In some embodiments, in the pharmaceutical compositions, methods, or uses described herein, the antibody or antigen-binding fragment that specifically binds to TRAIL comprises: (a) V H or the above V H and mutants of V L or the above V L and a variant of V Hcomprises an HC-CDR1 comprising the amino acid sequence SEQ ID NO: 1, an HC-CDR2 comprising the amino acid sequence SEQ ID NO: 3, and an HC-CDR3 comprising the amino acid sequence SEQ ID NO: 5, H The variant of V contains at most about five amino acid substitutions in its HC-CDRs, L comprises an LC-CDR1 comprising the amino acid sequence SEQ ID NO:7, an LC-CDR2 comprising the amino acid sequence SEQ ID NO:9, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO:11, L (b) a variant of V contains at most about five amino acid substitutions in its LC-CDRs; or H or the above V H and mutants of V L or the above V L and a variant of V H comprises an HC-CDR1 comprising the amino acid sequence SEQ ID NO:2, an HC-CDR2 comprising the amino acid sequence SEQ ID NO:4, and an HC-CDR3 comprising the amino acid sequence SEQ ID NO:6, H The variant of V contains at most about five amino acid substitutions in its HC-CDRs, L comprises an LC-CDR1 comprising the amino acid sequence SEQ ID NO:8, an LC-CDR2 comprising the amino acid sequence SEQ ID NO:10, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO:12, L The variant contains at most about five amino acid substitutions in its LC-CDRs.

[0070] In some embodiments, in the pharmaceutical compositions, methods or uses described herein, the antibody or antigen-binding fragment that specifically binds to FasL comprises: (a) V H or the above V H and mutants of V L or the above V L and a variant of V Hcomprises an HC-CDR1 comprising the amino acid sequence SEQ ID NO: 51, an HC-CDR2 comprising the amino acid sequence SEQ ID NO: 53, and an HC-CDR3 comprising the amino acid sequence SEQ ID NO: 55, H The variant of V contains at most about five amino acid substitutions in its HC-CDRs, L comprises an LC-CDR1 comprising the amino acid sequence SEQ ID NO: 57, an LC-CDR2 comprising the amino acid sequence SEQ ID NO: 59, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO: 61, L (b) a variant of V contains at most about five amino acid substitutions in its LC-CDRs; or H or the above V H and mutants of V L or the above V L and a variant of V H comprises an HC-CDR1 comprising the amino acid sequence SEQ ID NO: 52, an HC-CDR2 comprising the amino acid sequence SEQ ID NO: 54, and an HC-CDR3 comprising the amino acid sequence SEQ ID NO: 56, H The variant of V contains at most about five amino acid substitutions in its HC-CDRs, L comprises an LC-CDR1 comprising the amino acid sequence SEQ ID NO: 58, an LC-CDR2 comprising the amino acid sequence SEQ ID NO: 60, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO: 62, L The variant contains at most about five amino acid substitutions in its LC-CDRs.

[0071] In some embodiments, in the pharmaceutical compositions, methods, or uses described herein, the antibody or antigen-binding fragment that specifically binds to TRAIL comprises: (a) V H and V L and V H is the V shown in the amino acid sequence SEQ ID NO:13 H wherein V comprises an HCDR1, an HCDR2, and an HCDR3; L is the V shown in the amino acid sequence SEQ ID NO:22 Lor (b) V H and V L and V H is the V shown in the amino acid sequence SEQ ID NO:15 H wherein V comprises an HCDR1, an HCDR2, and an HCDR3; L is the V shown in the amino acid sequence SEQ ID NO:28 L includes LCDR1, LCDR2 and LCDR3.

[0072] In some embodiments, in the pharmaceutical compositions, methods, or uses described herein, the antibody or antigen-binding fragment that specifically binds to TRAIL comprises (i) a V antibody having the amino acid sequence SEQ ID NO:13 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO:13. H and V, including the amino acid sequence SEQ ID NO:22 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:22. L (ii) V comprising the amino acid sequence SEQ ID NO:14 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:14 H and V, including the amino acid sequence SEQ ID NO:23 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:23. L (iii) V comprising the amino acid sequence SEQ ID NO:14 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:14 H and V, including the amino acid sequence SEQ ID NO:24 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:24. L (iv) V comprising the amino acid sequence SEQ ID NO:14 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:14 Hand V, including the amino acid sequence SEQ ID NO: 25 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 25. L (v) V comprising the amino acid sequence SEQ ID NO:14 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:14 H and V, including the amino acid sequence SEQ ID NO:26 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:26. L (vi) V comprising the amino acid sequence SEQ ID NO:14 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:14 H and V, including the amino acid sequence SEQ ID NO:27 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:27. L (vii) V comprising the amino acid sequence SEQ ID NO:15 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:15 H and V, including the amino acid sequence SEQ ID NO:28 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:28. L (viii) V comprising the amino acid sequence SEQ ID NO:16 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:16. H and V, including the amino acid sequence SEQ ID NO:29 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:29. L (ix) V comprising the amino acid sequence SEQ ID NO:17 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:17 H and V, including the amino acid sequence SEQ ID NO:29 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:29. L(x) V comprising the amino acid sequence SEQ ID NO:18 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:18 H and V, including the amino acid sequence SEQ ID NO:29 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:29. L (xi) V comprising the amino acid sequence SEQ ID NO:19 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:19 H and V, including the amino acid sequence SEQ ID NO:29 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:29. L (xii) V comprising the amino acid sequence SEQ ID NO:20 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:20 H and V, including the amino acid sequence SEQ ID NO:29 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:29. L (xiii) V comprising the amino acid sequence SEQ ID NO:16 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:16. H and V, including the amino acid sequence SEQ ID NO: 30 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 30. L (xiv) V comprising the amino acid sequence SEQ ID NO:17 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:17. H and V, including the amino acid sequence SEQ ID NO: 30 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 30. L (xv) V comprising the amino acid sequence SEQ ID NO:18 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:18 Hand V, including the amino acid sequence SEQ ID NO: 30 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 30. L (xvi) V comprising the amino acid sequence SEQ ID NO:19 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:19 H and V, including the amino acid sequence SEQ ID NO: 30 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 30. L (xvii) V comprising the amino acid sequence SEQ ID NO:20 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:20 H and V, including the amino acid sequence SEQ ID NO: 30 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 30. L (xviii) V comprising the amino acid sequence SEQ ID NO:16 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:16. H and V, including the amino acid sequence SEQ ID NO: 31 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 31. L (xix) V, comprising the amino acid sequence SEQ ID NO: 17 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 17. H and V, including the amino acid sequence SEQ ID NO: 31 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 31. L (xx) V comprising the amino acid sequence SEQ ID NO: 18 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 18 H and V, including the amino acid sequence SEQ ID NO: 31 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 31. L(xxi) V comprising the amino acid sequence SEQ ID NO:19 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:19 H and V, including the amino acid sequence SEQ ID NO: 31 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 31. L (xxii) V comprising the amino acid sequence SEQ ID NO:20 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:20 H and V, including the amino acid sequence SEQ ID NO: 31 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 31. L or (xxiii) V comprising the amino acid sequence SEQ ID NO:21 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:21. H and V, including the amino acid sequence SEQ ID NO: 32 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 32. L , including.

[0073] In some embodiments, in the pharmaceutical compositions, methods or uses described herein, the antibody or antigen-binding fragment that specifically binds to FasL comprises: (a) V H and V L and V H is the V shown in the amino acid sequence SEQ ID NO:63 H wherein V comprises an HCDR1, an HCDR2, and an HCDR3; L is the V shown in the amino acid sequence SEQ ID NO:73 L or (b) V H and V L and V H is the V shown in the amino acid sequence SEQ ID NO:66 H wherein V comprises an HCDR1, an HCDR2, and an HCDR3; L is V shown in the amino acid sequence SEQ ID NO:76 Lincludes LCDR1, LCDR2 and LCDR3.

[0074] In some embodiments, in the pharmaceutical compositions, methods, or uses described herein, the antibody or antigen-binding fragment that specifically binds to FasL comprises (i) a V antibody comprising the amino acid sequence SEQ ID NO:63 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:63. H and V, including the amino acid sequence SEQ ID NO: 73 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 73. L (ii) V comprising the amino acid sequence SEQ ID NO:64 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:64 H and V, including the amino acid sequence SEQ ID NO: 74 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 74. L (iii) V comprising the amino acid sequence SEQ ID NO:65 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:65 H and V, including the amino acid sequence SEQ ID NO: 74 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 74. L (iv) V comprising the amino acid sequence SEQ ID NO:64 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:64 H and V, including the amino acid sequence SEQ ID NO: 75 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 75. L (v) V comprising the amino acid sequence SEQ ID NO:65 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:65 H and V, including the amino acid sequence SEQ ID NO: 75 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 75. L(vi) V comprising the amino acid sequence SEQ ID NO:66 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:66 H and V, including the amino acid sequence SEQ ID NO: 76 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 76. L (vii) V comprising the amino acid sequence SEQ ID NO:67 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:67 H and V, including the amino acid sequence SEQ ID NO: 77 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 77. L (viii) V comprising the amino acid sequence SEQ ID NO:68 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:68 H and V, including the amino acid sequence SEQ ID NO: 77 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 77. L (ix) V comprising the amino acid sequence SEQ ID NO:69 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:69 H and V, including the amino acid sequence SEQ ID NO: 77 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 77. L (x) V comprising the amino acid sequence SEQ ID NO:70 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:70 H and V, including the amino acid sequence SEQ ID NO: 77 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 77. L (xi) V comprising the amino acid sequence SEQ ID NO:71 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:71 Hand V, including the amino acid sequence SEQ ID NO: 77 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 77. L (xii) V comprising the amino acid sequence SEQ ID NO:72 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:72 H and V, including the amino acid sequence SEQ ID NO: 77 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 77. L (xiii) V comprising the amino acid sequence SEQ ID NO:67 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:67. H and V, including the amino acid sequence SEQ ID NO: 78 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 78. L (xiv) V comprising the amino acid sequence SEQ ID NO:68 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:68 H and V, including the amino acid sequence SEQ ID NO: 78 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 78. L (xv) V comprising the amino acid sequence SEQ ID NO:69 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:69 H and V, including the amino acid sequence SEQ ID NO: 78 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 78. L (xvi) V comprising the amino acid sequence SEQ ID NO:70 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:70 H and V, including the amino acid sequence SEQ ID NO: 78 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 78. L(xvii) V comprising the amino acid sequence SEQ ID NO:71 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:71 H and V, including the amino acid sequence SEQ ID NO: 78 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 78. L (xviii) V comprising the amino acid sequence SEQ ID NO:72 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:72 H and V, including the amino acid sequence SEQ ID NO: 78 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 78. L (xix) V comprising the amino acid sequence SEQ ID NO:67 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:67. H and V, including the amino acid sequence SEQ ID NO: 79 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 79. L (xx) V comprising the amino acid sequence SEQ ID NO:68 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:68 H and V, including the amino acid sequence SEQ ID NO: 79 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 79. L (xxi) V comprising the amino acid sequence SEQ ID NO:69 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:69 H and V, including the amino acid sequence SEQ ID NO: 79 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 79. L (xxii) V comprising the amino acid sequence SEQ ID NO:70 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:70 Hand V, including the amino acid sequence SEQ ID NO: 79 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 79. L (xxiii) V comprising the amino acid sequence SEQ ID NO:71 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:71 H and V, including the amino acid sequence SEQ ID NO: 79 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 79. L or (xxiv) V comprising the amino acid sequence SEQ ID NO:72 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:72. H and V, including the amino acid sequence SEQ ID NO: 79 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 79. L , including.

[0075] In some embodiments, in the pharmaceutical compositions, methods or uses described herein, the antibody or antigen-binding fragment that specifically binds to TRAIL is V H or the above V H and mutants of V L or the above V L and a variant of V H comprises an HC-CDR1 comprising the amino acid sequence SEQ ID NO: 1, an HC-CDR51 comprising the amino acid sequence SEQ ID NO: 3, and an HC-CDR3 comprising the amino acid sequence SEQ ID NO: 5, H The variant of V contains at most about five amino acid substitutions in its HC-CDRs, L comprises an LC-CDR1 comprising the amino acid sequence SEQ ID NO:7, an LC-CDR2 comprising the amino acid sequence SEQ ID NO:9, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO:11, L The variant of V contains at most about five amino acid substitutions in its LC-CDRs, and the antibody or antigen-binding fragment that specifically binds to FasL has V Hor the above V H and mutants of V L or the above V L and a variant of V H comprises an HC-CDR1 comprising the amino acid sequence SEQ ID NO: 51, an HC-CDR2 comprising the amino acid sequence SEQ ID NO: 53, and an HC-CDR3 comprising the amino acid sequence SEQ ID NO: 55, H The variant of V contains at most about five amino acid substitutions in its HC-CDRs, L comprises an LC-CDR1 comprising the amino acid sequence SEQ ID NO: 57, an LC-CDR2 comprising the amino acid sequence SEQ ID NO: 59, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO: 61, L The variant contains at most about five amino acid substitutions in its LC-CDRs.

[0076] In some embodiments, in the pharmaceutical compositions, methods or uses described herein, the antibody or antigen-binding fragment that specifically binds to TRAIL is V H or the above V H and mutants of V L or the above V L and a variant of V H comprises an HC-CDR1 comprising the amino acid sequence SEQ ID NO:2, an HC-CDR2 comprising the amino acid sequence SEQ ID NO:4, and an HC-CDR3 comprising the amino acid sequence SEQ ID NO:6, H The variant of V contains at most about five amino acid substitutions in its HC-CDRs, L comprises an LC-CDR1 comprising the amino acid sequence SEQ ID NO:8, an LC-CDR2 comprising the amino acid sequence SEQ ID NO:10, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO:12, L The variant of V contains at most about five amino acid substitutions in its LC-CDRs, and the antibody or antigen-binding fragment that specifically binds to FasL comprises V H or the above V H and mutants of V L or the above VL and a variant of V H comprises an HC-CDR1 comprising the amino acid sequence SEQ ID NO: 51, an HC-CDR2 comprising the amino acid sequence SEQ ID NO: 53, and an HC-CDR3 comprising the amino acid sequence SEQ ID NO: 55, H The variant of V contains at most about five amino acid substitutions in its HC-CDRs, L comprises an LC-CDR1 comprising the amino acid sequence SEQ ID NO: 57, an LC-CDR2 comprising the amino acid sequence SEQ ID NO: 59, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO: 61, L The variant contains at most about five amino acid substitutions in its LC-CDRs.

[0077] In some embodiments, in the pharmaceutical compositions, methods or uses described herein, the antibody or antigen-binding fragment that specifically binds to TRAIL is V H or the above V H and mutants of V L or the above V L and a variant of V H comprises an HC-CDR1 comprising the amino acid sequence SEQ ID NO: 1, an HC-CDR2 comprising the amino acid sequence SEQ ID NO: 3, and an HC-CDR3 comprising the amino acid sequence SEQ ID NO: 5, H The variant of V contains at most about five amino acid substitutions in its HC-CDRs, L comprises an LC-CDR1 comprising the amino acid sequence SEQ ID NO:7, an LC-CDR2 comprising the amino acid sequence SEQ ID NO:9, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO:11, L The variant of V contains at most about five amino acid substitutions in its LC-CDRs, and the antibody or antigen-binding fragment that specifically binds to FasL comprises V H or the above V H and mutants of V L or the above V L and a variant of V Hcomprises an HC-CDR1 comprising the amino acid sequence SEQ ID NO: 52, an HC-CDR2 comprising the amino acid sequence SEQ ID NO: 54, and an HC-CDR3 comprising the amino acid sequence SEQ ID NO: 56, H The variant of V contains at most about five amino acid substitutions in its HC-CDRs, L comprises an LC-CDR1 comprising the amino acid sequence SEQ ID NO: 58, an LC-CDR2 comprising the amino acid sequence SEQ ID NO: 60, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO: 62, L The variant contains at most about five amino acid substitutions in its LC-CDRs.

[0078] In some embodiments, in the pharmaceutical compositions, methods or uses described herein, the antibody or antigen-binding fragment that specifically binds to TRAIL is V H or the above V H and mutants of V L or the above V L and a variant of V H comprises an HC-CDR1 comprising the amino acid sequence SEQ ID NO:2, an HC-CDR52 comprising the amino acid sequence SEQ ID NO:4, and an HC-CDR3 comprising the amino acid sequence SEQ ID NO:6, H The variant of V contains at most about five amino acid substitutions in its HC-CDRs, L comprises an LC-CDR1 comprising the amino acid sequence SEQ ID NO:8, an LC-CDR2 comprising the amino acid sequence SEQ ID NO:10, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO:12, L The variant of V contains at most about five amino acid substitutions in its LC-CDRs, and the antibody or antigen-binding fragment that specifically binds to FasL comprises V H or the above V H and mutants of V L or the above V L and a variant of V Hcomprises an HC-CDR1 comprising the amino acid sequence SEQ ID NO: 52, an HC-CDR2 comprising the amino acid sequence SEQ ID NO: 54, and an HC-CDR3 comprising the amino acid sequence SEQ ID NO: 56, H The variant of V contains at most about five amino acid substitutions in its HC-CDRs, L comprises an LC-CDR1 comprising the amino acid sequence SEQ ID NO: 58, an LC-CDR2 comprising the amino acid sequence SEQ ID NO: 60, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO: 62, L The variant contains at most about five amino acid substitutions in its LC-CDRs.

[0079] In some embodiments, in the pharmaceutical compositions, methods, or uses described herein, the antibody or antigen-binding fragment that specifically binds to TRAIL comprises the amino acid sequence SEQ ID NO:14 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO:14. H and V, including the amino acid sequence SEQ ID NO:23 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:23. L and the antibody or antigen-binding fragment that specifically binds to FasL comprises V comprising the amino acid sequence SEQ ID NO:64 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO:64. H and V, including the amino acid sequence SEQ ID NO: 74 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 74. L Includes:

[0080] In some embodiments, in the pharmaceutical compositions, methods, or uses described herein, the antibody or antigen-binding fragment that specifically binds to TRAIL comprises the amino acid sequence SEQ ID NO:14 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO:14. Hand V, including the amino acid sequence SEQ ID NO:24 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:24. L and the antibody or antigen-binding fragment that specifically binds to FasL comprises V comprising the amino acid sequence SEQ ID NO:64 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO:64. H and V, including the amino acid sequence SEQ ID NO: 74 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 74. L Includes:

[0081] In some embodiments, in the pharmaceutical compositions, methods, or uses described herein, the antibody or antigen-binding fragment that specifically binds to TRAIL comprises the amino acid sequence SEQ ID NO:15 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO:15. H and V, including the amino acid sequence SEQ ID NO:28 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:28. L and the antibody or antigen-binding fragment that specifically binds to FasL comprises V comprising the amino acid sequence SEQ ID NO:66 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO:66. H and V, including the amino acid sequence SEQ ID NO: 76 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 76. L Includes:

[0082] In some embodiments, in the pharmaceutical compositions, methods, or uses described herein, the antibody or antigen-binding fragment that specifically binds to TRAIL comprises the amino acid sequence SEQ ID NO:16 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO:16. Hand V, including the amino acid sequence SEQ ID NO: 31 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 31. L and the antibody or antigen-binding fragment that specifically binds to FasL comprises V comprising the amino acid sequence SEQ ID NO:66 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO:66. H and V, including the amino acid sequence SEQ ID NO: 76 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 76. L Includes:

[0083] In some embodiments, in the pharmaceutical compositions, methods, or uses described herein, the antibody or antigen-binding fragment that specifically binds to TRAIL comprises the amino acid sequence SEQ ID NO:16 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO:16. H and V, including the amino acid sequence SEQ ID NO: 31 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 31. L and the antibody or antigen-binding fragment that specifically binds to FasL comprises V comprising the amino acid sequence SEQ ID NO:70 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO:70. H and V, including the amino acid sequence SEQ ID NO: 78 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 78. L Includes:

[0084] In some embodiments, in the pharmaceutical compositions, methods, or uses described herein, the antibody or antigen-binding fragment that specifically binds to TRAIL comprises the amino acid sequence SEQ ID NO:16 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO:16. Hand V, including the amino acid sequence SEQ ID NO: 31 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 31. L and the antibody or antigen-binding fragment that specifically binds to FasL comprises V comprising the amino acid sequence SEQ ID NO:69 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO:69. H and V, including the amino acid sequence SEQ ID NO: 79 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 79. L Includes:

[0085] In some embodiments, in the methods or uses described herein, the antibody or antigen-binding fragment that specifically binds TRAIL and the antibody or antigen-binding fragment that specifically binds FasL are administered simultaneously, while in other embodiments, the antibody or antigen-binding fragment that specifically binds TRAIL and the antibody or antigen-binding fragment that specifically binds FasL are administered sequentially.

[0086] In some embodiments, in the pharmaceutical compositions, methods, or uses described herein, the molar ratio of the antibody or antigen-binding fragment that specifically binds TRAIL to the antibody or antigen-binding fragment that specifically binds FasL is about 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, or 1:5. In other embodiments, the molar ratio of the antibody or antigen-binding fragment that specifically binds TRAIL to the antibody or antigen-binding fragment that specifically binds FasL is about 2:1 or 1:1.

[0087] In one aspect, the present application provides a method of treating and / or preventing a disease or condition in an individual in need thereof, comprising administering to the individual an effective amount of any antibody or antigen-binding fragment and / or bispecific antibody and / or any pharmaceutical composition described herein.

[0088] In some embodiments, according to any of the methods or uses described herein, the disease or condition comprises an inflammatory disease, an autoimmune disease, a transplant-related disease, a liver disease, a neurodegenerative disease or a cancer, wherein the disease or condition is related to the TRAIL and / or FasL signaling pathway. In some embodiments, the disease or condition is selected from the group consisting of transplant rejection, graft-versus-host disease, liver damage, pulmonary arterial hypertension, Alzheimer's disease, systemic inflammatory response syndrome, sepsis, multiple organ dysfunction syndrome, trauma, multiple sclerosis, idiopathic pulmonary fibrosis, osteoarthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, acute lung injury, acute respiratory distress syndrome, myocardial infarction, myocardial disease, ischemia-reperfusion injury, diabetes, brain injury, spinal cord injury, acute viral hepatitis B, acute viral hepatitis C, chronic hepatitis C, chronic hepatitis B, alcoholic hepatitis, non-alcoholic steatohepatitis, cirrhosis, drug-induced liver injury / liver failure, autoimmune hepatitis, chronic kidney disease, acute kidney disease, diabetic nephropathy, and cancer. [Brief explanation of the drawings]

[0089] [Figure 1] The results show that humanized antibodies G10-1, G10-2, G72-10, and G72-11 inhibit the killing of HepG2 cells by PBMCs. [Figure 2] The results show that humanized antibodies G10-1, G10-2, G72-10, and G72-11 inhibit granulocyte killing of HepG2 cells. [Figure 3] The results show that the anti-TRAIL antibody G72 suppresses the increase in ALT caused by APAP. [Figure 4A] The combined use of an antibody that specifically binds to TRAIL and an antibody that specifically binds to FasL inhibited PBMC killing of HepG2 cells (Fig. 4A) and Jurkat cells (Fig. 4B). [Figure 4B] The combined use of an antibody that specifically binds to TRAIL and an antibody that specifically binds to FasL inhibited PBMC killing of HepG2 cells (Fig. 4A) and Jurkat cells (Fig. 4B). [Figure 5A]FIG. 1 is a schematic diagram of the DVD-Ig (Dual-variable domain-Ig) bispecific antibody structure. [Figure 5B] FIG. 1 is a schematic diagram of the structure of the Bs4Ab bispecific antibody. [Figure 5C] 1 is a schematic diagram of the structure of a hetero H and crossMab bispecific antibody. [Figure 5D] FIG. 1 is a schematic diagram of the structure of an IgG-(scFv)2 bispecific antibody. [Figure 5E] FIG. 1 is a schematic diagram of the structure of a scFv-Fab IgG bispecific antibody. [Figure 6A] The results show that a bispecific antibody that specifically binds to TRAIL and FasL inhibits PBMC killing of HepG2 cells. [Figure 6B] The results show that a bispecific antibody that specifically binds to TRAIL and FasL inhibits PBMC killing of HepG2 cells. [Figure 6C] The results show that a bispecific antibody that specifically binds to TRAIL and FasL inhibits PBMC killing of HepG2 cells. [Figure 7A] This result shows that a bispecific antibody that specifically binds to TRAIL and FasL inhibits PBMC killing of Jurkat cells. [Figure 7B] This result shows that a bispecific antibody that specifically binds to TRAIL and FasL inhibits PBMC killing of Jurkat cells. [Figure 8A] In vivo in mice, the combination of a bispecific antibody that specifically binds to TRAIL and FasL, or an antibody that specifically binds to TRAIL and an antibody that specifically binds to FasL, both suppressed the APAP-induced increase in ALT. [Figure 8B] In vivo in mice, the combination of a bispecific antibody that specifically binds to TRAIL and FasL, or an antibody that specifically binds to TRAIL and an antibody that specifically binds to FasL, both suppressed the APAP-induced increase in ALT. [Figure 9A]The results show that a bispecific antibody that specifically binds to TRAIL and FasL suppresses APAP-induced increases in ALT (FIG. 9A) and AST (FIG. 9B) in cynomolgus monkeys in vivo. [Figure 9B] The results show that a bispecific antibody that specifically binds to TRAIL and FasL suppresses APAP-induced increases in ALT (FIG. 9A) and AST (FIG. 9B) in cynomolgus monkeys in vivo. DETAILED DESCRIPTION OF THE INVENTION

[0090] In one embodiment, the application provides an antibody or antigen-binding fragment that specifically binds to TRAIL. In another embodiment, the application provides a bispecific antibody that specifically binds to TRAIL and FasL. In another embodiment, the application provides a pharmaceutical composition comprising an antibody or antigen-binding fragment that specifically binds to TRAIL and / or an antibody or antigen-binding fragment that specifically binds to FasL, or a pharmaceutical composition comprising a bispecific antibody that specifically binds to TRAIL and FasL. In another embodiment, the application further provides a method of treating a disease or condition in an individual in need thereof, comprising administering to the individual an effective amount of an antibody or antigen-binding fragment that specifically binds to TRAIL or a pharmaceutical composition comprising same, a bispecific antibody that specifically binds to TRAIL and FasL or a pharmaceutical composition comprising same, or an antibody or antigen-binding fragment that specifically binds to TRAIL and an antibody or antigen-binding fragment that specifically binds to FasL or a pharmaceutical composition comprising same. In another aspect, the present application provides the use of an antibody or antigen-binding fragment that specifically binds to TRAIL, or a pharmaceutical composition comprising same, a bispecific antibody that specifically binds to TRAIL and FasL, or a pharmaceutical composition comprising same, or an antibody or antigen-binding fragment that specifically binds TRAIL and an antibody or antigen-binding fragment that specifically binds FasL, or a pharmaceutical composition comprising same, in the preparation of a medicament for preventing or treating a disease or condition in an individual in need thereof.

[0091] Through a well-designed combination of scFv phage library screening, affinity maturation, and biochemical and biological experiments, we identified antibodies or antigen-binding fragments that specifically bind to TRAIL and antibodies or antigen-binding fragments that specifically bind to FasL. At the same time, we prepared bispecific antibodies that specifically bind to TRAIL and FasL. Treating diseases using these antibodies (i) in the form of a pharmaceutical composition, (ii) in the form of a bispecific antibody, or (iii) in the form of a combination can achieve cumulative or synergistic effects, improving therapeutic efficacy.

[0092] The present application also provides nucleic acids encoding antibodies or antigen-binding fragments that specifically bind to TRAIL, or bispecific antibodies that specifically bind to TRAIL and FasL, compositions comprising antibodies or antigen-binding fragments that specifically bind to TRAIL and antibodies or antigen-binding fragments that specifically bind to FasL, and pharmaceutical compositions comprising antibodies or antigen-binding fragments that specifically bind to TRAIL, or antibodies or antigen-binding fragments that specifically bind to FasL, or bispecific antibodies that specifically bind to TRAIL and FasL, and any of the antibodies or antigen-binding fragments described above.

[0093] definition As used herein, "treatment" or "treating" refers to a method of obtaining a result, including a beneficial or desired clinical outcome. For purposes of this application, beneficial or desired clinical outcomes include, but are not limited to, one or more selected from the group consisting of alleviating one or more symptoms of a disease, reducing the extent of the disease, stabilizing the disease (e.g., preventing or slowing the worsening of the disease), preventing or slowing the spread of the disease, preventing or slowing the recurrence of the disease, slowing or slowing the progression of the disease, ameliorating the state of the disease, alleviating the disease (in part or in whole), reducing the amount of one or more other drugs required to treat the disease, slowing the progression of the disease, improving or enhancing vital mass, increasing body weight, and / or extending survival. At the same time, "treatment" also includes reducing the pathological consequences of an infection (e.g., host cell lysis or necrosis). The methods of this application contemplate any one or more of these treatments.

[0094] The term "prevent" and similar words such as "prevented," "preventing," "prevention," or "prophylactic" refer to a method of preventing, inhibiting, or reducing the likelihood of the occurrence or recurrence of a disease or condition (e.g., a pathogen infection). This further refers to delaying the occurrence or recurrence of a disease or condition, or delaying the occurrence or recurrence of symptoms of a disease or condition. As used herein, "prevention" and similar words further include reducing the intensity, impact, symptoms, and / or burden of a disease or condition before it occurs or recurs. As used herein, "prevention" and similar words further include reducing the risk and susceptibility of the occurrence or recurrence of a disease or condition, e.g., a pathogen infection.

[0095] As used herein, the term "antibody" refers to an antibody or antigen-binding fragment. The term "antibody" is used broadly to encompass various antibody structures, such as, but not limited to, monoclonal antibodies, polyclonal antibodies, monospecific antibodies, multispecific antibodies (e.g., bispecific antibodies), full-length antibodies, and antigen-binding fragments thereof, as long as they exhibit the desired antigen-binding activity. A full-length antibody comprises two heavy chains and two light chains. The heavy-chain variable region and the light-chain variable region are responsible for binding to an antigen. The variable regions in the two chains generally comprise three hypervariable loops, referred to as complementarity-determining regions (CDRs). (Light-chain (LC) CDRs comprise LC-CDR1, LC-CDR2, and LC-CDR3, and heavy-chain (HC) CDRs comprise HC-CDR1, HC-CDR2, and HC-CDR3.) The CDR boundaries of the antibodies or antigen-binding fragments described herein are defined or recognized according to the conventions of Kabat, Chothia, or Al-Lazikani (Al-Lazikani 1997; Chothia 1985; Chothia 1987; Chothia 1989; Kabat 1987; Kabat 1991). The three CDR regions of a heavy or light chain are interposed between flanking regions called framework regions (FRs), which are more highly conserved than the CDR regions and form supports for the hypervariable loops. The heavy and light chain constant regions do not participate in antigen binding but exhibit various effector functions. Antibodies are classified based on the amino acid sequences of their heavy chain constant regions. The five major antibody classes or isotypes are IgA, IgD, IgE, IgG, and IgM, which are characterized by having α, δ, ε, γ, and μ heavy chains, respectively. Some of the major classes are further divided into subclasses, e.g., IgG1 (γ1 heavy chain), IgG2 (γ2 heavy chain), IgG3 (γ3 heavy chain), IgG4 (γ4 heavy chain), IgA1 (α1 heavy chain), or IgA2 (α2 heavy chain).

[0096] As used herein, the term "antigen-binding fragment" includes antibody fragments including, for example, double-chain antibodies (diabodies), Fab, Fab', F(ab')2, Fv fragments, disulfide-stabilized Fv fragments (dsFv), (dsFv)2, bispecific dsFv (dsFv-dsFv'), disulfide-stabilized double-chain antibodies (dsdiabodies), single-chain antibodies (scFv), scFv dimers (bivalent double-chain antibodies), multispecific antibodies consisting of antibody fragments containing one or more CDRs, single-domain antibodies, nanobodies, domain antibodies, bivalent domain antibodies, or any other antibody fragment that can bind to an antigen but does not contain a complete antibody structure. Here, Fab (fragment antigen-binding) as used herein refers to the V of an antibody. L Domain, V H Domain, C L domain, and C H Antigen-binding fragments are monovalent fragments containing one domain. Antigen-binding fragments further include fusion proteins containing the antibody fragment. Antigen-binding fragments can bind to the same antigen as the parent antibody or parent antibody fragment (e.g., the parent scFv). In some examples, antigen-binding fragments can contain one or more CDRs from a particular human antibody grafted onto framework regions from one or more different human antibodies.

[0097] As used herein, the term "bispecific antibody" refers to an antibody molecule that has binding specificities for two different antigens or epitopes in a single molecule. The manufacturing process for bispecific antibodies involves designing the entire molecule, synthesizing and cloning the nucleotide sequences for each domain, expressing in mammalian cells, and purifying the final product. Exemplary bispecific antibody structures include those known in the art, such as DVD-Ig structures, Bs4Ab structures, Hetero H, CrossMab structures, IgG-(scFv)2 structures, or scFv-Fab IgG structures (see, e.g., Labrijn AF, et al. Nat Rev Drug Discov. 2019 Aug;18(8):585-608).

[0098] A bispecific antibody with a DVD-Ig (Dual-variable domain-Ig) structure is a full-length IgG antibody with the V domain of another antibody attached to the N-terminus of the light chain and the N-terminus of the heavy chain. L and V H The domains are concatenated, and V H and V LThe interaction of these two domains forms an antigen-binding domain (Fv), which simultaneously binds to the corresponding antigen, achieving bispecificity. An exemplary bispecific antibody with a DVD-Ig structure is also described in Wu C, et al., "Molecular construction and optimization of anti-human IL-1 alpha / beta dual variable domain immunoglobulin (DVD-Ig) molecules." MAbs. 2009 Jul-Aug;1(4):339-47. A Bs4Ab bispecific antibody is a type of bispecific tetravalent antibody that contains a full-length IgG1 structure and inserts an additional binding unit, an scFv, into its hinge region to achieve bispecificity. A bispecific antibody with a Bs4Ab structure is also described in Bezabeh B, et al., "Insertion of scFv into the hinge domain of full-length IgG1 monoclonal antibody results in tetravalent bispecific molecule with robust properties." MAbs. 2017 Feb / Mar;9(2):240-256. Bispecific antibodies with a Hetero H and CrossMab structure are engineered with a knobs-into-hole (KIH) structure in the Fc region, and two Cys residue mutations (S354C located in the "knob" and Y349C located in the "hole") that can form a stabilized disulfide bridge are introduced. At the same time, the CrossMab technology is used to ensure accurate pairing between the antibody light and heavy chains. The CrossMab technology involves the exchange of one Fab arm of a bispecific IgG antibody with an antibody domain, which can be the exchange of the entire Fab domain (CrossMAb Fab), or the exchange of only the variable region of the Fab domain (CrossMAb V). H -V L ) or constant region only exchange (CrossMAb C H 1-C L) Bispecific antibodies with a Hetero H and CrossMAb structure are also described in Klein C, et al. The use of CrossMAb technology for the generation of bi- and multispecific antibodies. MAbs. 2016 Aug-Sep;8(6):1010-20. Bispecific antibodies with an IgG-(scFv)2 structure achieve bispecificity by linking the scFv fragment of another antibody to the Fc termini of two heavy chains of one IgG antibody. Bispecific antibodies with an IgG-(scFv)2 structure are also described in Coloma MJ, Morrison SL. Design and production of novel tetravalent bispecific antibodies. Nat Biotechnol. 1997 Feb;15(2):159-63. Bispecific antibodies with an scFv-Fab IgG structure are heterodimeric antibodies, IgG antibody structures, in which one Fab arm is replaced with an scFv structure, the first monomer of which contains an scFv and an IgG Fc, and the scFv is linked to the IgG FcC via a linker peptide. H The second monomer contains the Fab and IgG Fc domains linked to the N-terminus of the two domains.

[0099] As described in this application, the term "antigen-binding domain" refers to a portion of an antigen-binding molecule that specifically binds to an antigen. More specifically, the term "antigen-binding domain" refers to a portion of an antibody that specifically binds to and comprises a region complementary to a part or all of an antigen. In the case of a large antigen, an antigen-binding molecule may bind only to a specific portion of the antigen, and this specific portion is called an antigen epitope. For example, an antigen-binding domain may be provided by one or more variable regions (also called variable domains). Preferably, the antigen-binding domain is provided by an antibody light chain variable region (V L ) and antibody heavy chain variable region (V H) whereas an antigen-binding domain can bind to that antigen and block or partially block the function of the antigen. Antigen-binding domains that specifically bind to TRAIL or FasL include antibodies and antigen-binding fragments as further defined in the present application.

[0100] As used herein, the term "epitope" refers to a specific group of atoms or amino acids on an antigen to which an antibody or antibody portion binds. If two antibodies or antibody portions exhibit competitive binding to an antigen, they may bind to the same epitope on the antigen.

[0101] As described in this application, a first antibody "competes" with a second antibody for binding to a TRAIL target if it inhibits target TRAIL binding of the second antibody by at least 50% (e.g., at least 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99%) in the presence of an equimolar concentration of the first antibody, or vice versa. PCT publication WO 03 / 48731 describes a method for high-throughput antibody "epitope typing" based on antibody cross-competition.

[0102] As used herein, the terms "specifically bind," "specifically recognize," or "specific for" refer to a measurable and reproducible interaction, e.g., binding between a target and an antibody, that determines the presence of the target in the presence of a heterogeneous population of molecules, including biomolecules. For example, an antibody can specifically recognize a target (which may be an epitope) if the antibody binds to the target with higher affinity, higher avidity, greater ease, and longer duration than the antibody's binding to other targets. In some examples, an antibody that specifically recognizes an antigen reacts with one or more antigenic determinants of the antigen with a binding affinity that is at least 10-fold greater than its binding affinity to other targets.

[0103] As used herein, an "isolated" antibody refers to an antibody that is (1) unrelated to naturally occurring proteins, (2) free from other proteins from the same source, (3) expressed by a cell of heterologous origin, or (4) not found in nature.

[0104] As used herein, the term "isolated nucleic acid" refers to a nucleic acid of genomic, cDNA, or synthetic origin, or a combination thereof. Depending on its origin, the "isolated nucleic acid" is (1) unrelated to all or part of the polynucleotide in which the "isolated nucleic acid" is found in nature, (2) operably linked to a polynucleotide with which it is not naturally linked, or (3) not naturally occurring as part of a larger sequence.

[0105] As used herein, the term "CDR" or "complementarity determining region" refers to the non-contiguous antigen-binding sites found in the variable regions of heavy and light chain polypeptides. ReferencesKabat et al., J.Biol.Chem.252:6609-6616(1977);Kabat et al.,USDept.of Health and Human Services, "Sequences of proteins of immunological interest" (1991);Chothia et al.,J.Mol.Biol.196:901-917(1987);Al-Lazikani B.et al., J.Mol.Biol.,273:927-948(1997);MacCallum et al.,J.Mol.Biol.262:732-745(1996);Abhinandan and Martin, Mol.Immunol.,45:3832-3839(2008);Lefranc MPet al.,Dev.Comp.Immunol.,27:55-77(2003); and Honegger and Pluckthun, J. Mol. Biol., 309:657-670 (2001) have already described these specific regions, and when compared to each other, these definitions include overlapping or subsets of amino acid residues. However, any definition of the CDR of an antibody or grafted antibody or variant thereof is intended to be within the scope of the term as defined and used in this application. The amino acid residues that comprise the CDRs as defined in each of the above cited documents are listed in Table 1 for comparison. CDR prediction algorithms and interfaces are known in the art and are described in the literature, including, for example, Abhinandan and Martin, Mol. Immunol., 45:3832-3839 (2008); Ehrenmann F. et al., Nucleic Acids Res., 38:D301-D307 (2010); and Adolf-Bryfogle J. et al., Nucleic Acids Res., 43:D432-D438 (2015).The contents of the references cited in this paragraph are incorporated into this application in their entirety, as if used herein and as if encompassed by one or more claims of the present invention.

[0106] [Table 1] 1 The amino acid residue numbers refer to the nomenclature in Kabat et al., supra. 2 The numbers of amino acid residues refer to the nomenclature in Chothia et al., supra. 3 The amino acid residue numbers refer to the nomenclature in MacCallum et al., supra. 4 The numbers of amino acid residues refer to the nomenclature in Lefranc et al., supra. 5 The amino acid residue numbers refer to the nomenclature in Honegger and Pluckthun, supra.

[0107] The term "chimeric antibody" refers to an antibody in which a portion of the heavy and / or light chain is identical to or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, and the remainder of the chain(s) is / are identical to or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, and such antibody fragments may possess the biological activity of the present application (see U.S. Patent No. 4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984)).

[0108] An "Fv" is the minimum antibody fragment containing an intact antigen-recognition and binding site. This fragment is a dimer of one heavy-chain variable region and one light-chain variable region in tight, non-covalent association. The folding of these two domains results in six hypervariable loops (three loops each in the light and heavy chains), which provide amino acid residues for antigen binding and confer antigen-binding specificity to the antibody. However, even a single variable region (or a half-Fv fragment containing only three antigen-specific CDRs) has the ability to recognize and bind antigen, albeit with lower affinity than an intact binding site.

[0109] "Single-chain Fv," also referred to as "sFv" or "scFv," is a Fv consisting of V linked to a single polypeptide chain. H Antibody domains and V L In some embodiments, the scFv polypeptide refers to an antibody fragment that contains an antibody domain. In some embodiments, the scFv polypeptide contains a V domain that allows the scFv to form an ideal structure for antigen binding. H and V L For a general overview of scFvs, see Pluckthun in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315 (1994).

[0110] The term "double-chain antibodies" refers to V H and V L This refers to a type of small antibody fragment prepared by constructing an scFv fragment (see the previous paragraph) using a short linker (e.g., 5-10 residues) between the V and V chains, thereby achieving inter-chain pairing of the variable regions rather than intra-chain pairing, resulting in a bivalent fragment, i.e., a fragment with two antigen-binding sites. Bispecific two-chain antibodies are heterodimers of two "crossover" scFv fragments, in which the V and V chains of the two antibodies are linked together. H Domains and V LThe domains are located on different polypeptide chains and have already been thoroughly described for double-chain antibodies in EP 404,097; WO 93 / 11161; Hollinger et al., Proc. Natl. Acad. Sci. USA, 90:6444-6448 (1993).

[0111] "Humanized" forms of non-human (e.g., rodent) antibodies are chimeric antibodies that contain minimal sequence derived from the non-human antibody. Humanized antibodies primarily consist of a human immunoglobulin (recipient antibody), in which residues from the hypervariable regions (HVRs) of the recipient antibody are replaced by hypervariable regions from a non-human species (donor antibody) such as mouse, rat, rabbit, or non-human primate, possessing the desired antibody specificity, affinity, and performance. In certain instances, residues in the framework regions (FRs) of the human immunoglobulin are replaced by corresponding non-human residues. Humanized antibodies may also contain residues that are not present in either the recipient or donor antibody. These modifications can further improve antibody performance. Humanized antibodies typically contain at least one, and typically two, variable regions, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin, and all or substantially all of the framework regions are human immunoglobulin sequences. The human antibody optionally also comprises at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. For details, see Jones et al., Nature 321:522-525 (1986); Riechmann et al., Nature 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol. 2:593-596 (1992).

[0112] The "percent amino acid sequence identity" or "homology" of the polypeptide and antibody sequences identified in this application is defined as the percentage of identical amino acid residues in a candidate sequence and a polypeptide sequence being compared, taking into account conservative substitutions as part of the sequence identity. Percent amino acid sequence identity can be determined by a variety of comparison methods within the skill of the art, including available computer software such as BLAST, BLAST-2, ALIGN, Megalign (DNASTAR), or MUSCLE software. Those skilled in the art can determine appropriate parameters for measurement and comparison, including any algorithms necessary to achieve maximal comparison across the entire length of the compared sequences. However, for purposes of this application, percent amino acid sequence identity values ​​are generated using the sequence comparison computer program MUSCLE (Edgar, R.C., Nucleic Acids Research 32(5):1792-1797, 2004; Edgar, R.C., BMC Bioinformatics 5(1):113, 2004).

[0113] The term "Fc (fragment crystallizable)" or "Fc region" refers to a polypeptide, whether monomeric or multimeric, that contains the complete antibody constant region, excluding the CH1 domain, and in some cases including a partial hinge. The original immunoglobulin origin of the native Fc is preferably human, and may be any immunoglobulin, e.g., IgG1, IgG2, IgG3, or IgG4. The native Fc is composed of monomeric polypeptides that can be linked together by covalent (i.e., disulfide) and non-covalent bonds into dimeric or multimeric forms. The Fc region of an immunoglobulin generally comprises the C heavy chain constant region. H 2 domain and C H Contains 3 domains and C H It may contain four domains.

[0114] In some embodiments, each of the two Fc monomers of an Fc dimer contains an amino acid substitution that promotes heterodimerization of the two monomers. In some embodiments, heterodimerization of Fc monomers can be promoted by introducing dissimilar but compatible substitutions, such as a "knob-into-hole" pair of residues, into the two Fc monomers. The "knob-into-hole" technique is also disclosed in U.S. Patent Publication No. 8,216,805. In some embodiments, one Fc monomer contains the knob mutation T366W, and the other Fc monomer contains the hole mutations T366S, L358A, and Y407V. In some embodiments, two Cys residues that form a stabilizing disulfide bridge (S354C located on the "knob" side and Y349C located on the "hole" side) are introduced.

[0115] The term "Fc receptor" or "FcR" is used to describe a receptor that binds to the Fc region of an antibody. In some embodiments, the FcR described in this application is an FcR that binds to IgG antibodies (a type of gamma receptor) and includes receptors of the FcγRI, FcγRII, and FcγRIII subclasses, including allelic variants and alternatively spliced ​​forms of these receptors. FcγRII receptors include FcγRIIA (activating receptors) and FcγRIIB (inhibiting receptors), which have similar amino acid sequences but differ primarily in their cytoplasmic domains. Activating receptor FcγRIIA contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain. The inhibitory receptor FcγRIIB contains an immunoreceptor tyrosine-based inhibitory motif (ITIM) in its cytoplasmic domain (see M. in Daeron, Annu. Rev. Immunol. 15:203-234 (1997)). The term further includes allogeneic forms, such as FcγRIIIA allogeneic forms: FcγRIIIA-Phe158, FcγRIIIA-Val158, FcγRIIA-R131, and / or FcγRIIA-H131. These are described for FcRs in Ravetch and Kinet, Annu. Rev. Immunol 9:457-92 (1991); and Capel et al., Immunomethods 4:25-34 (1994); and de Haas et al., J. Lab. Clin. Med. 126:330-41 (1995). The term FcR in this application includes other types of FcRs, including those to be identified in the future. The term FcR also includes the neonatal receptor FcRn, which is responsible for the transfer of maternal IgGs to the neonate (Guyer et al., J. Immunol. 117:587 (1976) and Kim et al., J. Immunol. 24:249 (1994)).

[0116] The term "FcRn" refers to the neonatal Fc receptor (FcRn). FcRn is structurally similar to the major histocompatibility complex (MHC) and consists of an α chain noncovalently bound to β2-microglobulin. The multiple functions of the neonatal Fc receptor FcRn are described in Ghetie and Ward (2000) Annu. Rev. Immunol. 18, 739-766. FcRn plays an important role in the passive transport of immunoglobulin IgGs from mother to neonate and in regulating serum IgG levels. As a rescue receptor, FcRn binds and transports intact endocytosed IgGs within and between cells, rescuing them from the default degradation pathway.

[0117] "C" of the human IgG heavy chain constant region H The "1 domain" typically extends from amino acid 118 to amino acid 215 (EU numbering system).

[0118] The "hinge region" is usually defined as the region extending from Glu at position 216 of human IgG1 to Pro at position 230 (Burton, Molec. Immunol. 22:161-206 (1985)). The hinge regions of other IgG subtypes can be compared to the IgG1 sequence by placing the first and last cysteine ​​residues that form the inter-heavy chain disulfide bond in the same positions as in IgG1.

[0119] "C" in the human IgG Fc region H The "C2 domain" typically extends from amino acid 231 to amino acid 340. H The 2 domain is unique in that it is not tightly paired with another domain. Instead, two N-terminally linked branched glycans are linked to the two C domains of the intact native IgG molecule. H The sugar can be a replacement for the domain-to-domain pairing, and C H It is speculated that this contributes to the stability of the two domains. Burton, Molec Immunol. 22:161-206 (1985).

[0120] "C H The "3" domain comprises the portion of the Fc region extending from the C-terminal residue to the CH2 domain (amino acid 341 to the C-terminus of the antibody sequence, usually amino acid residue 446 or 447 for IgG).

[0121] A "functional Fc fragment" has an "effector function" possessed by the sequence of a native Fc region. Exemplary "effector functions" include C1q binding, complement-dependent cytotoxicity (CDC), Fc receptor binding, antibody-dependent cellular cytotoxicity (ADCC), phagocytosis, down-regulation of cell surface receptors (e.g., B cell receptors; BCR), etc. Such effector functions generally require the combination of an Fc region with a binding domain (e.g., an antibody variable region), and can be evaluated using various experimental methods known in the art.

[0122] IgG Fc variant antibodies with "altered" FcR binding affinity or ADCC activity have increased or decreased FcR binding activity and / or ADCC activity compared to the parent polypeptide or a polypeptide comprising a native Fc sequence. Fc variants that exhibit "enhanced binding" to FcR have a higher affinity (e.g., a lower apparent Kd or IC50 value) for at least one FcR than the parent polypeptide or a polypeptide comprising a native IgG Fc sequence. In some embodiments, the binding ability is increased by 3-fold, e.g., 5-, 10-, 25-, 50-, 60-, 100-, 150-, 200-, or 500-fold, or even by 25% to 1000%. Fc variants that exhibit "reduced binding" to FcR have a lower affinity (e.g., a higher apparent Kd or IC50 value) for at least one FcR than the parent polypeptide. Their binding ability is reduced by 40% or more compared to the parent polypeptide.

[0123] "Antibody-dependent cellular cytotoxicity" or "ADCC" is a form of cytotoxicity in which secreted Ig binds to Fc receptors (FcRs) present on certain cytotoxic cells (e.g., natural killer cells (NK), neutrophils, and macrophages), allowing these cytotoxic effector cells to specifically bind to antigen-bearing target cells and then kill them using cytotoxins. Antibodies "arm" the cytotoxic cells and are required for their killing. Of the major cell types mediating ADCC, NK cells express only FcγRIII, whereas monocytes express FcγRI, FcγRII, and FcγRIII. Table 3 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol 9:457-92 (1991) summarizes FcR expression on hematopoietic cells. To evaluate the ADCC activity of a molecule of interest, in vitro ADCC experiments can be performed, as described in U.S. Patent No. 5,500,362 or 5,821,337. Suitable effector cells for such experiments include peripheral blood mononuclear cells (PBMC) and natural killer cells (NK). Alternatively, the ADCC activity of a molecule of interest can be evaluated in vivo, as described, for example, in the animal model disclosed in Clynes et al. PNAS (USA) 95:652-656 (1998).

[0124] A polypeptide comprising a mutant Fc may exhibit "enhanced ADCC activity" or mediate ADCC effects more effectively in the presence of human effector cells than a polypeptide comprising a wild-type IgG Fc or a parent polypeptide. The mutant Fc-containing polypeptide may mediate ADCC more effectively in vitro or in vivo when used in substantially the same amount as a polypeptide comprising a wild-type IgG Fc (or parent polypeptide) during an experiment. Typically, such variants are identified using any in vitro ADCC experimental method known in the art and used in experiments and methods, such as those using animal models, to identify ADCC activity. In some embodiments, the ADCC-mediation effect of such variants is 5- to 100-fold, e.g., 25- to 50-fold, improved compared to the wild-type Fc (or parent polypeptide).

[0125] "Complement-dependent cytotoxicity" or "CDC" refers to the lysis of target cells in the presence of complement. Activation of the typical complement pathway is initiated by the binding of the first component of the complement system (C1q) to an antibody (of the appropriate structural subclass) that binds to the homologous antigen. To assess complement activation, a CDC experiment, for example, as described in Gazzano-Santoro et al., J. Immunol. Methods 202:163 (1996), may be performed. U.S. Patent No. 6,194,551 B1 and WO 99 / 51642 describe polypeptide variants with altered Fc region amino acid sequences and increased or decreased C1q binding ability. The contents of these patent publications are expressly incorporated herein by reference. See also Idusogie et al., J. Immunol. 164:4178-4184 (2000).

[0126] Unless otherwise specified, a "nucleotide sequence encoding an amino acid sequence" includes all nucleotide sequences that are degenerate and encode the same amino acid sequence. A nucleotide sequence encoding a protein or RNA may further include introns; for example, a nucleotide sequence encoding a protein contains introns in some forms.

[0127] The term "operably linked" refers to a functional linkage between a regulatory sequence and a heterologous nucleotide sequence, thereby permitting expression of the latter. For example, a first nucleotide sequence and a second nucleotide sequence are operably linked when they are in a functional relationship. For example, a promoter and a coding sequence are operably linked if the promoter affects the transcription or expression of the coding sequence. Usually, operably linked DNA sequences are contiguous; where necessary, two protein-coding regions can be linked in the same open reading frame.

[0128] "Homologous" refers to the sequence similarity or sequence identity between two polypeptides or two nucleic acid molecules. If both positions in two compared sequences contain the same base or amino acid monomer subunit, e.g., if both DNA molecules contain adenine at the same position, the two DNA molecules are homologous at that position. The percentage identity between two sequences is a function of the ratio of the number of shared matching or homologous positions to the total number of positions in the two sequences multiplied by 100. For example, if six out of ten positions in two sequences are matching or homologous, the two sequences are 60% identical. For example, the DNA sequences ATTGCC and TATTGC are 50% identical. Typically, when comparing two sequences, the comparison is performed to obtain the maximum homology.

[0129] An "effective amount" of an antibody (including a bispecific antibody) or composition disclosed herein refers to an amount sufficient to achieve a particular purpose. An "effective amount" can be determined empirically and by known methods relevant to said purpose.

[0130] The term "therapeutically effective amount" refers to an amount of an antibody (including a bispecific antibody) or composition described herein that effectively "treats" a disease or condition in an individual, i.e., an amount sufficient to reduce or ameliorate the severity and / or duration of the disease or one or more symptoms thereof, prevent progression of the disease, cause regression of the disease, prevent the recurrence, progression, onset, or development of one or more symptoms associated with the disease, detect the disease, or enhance / improve the prophylactic or therapeutic efficacy of another treatment (e.g., a prophylactic or therapeutic agent).

[0131] As used herein, "pharmaceutically acceptable" or "pharmacologically compatible" refers to a material that is not biologically active or has other undesirable properties, e.g., the material can be added to a pharmaceutical composition administered to a patient without causing adverse biological effects or interacting in a deleterious manner with any other ingredients included in the composition. A pharmaceutically acceptable vector or excipient preferably meets the standards required for toxicology or manufacturing testing and / or is included in the Inactive Ingredients Guide compiled by the U.S. Food and Drug Administration.

[0132] References to embodiments of the present application described herein should be understood to include embodiments that "consist of" and / or "consist essentially of."

[0133] "About" as used herein refers to a number or parameter and also includes (and describes) variations of that number or parameter. For example, a description of "about X" includes a description of "X."

[0134] As used in this application, a statement about "not" a value or parameter generally means "other than" that value or parameter. For example, saying that the method cannot be used to treat type X infections means that the method is generally used to treat types other than type X infections.

[0135] As used in this application and the claims, the singular forms "a," "one," and "the" include plural referents unless expressly stated otherwise.

[0136] Antibodies that specifically bind to TRAIL In one embodiment, the present application provides antibodies or antigen-binding fragments that specifically bind to TRAIL, including, but not limited to, humanized antibodies, chimeric antibodies, murine antibodies, human antibodies, and antibody molecules comprising the heavy and / or light chain CDRs described herein. In one embodiment, the antibodies or antigen-binding fragments are isolated antibodies that bind to a TRAIL antigen. Antibodies or antigen-binding fragments of interest that specifically bind to TRAIL include full-length antibodies or fragments thereof (e.g., full-length IgG1, IgG2, or IgG4) that specifically bind to TRAIL, single-chain antibodies that specifically bind to TRAIL, antibodies that multispecifically (e.g., bispecific) bind to TRAIL, and immunoconjugates that specifically bind to TRAIL. In some examples, the antibodies or antigen-binding fragments that specifically bind to TRAIL are Fab, Fab', F(ab)'2, Fab'-SH, single-chain Fv (scFv), Fv fragments, dAb, Fd, nanobody, double-chain antibody (diabody), or linear antibody. In some examples, an antibody or antigen-binding fragment that specifically binds to TRAIL refers to an antibody or antigen-binding fragment whose binding affinity to TRAIL is at least 10 times (e.g., 10, 10) greater than the binding affinity of the antibody or antigen-binding fragment to a non-target. 2 , 10 3 , 10 4 , 10 5 , 10 6 , or 10 7 In some embodiments, non-target refers to an antigen that is not TRAIL.

[0137] Binding affinity can be measured by methods known in the art, such as ELISA, fluorescence-activated cell sorting (FACS) analysis, or radioimmunoprecipitation analysis (RIA). Kd values ​​can be measured by methods known in the art, such as surface plasmon resonance (SPR) or biolayer interferometry (BLI) techniques.

[0138] While the present application details antibodies or antigen-binding fragments that specifically bind to TRAIL comprising human sequences (e.g., human heavy and light chain variable regions comprising human CDR sequences), non-human antibodies are also contemplated. In some embodiments, the non-human antibody comprises the human CDR sequences and non-human framework region sequences of an antibody or antigen-binding fragment that specifically binds to TRAIL described herein, and in some embodiments, the non-human framework region sequences include any sequences used to generate heavy and / or light chain variable regions using one or more human CDR sequences described herein, including mammals such as mouse, rat, rabbit, pig, bovine (e.g., cow, ox, water buffalo), deer, sheep, goat, chicken, cat, dog, ferret, primate (e.g., chinese monkey, macaque), etc. In some examples, antibodies or antigen-binding fragments that specifically bind to non-human TRAIL include antibodies or antigen-binding fragments that specifically bind to TRAIL that are generated by grafting one or more human CDR sequences described in the present application into non-human framework regions (e.g., mouse or chicken framework region sequences).

[0139] In some embodiments, the antibody or antigen-binding fragment that specifically binds to TRAIL binds to an epitope in human TRAIL. In some embodiments, the antibody or antigen-binding fragment that specifically binds to TRAIL cross-reacts with TRAIL antigens of species other than human. In some embodiments, the antibody or antigen-binding fragment that specifically binds to TRAIL is completely specific for human TRAIL and does not cross-react with other non-human species.

[0140] In some embodiments, the antibody or antigen-binding fragment that specifically binds to TRAIL is V H and V L Including V H is the V shown in the amino acid sequence SEQ ID NO:13 H V comprises HC-CDR1, HC-CDR2 and HC-CDR3, L is the V shown in the amino acid sequence SEQ ID NO:22 L comprises LC-CDR1, LC-CDR2 and LC-CDR3.

[0141] In some embodiments, the antibody or antigen-binding fragment that specifically binds to TRAIL is V H or the above V H and mutants of V L or the above V L and a variant of V H comprises an HC-CDR1 comprising the amino acid sequence SEQ ID NO: 1, an HC-CDR2 comprising the amino acid sequence SEQ ID NO: 3, and an HC-CDR3 comprising the amino acid sequence SEQ ID NO: 5, H The variant of V contains at most about five amino acid substitutions in its HC-CDRs, L comprises an LC-CDR1 comprising the amino acid sequence SEQ ID NO:7, an LC-CDR2 comprising the amino acid sequence SEQ ID NO:9, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO:11, L The variant contains at most about five amino acid substitutions in its LC-CDRs.

[0142] In some embodiments, the antibody or antigen-binding fragment that specifically binds to TRAIL comprises a V antibody having an amino acid sequence set forth in any one of SEQ ID NOs: 13-14 or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 13-14. Hand V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 22 to 27 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 22 to 27. L Includes:

[0143] In some embodiments, the antibody or antigen-binding fragment that specifically binds to TRAIL comprises (i) a V antibody comprising the amino acid sequence SEQ ID NO:13 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO:13. H and V, including the amino acid sequence SEQ ID NO:22 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:22. L (ii) V comprising the amino acid sequence SEQ ID NO:14 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:14 H and V, including the amino acid sequence SEQ ID NO:23 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:23. L (iii) V comprising the amino acid sequence SEQ ID NO:14 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:14 H and V, including the amino acid sequence SEQ ID NO:24 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:24. L (iv) V comprising the amino acid sequence SEQ ID NO:14 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:14 H and V, including the amino acid sequence SEQ ID NO: 25 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 25. L (v) V comprising the amino acid sequence SEQ ID NO:14 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:14 Hand V, including the amino acid sequence SEQ ID NO:26 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:26. L or (vi) V comprising the amino acid sequence SEQ ID NO:14 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:14. H and V, including the amino acid sequence SEQ ID NO:27 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:27. L , including.

[0144] In some embodiments, the antibody or antigen-binding fragment that specifically binds to TRAIL is V H and V L Including V H is the V shown in the amino acid sequence SEQ ID NO:15 H V comprises HC-CDR1, HC-CDR2 and HC-CDR3, L is the V shown in the amino acid sequence SEQ ID NO:28 L comprises LC-CDR1, LC-CDR2 and LC-CDR3.

[0145] In some embodiments, the antibody or antigen-binding fragment that specifically binds to TRAIL is V H or the above V H and mutants of V L or the above V L and a variant of V H comprises an HC-CDR1 comprising the amino acid sequence SEQ ID NO:2, an HC-CDR2 comprising the amino acid sequence SEQ ID NO:4, and an HC-CDR3 comprising the amino acid sequence SEQ ID NO:6, H The variant of V contains at most about five amino acid substitutions in its HC-CDRs, L comprises an LC-CDR1 comprising the amino acid sequence SEQ ID NO:8, an LC-CDR2 comprising the amino acid sequence SEQ ID NO:10, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO:12, LThe variant contains at most about five amino acid substitutions in its LC-CDRs.

[0146] In some embodiments, the antibody or antigen-binding fragment that specifically binds to TRAIL comprises an amino acid sequence set forth in any one of SEQ ID NOs: 15-21 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 15-21. H and V, including the amino acid sequence set forth in any one of SEQ ID NOs: 28-32 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 28-32. L , including.

[0147] In some embodiments, the antibody or antigen-binding fragment that specifically binds to TRAIL comprises (i) a V that contains the amino acid sequence SEQ ID NO:15 or a variant thereof that has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence SEQ ID NO:15. H and V, including the amino acid sequence SEQ ID NO:28 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO:28. L (ii) V, including the amino acid sequence SEQ ID NO:16 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence SEQ ID NO:16. Hand V, including the amino acid sequence SEQ ID NO:29 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO:29. L (iii) V, including the amino acid sequence SEQ ID NO:17 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence SEQ ID NO:17. H and V, including the amino acid sequence SEQ ID NO:29 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO:29. L (iv) V, including the amino acid sequence SEQ ID NO:18 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence SEQ ID NO:18. H and V, including the amino acid sequence SEQ ID NO:29 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO:29. L (v) V, including the amino acid sequence SEQ ID NO:19 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence SEQ ID NO:19. H and V, including the amino acid sequence SEQ ID NO:29 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO:29. L(vi) V, including the amino acid sequence SEQ ID NO:20 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence SEQ ID NO:20. H and V, including the amino acid sequence SEQ ID NO:29 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO:29. L (vii) V, including the amino acid sequence SEQ ID NO:16 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence SEQ ID NO:16. H and V, including the amino acid sequence SEQ ID NO:30 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO:30. L (viii) V, including the amino acid sequence SEQ ID NO:17 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence SEQ ID NO:17. H and V, including the amino acid sequence SEQ ID NO:30 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO:30. L (ix) V, including the amino acid sequence SEQ ID NO:18 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence SEQ ID NO:18. Hand V, including the amino acid sequence SEQ ID NO:30 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO:30. L (x) V, including the amino acid sequence SEQ ID NO:19 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence SEQ ID NO:19 H and V, including the amino acid sequence SEQ ID NO:30 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO:30. L (xi) V, including the amino acid sequence SEQ ID NO:20 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence SEQ ID NO:20. H and V, including the amino acid sequence SEQ ID NO:30 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO:30. L (xii) V, including the amino acid sequence SEQ ID NO:16 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence SEQ ID NO:16. H and V, including the amino acid sequence SEQ ID NO:31 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO:31. L(xiii) V, including the amino acid sequence SEQ ID NO:17 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence SEQ ID NO:17. H and V, including the amino acid sequence SEQ ID NO:31 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO:31. L (xiv) V, including the amino acid sequence SEQ ID NO:18 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence SEQ ID NO:18. H and V, including the amino acid sequence SEQ ID NO:31 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO:31. L (xv) V, including the amino acid sequence SEQ ID NO:19 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence SEQ ID NO:19 H and V, including the amino acid sequence SEQ ID NO:31 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO:31. L (xvi) V, including the amino acid sequence SEQ ID NO:20 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence SEQ ID NO:20. Hand V, including the amino acid sequence SEQ ID NO:31 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO:31. L or (xvii) V, comprising the amino acid sequence SEQ ID NO:21 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence SEQ ID NO:21. H and V, including the amino acid sequence SEQ ID NO:32 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence SEQ ID NO:32. L , including.

[0148] In some embodiments, the amino acid substitutions described above are limited to the "exemplary substitutions" shown in Table 10 of the present application. In some embodiments, the amino acids are limited to the "preferred substitutions" shown in Table 10 of the present application.

[0149] In some embodiments, functional epitopes can be characterized by combinatorial alanine scanning. In this process, combinatorial alanine scanning techniques can be used to identify amino acids required for the interaction between a TRAIL protein and an antibody or antigen-binding fragment that specifically binds to TRAIL. In some embodiments, the epitope is structural, and the crystal structure of an anti-TRAIL antibody bound to a TRAIL protein can be employed to identify the epitope.

[0150] In some embodiments, the present application provides an antibody or antigen-binding fragment that competitively binds to TRAIL with any one of the above-described antibodies or antigen-binding fragments that specifically bind to TRAIL. In some embodiments, the present application provides an antibody or antigen-binding fragment that can competitively bind to an epitope on TRAIL with any one of the above-described antibodies or antigen-binding fragments that specifically bind to TRAIL. In some embodiments, the present application provides an antibody or antigen-binding fragment that specifically binds to TRAIL, which is V H and V L and binds to the same epitope as an anti-TRAIL antibody molecule comprising said V H is an amino acid sequence shown in any one of SEQ ID NOs: 13 to 21, and L comprises the amino acid sequence set forth in any one of SEQ ID NOs: 22 to 32. In some embodiments, an antibody or antigen-binding fragment that specifically binds to TRAIL is provided, which comprises V H and V L competitively binds to TRAIL with an anti-TRAIL antibody comprising the V H is an amino acid sequence shown in any one of SEQ ID NOs: 13 to 21, and L comprises the amino acid sequence shown in any one of SEQ ID NOs: 22 to 32.

[0151] In some embodiments, a monoclonal antibody that competitively binds to TRAIL can be identified by a competition experiment with an antibody or antigen-binding fragment that specifically binds to TRAIL described herein. Competition experiments determine whether two antibodies bind the same epitope by recognizing the same or spatially overlapping epitopes or by competitively inhibiting the binding of one antibody to an antigen by another antibody. In some embodiments, such a competing antibody binds the same epitope as an antibody described herein. Some exemplary competition experiments include, but are not limited to, routine experiments such as those described in Harlow and Lane (1988) Antibodies: A Laboratory Manual, ch. 14 (Cold Spring Harbor Laboratory, Cold Spring Harbor, NY). Detailed exemplary methods for analyzing epitopes bound by antibodies are described, for example, in Morris (1996) "Epitope Mapping Protocols," in Methods in Molecular Biology, vol. 66 (Humana Press, Totowa, NJ). In some embodiments, antibodies are said to bind the same epitope if they block the binding of another antibody by 50% or more. In some embodiments, antibodies that compete with the antibodies or antigen-binding fragments that specifically bind to TRAIL described herein are chimeric, humanized, or fully human antibodies.

[0152] Exemplary antibody sequences that specifically bind to TRAIL are numbered according to the Chothia definition, as shown in Tables 2, 3-1, and 3-2. Those skilled in the art will recognize that there are many known algorithms for predicting the locations of CDRs and for defining the light and heavy chain variable regions of antibodies. The CDRs of the antibodies of the present application, V H and / or V L Antibodies that contain sequences but are not exemplified in the table below based on the prediction algorithm are also within the scope of this application.

[0153] Full-length antibody that specifically binds to TRAIL In some embodiments, the antibody that specifically binds to TRAIL is a full-length antibody. In some embodiments, the full-length antibody that specifically binds to TRAIL is IgA, IgD, IgE, IgG, or IgM. In some embodiments, the antibody or antigen-binding fragment that specifically binds to TRAIL comprises an antibody heavy chain constant region and an antibody light chain constant region. In some embodiments, the full-length antibody that specifically binds to TRAIL comprises an IgG constant region, for example, the constant region of IgG1, IgG2, IgG3, IgG4, or a variant thereof. In some embodiments, the antibody or antigen-binding fragment that specifically binds to TRAIL comprises an IgG1-type heavy chain constant region. In some embodiments, the antibody or antigen-binding fragment that specifically binds to TRAIL comprises an IgG2-type heavy chain constant region. In some embodiments, the antibody or antigen-binding fragment that specifically binds to TRAIL comprises an IgG3-type heavy chain constant region. In some embodiments, the antibody or antigen-binding fragment that specifically binds to TRAIL comprises an IgG4-type heavy chain constant region. In some embodiments, the IgG refers to human IgG. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97. In some embodiments, the antibody or antigen-binding fragment that specifically binds to TRAIL comprises a kappa light chain constant region. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the antibody or antigen-binding fragment that specifically binds to TRAIL comprises a lambda light chain constant region. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the antibody or antigen-binding fragment that specifically binds to TRAIL comprises an antibody heavy chain variable region and an antibody light chain variable region.In some embodiments, a full-length antibody that specifically binds TRAIL has enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) effector function by comprising an altered or otherwise modified Fc sequence.

[0154] In some embodiments, a full-length antibody that specifically binds to TRAIL is provided, comprising an IgG1, IgG2, IgG3, or IgG4 constant region, wherein the antibody that specifically binds to TRAIL comprises: a) a heavy chain variable region comprising: an HC-CDR1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 1-2 or a variant thereof comprising at most about three (e.g., one, two, or three) amino acid substitutions; an HC-CDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 3-4 or a variant thereof comprising at most about three (e.g., one, two, or three) amino acid substitutions; and an HC-CDR3 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 5-6 or a variant thereof comprising at most about three (e.g., one, two, or three) amino acid substitutions; and b) an LC-CDR1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 7-8 or a variant thereof comprising at most about three (e.g., one, two, or three) amino acid substitutions. and a light chain variable region comprising an LC-CDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs:9-10 or a variant thereof comprising at most about three (e.g., one, two, or three) amino acid substitutions, and an LC-CDR3 comprising the amino acid sequence set forth in any one of SEQ ID NOs:11-12 or a variant thereof comprising at most about three (e.g., one, two, or three) amino acid substitutions. In some embodiments, the IgG1 is a human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98.In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:96, and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:99. In some embodiments, the IgG2 is human IgG2. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:99. In some embodiments, the IgG3 is human IgG3. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:99. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:97. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 99. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 97 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 98. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 97 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO: 99.

[0155] In some embodiments, a full-length antibody that specifically binds to TRAIL is provided, comprising an IgG1, IgG2, IgG3, or IgG4 constant region, wherein the antibody that specifically binds to TRAIL comprises: a) a heavy chain variable region or a variant of the heavy chain variable region, wherein the heavy chain variable region comprises an HC-CDR1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 1-2, an HC-CDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 3-4, and an HC-CDR3 having the amino acid sequence set forth in any one of SEQ ID NOs: 5-6, and the variant of the heavy chain variable region comprises at most about five (e.g., one, two, three, four, or five) amino acid substitutions in the HC-CDR sequence; and b) a light chain variable region or a variant of the light chain variable region, wherein the light chain variable region comprises an LC-CDR1 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 7-8, an LC-CDR2 comprising the amino acid sequence set forth in any one of SEQ ID NOs: 9-10, and an HC-CDR3 having the amino acid sequence set forth in any one of SEQ ID NOs: and an LC-CDR3 comprising the amino acid sequence set forth in any one of SEQ ID NOs:11-12, wherein the variant light chain variable region comprises at most about five (e.g., one, two, three, four, or five) amino acid substitutions in the LC-CDR sequence. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 96 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO: 99. In some embodiments, the IgG2 is human IgG2.In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:99. In some embodiments, the IgG3 is human IgG3. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:99. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:97. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:99. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:97 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:98. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:97 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:99.

[0156] In some embodiments, a full-length antibody that specifically binds to TRAIL is provided, comprising an IgG1 or IgG4 constant region, wherein the antibody that specifically binds to TRAIL comprises: a) a heavy chain variable region comprising an HC-CDR1 comprising the amino acid sequence SEQ ID NO:1, an HC-CDR2 comprising the amino acid sequence SEQ ID NO:3, and an HC-CDR3 comprising the amino acid sequence SEQ ID NO:5; and b) a light chain variable region comprising an LC-CDR1 comprising the amino acid sequence SEQ ID NO:7, an LC-CDR2 comprising the amino acid sequence SEQ ID NO:9, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO:11. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:96, and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:98. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:96, and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:99. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:97. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:99. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:97, and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:98.In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99.

[0157] In some embodiments, a full-length antibody that specifically binds to TRAIL is provided, comprising an IgG2 or IgG4 constant region, wherein the antibody that specifically binds to TRAIL comprises: a) a heavy chain variable region comprising an HC-CDR1 comprising the amino acid sequence SEQ ID NO:2, an HC-CDR2 comprising the amino acid sequence SEQ ID NO:4, and an HC-CDR3 comprising the amino acid sequence SEQ ID NO:6; and b) a light chain variable region comprising an LC-CDR1 comprising the amino acid sequence SEQ ID NO:8, an LC-CDR2 comprising the amino acid sequence SEQ ID NO:10, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO:12. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:96, and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:98. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:96, and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:99. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:97. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:99. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:97, and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:98.In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99.

[0158] In some embodiments, a full-length antibody that specifically binds to TRAIL is provided, comprising an IgG1 or IgG4 constant region, wherein the antibody that specifically binds to TRAIL comprises: a) a heavy chain variable region comprising the amino acid sequence set forth in any one of SEQ ID NOs: 13 to 21 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 13 to 21; and b) a light chain variable region comprising the amino acid sequence set forth in any one of SEQ ID NOs: 22 to 32 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 22 to 32. In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99.In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:97 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:98. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:97 and the light chain constant region comprises or consists of the amino acid sequence of SEQ ID NO:99.

[0159] In some embodiments, a full-length antibody that specifically binds to TRAIL is provided, comprising an IgG1 or IgG4 constant region, wherein the antibody that specifically binds to TRAIL comprises a V constant region comprising the amino acid sequence SEQ ID NO:13 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO:13. H and V, including the amino acid sequence SEQ ID NO:22 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:22. LIn some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96, and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96, and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99.

[0160] In some embodiments, a full-length antibody that specifically binds to TRAIL is provided, comprising an IgG1 or IgG4 constant region, wherein the antibody that specifically binds to TRAIL comprises a V constant region comprising the amino acid sequence SEQ ID NO:14 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO:14. Hand V, including the amino acid sequence SEQ ID NO:23 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:23. L In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96, and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96, and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99.

[0161] In some embodiments, a full-length antibody that specifically binds to TRAIL is provided, comprising an IgG1 or IgG4 constant region, wherein the antibody that specifically binds to TRAIL comprises a V constant region comprising the amino acid sequence SEQ ID NO:14 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO:14. H and V, including the amino acid sequence SEQ ID NO:24 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:24. LIn some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96, and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96, and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99.

[0162] In some embodiments, a full-length antibody that specifically binds to TRAIL is provided, comprising an IgG1 or IgG4 constant region, wherein the antibody that specifically binds to TRAIL comprises a V constant region comprising the amino acid sequence SEQ ID NO:14 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO:14. Hand V, including the amino acid sequence SEQ ID NO: 25 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 25. L In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96, and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96, and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99.

[0163] In some embodiments, a full-length antibody that specifically binds to TRAIL is provided, comprising an IgG1 or IgG4 constant region, wherein the antibody that specifically binds to TRAIL comprises a V constant region comprising the amino acid sequence SEQ ID NO:14 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO:14. H and V, including the amino acid sequence SEQ ID NO:26 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:26. LIn some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96, and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96, and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99.

[0164] In some embodiments, a full-length antibody that specifically binds to TRAIL is provided, comprising an IgG1 or IgG4 constant region, wherein the antibody that specifically binds to TRAIL comprises a V constant region comprising the amino acid sequence SEQ ID NO:14 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO:14. Hand V, including the amino acid sequence SEQ ID NO:27 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:27. L In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96, and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96, and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99.

[0165] In some embodiments, a full-length antibody that specifically binds to TRAIL is provided, comprising an IgG1 or IgG4 constant region, wherein the antibody that specifically binds to TRAIL comprises a V constant region comprising the amino acid sequence SEQ ID NO:15 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO:15. H and V, including the amino acid sequence SEQ ID NO:28 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:28. LIn some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96, and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96, and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99.

[0166] In some embodiments, a full-length antibody that specifically binds to TRAIL is provided, comprising an IgG1 or IgG4 constant region, wherein the antibody that specifically binds to TRAIL comprises a V constant region comprising the amino acid sequence SEQ ID NO:16 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO:16. Hand V, including the amino acid sequence SEQ ID NO:29 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:29. L In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96, and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96, and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99.

[0167] In some embodiments, a full-length antibody that specifically binds to TRAIL is provided, comprising an IgG1 or IgG4 constant region, wherein the antibody that specifically binds to TRAIL comprises a V constant region comprising the amino acid sequence SEQ ID NO:17 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO:17. H and V, including the amino acid sequence SEQ ID NO:29 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:29. LIn some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96, and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96, and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99.

[0168] In some embodiments, a full-length antibody that specifically binds to TRAIL is provided, comprising an IgG1 or IgG4 constant region, wherein the antibody that specifically binds to TRAIL comprises a V antibody having the amino acid sequence SEQ ID NO:18 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO:18. Hand V, including the amino acid sequence SEQ ID NO:29 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:29. L In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96, and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96, and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99.

[0169] In some embodiments, a full-length antibody that specifically binds to TRAIL is provided, comprising an IgG1 or IgG4 constant region, wherein the antibody that specifically binds to TRAIL comprises a V constant region comprising the amino acid sequence SEQ ID NO:19 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO:19. H and V, including the amino acid sequence SEQ ID NO:29 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:29. LIn some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96, and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96, and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99.

[0170] In some embodiments, a full-length antibody that specifically binds to TRAIL is provided, comprising an IgG1 or IgG4 constant region, wherein the antibody that specifically binds to TRAIL comprises a V constant region comprising the amino acid sequence SEQ ID NO:20 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO:20. Hand V, including the amino acid sequence SEQ ID NO:29 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:29. L In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96, and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96, and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99.

[0171] In some embodiments, a full-length antibody that specifically binds to TRAIL is provided, comprising an IgG1 or IgG4 constant region, wherein the antibody that specifically binds to TRAIL comprises a V constant region comprising the amino acid sequence SEQ ID NO:16 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO:16. H and V, including the amino acid sequence SEQ ID NO: 30 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 30. LIn some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96, and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96, and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99.

[0172] In some embodiments, a full-length antibody that specifically binds to TRAIL is provided, comprising an IgG1 or IgG4 constant region, wherein the antibody that specifically binds to TRAIL comprises a V constant region comprising the amino acid sequence SEQ ID NO:17 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO:17. Hand V, including the amino acid sequence SEQ ID NO: 30 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 30. L In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96, and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96, and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99.

[0173] In some embodiments, a full-length antibody that specifically binds to TRAIL is provided, comprising an IgG1 or IgG4 constant region, wherein the antibody that specifically binds to TRAIL comprises a V antibody having the amino acid sequence SEQ ID NO:18 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO:18. H and V, including the amino acid sequence SEQ ID NO: 30 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 30. LIn some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96, and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96, and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99.

[0174] In some embodiments, a full-length antibody that specifically binds to TRAIL is provided, comprising an IgG1 or IgG4 constant region, wherein the antibody that specifically binds to TRAIL comprises a V constant region comprising the amino acid sequence SEQ ID NO:19 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO:19. Hand V, including the amino acid sequence SEQ ID NO: 30 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 30. L In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96, and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96, and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99.

[0175] In some embodiments, a full-length antibody that specifically binds to TRAIL is provided, comprising an IgG1 or IgG4 constant region, wherein the antibody that specifically binds to TRAIL comprises a V constant region comprising the amino acid sequence SEQ ID NO:20 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO:20. H and V, including the amino acid sequence SEQ ID NO: 30 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 30. LIn some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96, and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96, and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99.

[0176] In some embodiments, a full-length antibody that specifically binds to TRAIL is provided, comprising an IgG1 or IgG4 constant region, wherein the antibody that specifically binds to TRAIL comprises a V constant region comprising the amino acid sequence SEQ ID NO:16 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO:16. Hand V, including the amino acid sequence SEQ ID NO: 31 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 31. L In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96, and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96, and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99.

[0177] In some embodiments, a full-length antibody that specifically binds to TRAIL is provided, comprising an IgG1 or IgG4 constant region, wherein the antibody that specifically binds to TRAIL comprises a V constant region comprising the amino acid sequence SEQ ID NO:17 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO:17. H and V, including the amino acid sequence SEQ ID NO: 31 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 31. LIn some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96, and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96, and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99.

[0178] In some embodiments, a full-length antibody that specifically binds to TRAIL is provided, comprising an IgG1 or IgG4 constant region, wherein the antibody that specifically binds to TRAIL comprises a V antibody having the amino acid sequence SEQ ID NO:18 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO:18. Hand V, including the amino acid sequence SEQ ID NO: 31 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 31. L In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96, and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96, and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99.

[0179] In some embodiments, a full-length antibody that specifically binds to TRAIL is provided, comprising an IgG1 or IgG4 constant region, wherein the antibody that specifically binds to TRAIL comprises a V constant region comprising the amino acid sequence SEQ ID NO:19 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO:19. H and V, including the amino acid sequence SEQ ID NO: 31 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 31. LIn some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96, and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96, and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99.

[0180] In some embodiments, a full-length antibody that specifically binds to TRAIL is provided, comprising an IgG1 or IgG4 constant region, wherein the antibody that specifically binds to TRAIL comprises a V constant region comprising the amino acid sequence SEQ ID NO:19 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO:19. Hand V, including the amino acid sequence SEQ ID NO: 31 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 31. L In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96, and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96, and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99.

[0181] In some embodiments, a full-length antibody that specifically binds to TRAIL is provided, comprising an IgG1 or IgG4 constant region, wherein the antibody that specifically binds to TRAIL comprises a V constant region comprising the amino acid sequence SEQ ID NO:20 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO:20. H and V, including the amino acid sequence SEQ ID NO: 31 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 31. LIn some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96, and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96, and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99.

[0182] In some embodiments, a full-length antibody that specifically binds to TRAIL is provided, comprising an IgG1 or IgG4 constant region, wherein the antibody that specifically binds to TRAIL comprises a V constant region comprising the amino acid sequence SEQ ID NO:21 or a variant thereof having at least about 80% sequence identity to the amino acid sequence SEQ ID NO:21. Hand V, including the amino acid sequence SEQ ID NO: 32 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 32. L In some embodiments, the IgG1 is human IgG1. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96, and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96, and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the IgG4 is human IgG4. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97 and the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99.

[0183] Antibodies that specifically bind to FasL In some embodiments, the antibody or antigen-binding fragment that specifically binds to FasL includes, but is not limited to, a humanized antibody, a chimeric antibody, a murine antibody, a human antibody, and an antibody molecule comprising the heavy and / or light chain CDRs described herein. In one embodiment, the antibody or antigen-binding fragment is an isolated antibody that binds to FasL. Antibodies or antigen-binding fragments of interest that specifically bind to FasL include full-length antibodies or fragments thereof that specifically bind to FasL (e.g., full-length IgG1, IgG2, or IgG4), single-chain antibodies that specifically bind to FasL, antibodies that multispecifically (e.g., bispecifically) bind to FasL, and immunoconjugates that specifically bind to FasL. In some embodiments, the antibody that specifically binds to FasL is a Fab, Fab', F(ab)', Fab'-SH, a single-chain antibody (scFv), an Fv fragment, a dAb, an Fd, a nanobody, or a double-chain antibody (diabody). In some embodiments, an antibody or antigen-binding fragment that specifically binds to FasL is one in which the binding affinity of the antibody or antigen-binding fragment to FasL is at least 10 times (e.g., 10, 10) greater than the binding affinity of the antibody or antigen-binding fragment to a non-target. 2 , 10 3 , 10 4 , 10 5 , 10 6 , or 10 7 In some embodiments, non-target refers to an antigen that is not FasL.

[0184] Binding affinity can be measured by methods known in the art, such as ELISA, fluorescence-activated cell sorting (FACS) analysis, or radioimmunoprecipitation analysis (RIA). Kd values ​​can be measured by methods known in the art, such as surface plasmon resonance (SPR) or biolayer interferometry (BLI) techniques.

[0185] While the present application details antibodies or antigen-binding fragments comprising human sequences (e.g., human heavy and light chain variable regions comprising human CDR sequences), non-human antibodies or antigen-binding fragments are also contemplated. In some examples, the non-human antibody or antigen-binding fragment comprises the human CDR sequences and non-human framework region sequences of an antibody or antigen-binding fragment described herein. In some examples, the non-human framework region sequences include any sequences used to generate heavy and / or light chain variable regions using one or more human CDR sequences described herein, including mammals such as mouse, rat, rabbit, pig, bovine (e.g., cow, ox, buffalo), deer, sheep, goat, chicken, cat, dog, ferret, primate (e.g., chinese monkey, macaque), etc. In some examples, the non-human antibody or antigen-binding fragment includes an antibody or antigen-binding fragment generated by grafting one or more human CDR sequences described herein into non-human framework regions (e.g., mouse or chicken framework region sequences).

[0186] In some embodiments, the antibodies or antigen-binding fragments that specifically bind to FasL described herein bind to an epitope in human FasL. In some embodiments, the antibodies or antigen-binding fragments that specifically bind to FasL are completely specific for human FasL and do not cross-react with species or other types of non-FasL. In some embodiments, the antibodies or antigen-binding fragments that specifically bind to FasL cross-react with TRAIL antigens from species other than human.

[0187] In some embodiments, the antibody or antigen-binding fragment that specifically binds to FasL comprises an antibody heavy chain constant region and an antibody light chain constant region. In some embodiments, the antibody or antigen-binding fragment that specifically binds to FasL comprises an IgG1-type heavy chain constant region. In some embodiments, the antibody or antigen-binding fragment that specifically binds to FasL comprises an IgG2-type heavy chain constant region. In some embodiments, the antibody or antigen-binding fragment that specifically binds to FasL comprises an IgG3-type heavy chain constant region. In some embodiments, the antibody or antigen-binding fragment that specifically binds to FasL comprises an IgG4-type heavy chain constant region. In some embodiments, the IgG refers to human IgG. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:96. In some embodiments, the heavy chain constant region comprises or consists of the amino acid sequence SEQ ID NO:97. In some embodiments, the antibody or antigen-binding fragment that specifically binds to FasL comprises a kappa light chain constant region. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:98. In some embodiments, the antibody or antigen-binding fragment that specifically binds to FasL comprises a lambda light chain constant region. In some embodiments, the light chain constant region comprises or consists of the amino acid sequence SEQ ID NO:99. In some embodiments, the antibody or antigen-binding fragment that specifically binds to FasL comprises an antibody heavy chain variable region and an antibody light chain variable region. In some embodiments, the full-length antibody that specifically binds to FasL has enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) effector function by comprising an altered or otherwise modified Fc sequence.

[0188] In some embodiments, the antibody or antigen-binding fragment that specifically binds to FasL is selected from the antibodies that specifically bind to FasL described in PCT application PCT / CN2023 / 072293.

[0189] Bispecific antibodies that specifically bind to TRAIL and FasL The present application provides a bispecific antibody comprising a first antigen-binding domain that specifically binds to TRAIL and a second antigen-binding domain that specifically binds to FasL. In some embodiments, the bispecific antibody can bind to either TRAIL or FasL. In other preferred embodiments, the bispecific antibody can bind to both TRAIL and FasL. In other more preferred embodiments, the bispecific antibody can simultaneously bind to TRAIL and FasL.

[0190] In some embodiments, the present application provides a bispecific antibody comprising a first antigen-binding domain that specifically binds to TRAIL and a second antigen-binding domain that specifically binds to FasL, wherein the first antigen-binding domain comprises: (i) a V-CDR1 comprising an HC-CDR1 having the amino acid sequence SEQ ID NO:1, an HC-CDR2 having the amino acid sequence SEQ ID NO:3, and an HC-CDR3 having the amino acid sequence SEQ ID NO:5; H and V comprising an LC-CDR1 comprising the amino acid sequence SEQ ID NO:7, an LC-CDR2 comprising the amino acid sequence SEQ ID NO:9, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO:11. L or (ii) a V comprising an HC-CDR1 comprising the amino acid sequence SEQ ID NO:2, an HC-CDR2 comprising the amino acid sequence SEQ ID NO:4, and an HC-CDR3 comprising the amino acid sequence SEQ ID NO:6. H and V comprising an LC-CDR1 having the amino acid sequence SEQ ID NO:8, an LC-CDR2 having the amino acid sequence SEQ ID NO:10, and an LC-CDR3 having the amino acid sequence SEQ ID NO:12. L or (iii) a V comprising an HC-CDR1 comprising the amino acid sequence SEQ ID NO:2, an HC-CDR2 comprising the amino acid sequence SEQ ID NO:161, and an HC-CDR3 comprising the amino acid sequence SEQ ID NO:6. Hand V comprising an LC-CDR1 having the amino acid sequence SEQ ID NO:8, an LC-CDR2 having the amino acid sequence SEQ ID NO:10, and an LC-CDR3 having the amino acid sequence SEQ ID NO:12. L In some embodiments, the second antigen-binding domain comprises (i) a V-CDR1 comprising an HC-CDR1 having the amino acid sequence SEQ ID NO:51, an HC-CDR2 having the amino acid sequence SEQ ID NO:53, and an HC-CDR3 having the amino acid sequence SEQ ID NO:55. H and V comprising an LC-CDR1 having the amino acid sequence SEQ ID NO: 57, an LC-CDR2 having the amino acid sequence SEQ ID NO: 59, and an LC-CDR3 having the amino acid sequence SEQ ID NO: 61. L or (ii) a V comprising an HC-CDR1 comprising the amino acid sequence SEQ ID NO: 52, an HC-CDR2 comprising the amino acid sequence SEQ ID NO: 54, and an HC-CDR3 comprising the amino acid sequence SEQ ID NO: 56. H and V comprising an LC-CDR1 having the amino acid sequence SEQ ID NO: 58, an LC-CDR2 having the amino acid sequence SEQ ID NO: 60, and an LC-CDR3 having the amino acid sequence SEQ ID NO: 62. L or (iii) a V comprising an HC-CDR1 comprising the amino acid sequence SEQ ID NO: 52, an HC-CDR2 comprising the amino acid sequence SEQ ID NO: 54, and an HC-CDR3 comprising the amino acid sequence SEQ ID NO: 56. H and a V comprising an LC-CDR1 having the amino acid sequence SEQ ID NO: 162, an LC-CDR2 having the amino acid sequence SEQ ID NO: 60, and an LC-CDR3 having the amino acid sequence SEQ ID NO: 62. L , including.

[0191] In some embodiments, the present application provides a bispecific antibody comprising a first antigen-binding domain that specifically binds to TRAIL and a second antigen-binding domain that specifically binds to FasL, wherein the second antigen-binding domain comprises: (i) a V-CDR1 comprising an HC-CDR1 having the amino acid sequence SEQ ID NO:51, an HC-CDR2 having the amino acid sequence SEQ ID NO:53, and an HC-CDR3 having the amino acid sequence SEQ ID NO:55; H and V comprising an LC-CDR1 having the amino acid sequence SEQ ID NO: 57, an LC-CDR2 having the amino acid sequence SEQ ID NO: 59, and an LC-CDR3 having the amino acid sequence SEQ ID NO: 61. L or (ii) a V comprising an HC-CDR1 comprising the amino acid sequence SEQ ID NO: 52, an HC-CDR2 comprising the amino acid sequence SEQ ID NO: 54, and an HC-CDR3 comprising the amino acid sequence SEQ ID NO: 56. H and V comprising an LC-CDR1 having the amino acid sequence SEQ ID NO: 58, an LC-CDR2 having the amino acid sequence SEQ ID NO: 60, and an LC-CDR3 having the amino acid sequence SEQ ID NO: 62. L or (iii) a V comprising an HC-CDR1 comprising the amino acid sequence SEQ ID NO: 52, an HC-CDR2 comprising the amino acid sequence SEQ ID NO: 54, and an HC-CDR3 comprising the amino acid sequence SEQ ID NO: 56. H and a V comprising an LC-CDR1 having the amino acid sequence SEQ ID NO: 162, an LC-CDR2 having the amino acid sequence SEQ ID NO: 60, and an LC-CDR3 having the amino acid sequence SEQ ID NO: 62. L , including.

[0192] In some embodiments, the first antigen-binding domain that specifically binds to TRAIL is V H and V L and V H is the V shown in the amino acid sequence SEQ ID NO:13 H wherein V comprises an HCDR1, an HCDR2, and an HCDR3; Lis the V shown in the amino acid sequence SEQ ID NO:22 L includes LCDR1, LCDR2 and LCDR3.

[0193] In some embodiments, the first antigen-binding domain that specifically binds to TRAIL is V H and V L and V H is the V shown in the amino acid sequence SEQ ID NO:15 H wherein V comprises an HCDR1, an HCDR2, and an HCDR3; L is the V shown in the amino acid sequence SEQ ID NO:28 L includes LCDR1, LCDR2 and LCDR3.

[0194] In some embodiments, the first antigen-binding domain that specifically binds to TRAIL is V H and V L and V H is the V shown in the amino acid sequence SEQ ID NO:164 H wherein V comprises an HCDR1, an HCDR2, and an HCDR3; L is the amino acid sequence shown in SEQ ID NO:168 L includes LCDR1, LCDR2 and LCDR3.

[0195] In some embodiments, the first antigen-binding domain that specifically binds to TRAIL is V H and V L and V H is the amino acid sequence shown in SEQ ID NO:166 H wherein V comprises an HCDR1, an HCDR2, and an HCDR3; L is the V shown in the amino acid sequence SEQ ID NO:170 L includes LCDR1, LCDR2 and LCDR3.

[0196] In some embodiments, the second antigen-binding domain that specifically binds to FasL is V H and V L and V His the V shown in the amino acid sequence SEQ ID NO:63 H wherein V comprises an HCDR1, an HCDR2, and an HCDR3; L is the V shown in the amino acid sequence SEQ ID NO:73 L includes LCDR1, LCDR2 and LCDR3.

[0197] In some embodiments, the second antigen-binding domain that specifically binds to FasL is V H and V L and V H is the V shown in the amino acid sequence SEQ ID NO:66 H wherein V comprises an HCDR1, an HCDR2, and an HCDR3; L is V shown in the amino acid sequence SEQ ID NO:76 L includes LCDR1, LCDR2 and LCDR3.

[0198] In some embodiments, the second antigen-binding domain that specifically binds to FasL is V H and V L and V H is the V shown in the amino acid sequence SEQ ID NO:163 H wherein V comprises an HCDR1, an HCDR2, and an HCDR3; L is the V shown in the amino acid sequence SEQ ID NO:167 L includes LCDR1, LCDR2 and LCDR3.

[0199] In some embodiments, the second antigen-binding domain that specifically binds to FasL is V H and V L and V H is the V shown in the amino acid sequence SEQ ID NO:165 H wherein V comprises an HCDR1, an HCDR2, and an HCDR3; L is the V shown in the amino acid sequence SEQ ID NO:169 L includes LCDR1, LCDR2 and LCDR3.

[0200] In some embodiments, the first antigen-binding domain that specifically binds to TRAIL comprises an amino acid sequence set forth in any one of SEQ ID NOs: 13-20, 33-40, 164, and 166, or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 13-20, 33-40, 164, and 166. H and V, including the amino acid sequence set forth in any one of SEQ ID NOs: 22-31, 41-50, 168, and 170, or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 22-31, 41-50, 168, and 170. L , including.

[0201] In some embodiments, the first antigen-binding domain that specifically binds to TRAIL comprises an amino acid sequence set forth in any one of SEQ ID NOs: 13 and 33, or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 13 and 33. H and V, including the amino acid sequence set forth in any one of SEQ ID NOs: 22 and 41, or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 22 and 41. L , including.

[0202] In some embodiments, the first antigen-binding domain that specifically binds to TRAIL comprises an amino acid sequence set forth in any one of SEQ ID NOs: 14 and 34, or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 14 and 34. H and V, including the amino acid sequence set forth in any one of SEQ ID NOs: 23 and 42, or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 23 and 42. L , including.

[0203] In some embodiments, the first antigen-binding domain that specifically binds to TRAIL comprises an amino acid sequence set forth in any one of SEQ ID NOs: 14 and 34, or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 14 and 34. H and V, including the amino acid sequence set forth in any one of SEQ ID NOs: 24 and 43, or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 24 and 43. L , including.

[0204] In some embodiments, the first antigen-binding domain that specifically binds to TRAIL comprises an amino acid sequence set forth in any one of SEQ ID NOs: 14 and 34, or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 14 and 34. Hand V, including the amino acid sequence set forth in any one of SEQ ID NOs: 25 and 44, or variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 25 and 44. L , including.

[0205] In some embodiments, the first antigen-binding domain that specifically binds to TRAIL comprises an amino acid sequence set forth in any one of SEQ ID NOs: 14 and 34, or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 14 and 34. H and V, including the amino acid sequence set forth in any one of SEQ ID NOs: 26 and 45, or variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 26 and 45. L , including.

[0206] In some embodiments, the first antigen-binding domain that specifically binds to TRAIL comprises an amino acid sequence set forth in any one of SEQ ID NOs: 14 and 34, or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 14 and 34. H and V, including the amino acid sequence set forth in any one of SEQ ID NOs: 27 and 46, or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 27 and 46. L , including.

[0207] In some embodiments, the first antigen-binding domain that specifically binds to TRAIL comprises an amino acid sequence set forth in any one of SEQ ID NOs: 15 and 35, or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 15 and 35. H and V, including the amino acid sequence set forth in any one of SEQ ID NOs: 28 and 47, or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 28 and 47. L , including.

[0208] In some embodiments, the first antigen-binding domain that specifically binds to TRAIL comprises an amino acid sequence set forth in any one of SEQ ID NOs: 16 and 36, or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 16 and 36. H and V, including the amino acid sequence set forth in any one of SEQ ID NOs: 29 and 48, or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 29 and 48. L , including.

[0209] In some embodiments, the first antigen-binding domain that specifically binds to TRAIL comprises an amino acid sequence set forth in any one of SEQ ID NOs: 17 and 37, or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 17 and 37. Hand V, including the amino acid sequence set forth in any one of SEQ ID NOs: 29 and 48, or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 29 and 48. L , including.

[0210] In some embodiments, the first antigen-binding domain that specifically binds to TRAIL comprises an amino acid sequence set forth in any one of SEQ ID NOs: 18 and 38, or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 18 and 38. H and V, including the amino acid sequence set forth in any one of SEQ ID NOs: 29 and 48, or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 29 and 48. L , including.

[0211] In some embodiments, the first antigen-binding domain that specifically binds to TRAIL comprises an amino acid sequence set forth in any one of SEQ ID NOs: 19 and 39, or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 19 and 39. H and V, including the amino acid sequence set forth in any one of SEQ ID NOs: 29 and 48, or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 29 and 48. L , including.

[0212] In some embodiments, the first antigen-binding domain that specifically binds to TRAIL comprises an amino acid sequence set forth in any one of SEQ ID NOs: 20 and 40, or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 20 and 40. H and V, including the amino acid sequence set forth in any one of SEQ ID NOs: 29 and 48, or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 29 and 48. L , including.

[0213] In some embodiments, the first antigen-binding domain that specifically binds to TRAIL comprises an amino acid sequence set forth in any one of SEQ ID NOs: 16 and 36, or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 16 and 36. H and V, including the amino acid sequence set forth in any one of SEQ ID NOs: 30 and 49, or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 30 and 49. L , including.

[0214] In some embodiments, the first antigen-binding domain that specifically binds to TRAIL comprises an amino acid sequence set forth in any one of SEQ ID NOs: 17 and 37, or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 17 and 37. Hand V, including the amino acid sequence set forth in any one of SEQ ID NOs: 30 and 49, or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 30 and 49. L , including.

[0215] In some embodiments, the first antigen-binding domain that specifically binds to TRAIL comprises an amino acid sequence set forth in any one of SEQ ID NOs: 18 and 38, or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 18 and 38. H and V, including the amino acid sequence set forth in any one of SEQ ID NOs: 30 and 49, or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 30 and 49. L , including.

[0216] In some embodiments, the first antigen-binding domain that specifically binds to TRAIL comprises an amino acid sequence set forth in any one of SEQ ID NOs: 19 and 39, or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 19 and 39. H and V, including the amino acid sequence set forth in any one of SEQ ID NOs: 30 and 49, or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 30 and 49. L , including.

[0217] In some embodiments, the first antigen-binding domain that specifically binds to TRAIL comprises an amino acid sequence set forth in any one of SEQ ID NOs: 20 and 40, or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 20 and 40. H and V, including the amino acid sequence set forth in any one of SEQ ID NOs: 30 and 49, or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 30 and 49. L , including.

[0218] In some embodiments, the first antigen-binding domain that specifically binds to TRAIL comprises an amino acid sequence set forth in any one of SEQ ID NOs: 16 and 36, or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 16 and 36. H and V, including the amino acid sequence set forth in any one of SEQ ID NOs: 31 and 50, or variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 31 and 50. L , including.

[0219] In some embodiments, the first antigen-binding domain that specifically binds to TRAIL comprises an amino acid sequence set forth in any one of SEQ ID NOs: 17 and 37, or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 17 and 37. Hand V, including the amino acid sequence set forth in any one of SEQ ID NOs: 31 and 50, or variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 31 and 50. L , including.

[0220] In some embodiments, the first antigen-binding domain that specifically binds to TRAIL comprises an amino acid sequence set forth in any one of SEQ ID NOs: 18 and 38, or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 18 and 38. H and V, including the amino acid sequence set forth in any one of SEQ ID NOs: 31 and 50, or variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 31 and 50. L , including.

[0221] In some embodiments, the first antigen-binding domain that specifically binds to TRAIL comprises an amino acid sequence set forth in any one of SEQ ID NOs: 19 and 39, or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 19 and 39. H and V, including the amino acid sequence set forth in any one of SEQ ID NOs: 31 and 50, or variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 31 and 50. L , including.

[0222] In some embodiments, the first antigen-binding domain that specifically binds to TRAIL comprises a V that has at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 20 and 40, or a variant thereof set forth in any one of SEQ ID NOs: 16 and 36. H and V, including the amino acid sequence set forth in any one of SEQ ID NOs: 31 and 50, or variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 31 and 50. L , including.

[0223] In some embodiments, the first antigen-binding domain that specifically binds to TRAIL comprises a V that comprises the amino acid sequence set forth in SEQ ID NO: 164 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence set forth in SEQ ID NO: 164. H and V, including the amino acid sequence set forth in any one of SEQ ID NOs: 168 and 41, or variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence set forth in SEQ ID NO: 168. L , including.

[0224] In some embodiments, the first antigen-binding domain that specifically binds to TRAIL comprises the amino acid sequence set forth in SEQ ID NO: 166 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence set forth in SEQ ID NO: 166. Hand V, including the amino acid sequence set forth in SEQ ID NO: 170 or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence set forth in SEQ ID NO: 170. L , including.

[0225] In some embodiments, the second antigen-binding domain that specifically binds to FasL comprises an amino acid sequence set forth in any one of SEQ ID NOs: 63-72, 80-88, 163, and 165, or a variant thereof having at least about 80% sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 63-72, 80-88, 163, and 165. H and V comprising an amino acid sequence set forth in any one of SEQ ID NOs: 73-79, 89-95, 167 and 169, or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 73-79, 89-95, 167 and 169. L , including.

[0226] In some embodiments, the second antigen-binding domain that specifically binds to FasL comprises an amino acid sequence set forth in any one of SEQ ID NOs: 63 and 80, or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 63 and 80. H and V, including the amino acid sequence set forth in any one of SEQ ID NOs: 73 and 89, or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 73 and 89. L , including.

[0227] In some embodiments, the second antigen-binding domain that specifically binds to FasL comprises an amino acid sequence set forth in any one of SEQ ID NOs:64 and 81, or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs:64 and 81. H and V, including the amino acid sequence set forth in any one of SEQ ID NOs: 74 and 90, or variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 74 and 90. L , including.

[0228] In some embodiments, the second antigen-binding domain that specifically binds to FasL comprises an amino acid sequence set forth in any one of SEQ ID NOs: 65 and 81, or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 65 and 81. H and V, including the amino acid sequence set forth in any one of SEQ ID NOs: 74 and 90, or variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 74 and 90. L , including.

[0229] In some embodiments, the second antigen-binding domain that specifically binds to FasL comprises an amino acid sequence set forth in any one of SEQ ID NOs:64 and 81, or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs:64 and 81. Hand V, including the amino acid sequence set forth in any one of SEQ ID NOs: 75 and 91, or variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 75 and 91. L , including.

[0230] In some embodiments, the second antigen-binding domain that specifically binds to FasL comprises an amino acid sequence set forth in any one of SEQ ID NOs: 65 and 81, or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 65 and 81. H and V, including the amino acid sequence set forth in any one of SEQ ID NOs: 75 and 91, or variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 75 and 91. L , including.

[0231] In some embodiments, the second antigen-binding domain that specifically binds to FasL comprises an amino acid sequence set forth in any one of SEQ ID NOs: 66 and 82, or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 66 and 82. H and V, including the amino acid sequence set forth in any one of SEQ ID NOs: 76 and 92, or variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 76 and 92. L , including.

[0232] In some embodiments, the second antigen-binding domain that specifically binds to FasL comprises an amino acid sequence set forth in any one of SEQ ID NOs: 67 and 83, or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 67 and 83. H and V, including the amino acid sequence set forth in any one of SEQ ID NOs: 77 and 93, or variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 77 and 93. L , including.

[0233] In some embodiments, the second antigen-binding domain that specifically binds to FasL comprises an amino acid sequence set forth in any one of SEQ ID NOs: 68 and 84, or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 68 and 84. H and V, including the amino acid sequence set forth in any one of SEQ ID NOs: 77 and 93, or variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 77 and 93. L , including.

[0234] In some embodiments, the second antigen-binding domain that specifically binds to FasL comprises an amino acid sequence set forth in any one of SEQ ID NOs: 69 and 85, or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 69 and 85. Hand V, including the amino acid sequence set forth in any one of SEQ ID NOs: 77 and 93, or variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 77 and 93. L , including.

[0235] In some embodiments, the second antigen-binding domain that specifically binds to FasL comprises an amino acid sequence set forth in any one of SEQ ID NOs:70 and 86, or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs:70 and 86. H and V, including the amino acid sequence set forth in any one of SEQ ID NOs: 77 and 93, or variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 77 and 93. L , including.

[0236] In some embodiments, the second antigen-binding domain that specifically binds to FasL comprises an amino acid sequence set forth in any one of SEQ ID NOs: 71 and 87, or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 71 and 87. H and V, including the amino acid sequence set forth in any one of SEQ ID NOs: 77 and 93, or variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 77 and 93. L , including.

[0237] In some embodiments, the second antigen-binding domain that specifically binds to FasL comprises an amino acid sequence set forth in any one of SEQ ID NOs: 72 and 88, or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 72 and 88. H and V, including the amino acid sequence set forth in any one of SEQ ID NOs: 77 and 93, or variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 77 and 93. L , including.

[0238] In some embodiments, the second antigen-binding domain that specifically binds to FasL comprises an amino acid sequence set forth in any one of SEQ ID NOs: 67 and 83, or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 67 and 83. H and V, including the amino acid sequence set forth in any one of SEQ ID NOs: 78 and 94, or variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 78 and 94. L , including.

[0239] In some embodiments, the second antigen-binding domain that specifically binds to FasL comprises an amino acid sequence set forth in any one of SEQ ID NOs: 68 and 84, or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 68 and 84. Hand V, including the amino acid sequence set forth in any one of SEQ ID NOs: 78 and 94, or variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 78 and 94. L , including.

[0240] In some embodiments, the second antigen-binding domain that specifically binds to FasL comprises an amino acid sequence set forth in any one of SEQ ID NOs: 69 and 85, or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 69 and 85. H and V, including the amino acid sequence set forth in any one of SEQ ID NOs: 78 and 94, or variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 78 and 94. L , including.

[0241] In some embodiments, the second antigen-binding domain that specifically binds to FasL comprises an amino acid sequence set forth in any one of SEQ ID NOs:70 and 86, or a variant thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs:70 and 86. H and V, including the amino acid sequence set forth in any one of SEQ ID NOs: 78 and 94, or variants thereof having at least about 80% (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity to the amino acid sequence set forth in any one of SEQ ID NOs: 78 and 94. L , including.

[0242] In some embodiments, the second antigen-binding domain that specifically binds to FasL comprises an amino acid sequence set forth in any one ...

Claims

1. V Ｈ or the V Ｈ and mutants of V Ｌ or the V Ｌ and a variant of: The V Ｈ teeth, HC-CDR1 comprising the amino acid sequence SEQ ID NO: 1, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 3, and HC-CDR3 comprising the amino acid sequence SEQ ID NO: 5; The V Ｈ wherein the variant comprises at most about five amino acid substitutions in its HC-CDRs, The V Ｌ teeth, LC-CDR1 comprising the amino acid sequence SEQ ID NO: 7, LC-CDR2 comprising the amino acid sequence SEQ ID NO: 9, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO: 11; The V Ｌ The variant of comprises at most about five amino acid substitutions in its LC-CDRs, An isolated antibody or antigen-binding fragment that specifically binds to TRAIL.

2. V Ｈ and V Ｌ 1. An antibody or antigen-binding fragment comprising: The V Ｈ is the V shown in the amino acid sequence SEQ ID NO: 13 Ｈ and a HC-CDR1, a HC-CDR2, and a HC-CDR3 comprising: The V Ｌ is the V shown in the amino acid sequence SEQ ID NO: 22 Ｌ comprising LC-CDR1, LC-CDR2 and LC-CDR3, An isolated antibody or antigen-binding fragment that specifically binds to TRAIL.

3. (i) a V comprising the amino acid sequence SEQ ID NO: 13 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 13; Ｈ and V comprising the amino acid sequence SEQ ID NO: 22 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

22. Ｌ , (ii) V comprising the amino acid sequence SEQ ID NO: 14 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

14. Ｈ and V comprising the amino acid sequence SEQ ID NO: 23 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

23. Ｌ , (iii) V comprising the amino acid sequence SEQ ID NO: 14 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

14. Ｈ and V comprising the amino acid sequence SEQ ID NO: 24 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

24. Ｌ , (iv) V comprising the amino acid sequence SEQ ID NO: 14 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

14. Ｈ and V comprising the amino acid sequence SEQ ID NO: 25 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

25. Ｌ , (v) V comprising the amino acid sequence SEQ ID NO: 14 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

14. Ｈ and V comprising the amino acid sequence SEQ ID NO: 26 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

26. Ｌ ,or (vi) V comprising the amino acid sequence SEQ ID NO: 14 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

14. Ｈ and V comprising the amino acid sequence SEQ ID NO: 27 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

27. Ｌ , including An isolated antibody or antigen-binding fragment that specifically binds to TRAIL according to claim 1 or 2.

4. V Ｈ or the V Ｈ and mutants of V Ｌ or the V Ｌ and a variant of: The V Ｈ teeth, HC-CDR1 comprising the amino acid sequence SEQ ID NO: 2, HC-CDR2 comprising the amino acid sequence SEQ ID NO: 4, and HC-CDR3 comprising the amino acid sequence SEQ ID NO: 6; The V Ｈ wherein the variant comprises at most about five amino acid substitutions in its HC-CDRs, The V Ｌ teeth, LC-CDR1 comprising the amino acid sequence SEQ ID NO: 8, LC-CDR2 comprising the amino acid sequence SEQ ID NO: 10, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO: 12; The V Ｌ The variant of comprises at most about five amino acid substitutions in its LC-CDRs, An isolated antibody or antigen-binding fragment that specifically binds to TRAIL.

5. V Ｈ and V Ｌ 1. An antibody or antigen-binding fragment comprising: The V Ｈ is the V shown in the amino acid sequence SEQ ID NO: 15 Ｈ and a HC-CDR1, a HC-CDR2, and a HC-CDR3 comprising: The V Ｌ is the V shown in the amino acid sequence SEQ ID NO: 28 Ｌ comprising LC-CDR1, LC-CDR2 and LC-CDR3, An isolated antibody or antigen-binding fragment that specifically binds to TRAIL.

6. (i) V comprising the amino acid sequence SEQ ID NO: 15 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

15. Ｈ and V comprising the amino acid sequence SEQ ID NO: 28 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

28. Ｌ , (ii) V comprising the amino acid sequence SEQ ID NO: 16 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

16. Ｈ and V comprising the amino acid sequence SEQ ID NO: 29 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

29. Ｌ , (iii) V comprising the amino acid sequence SEQ ID NO: 17 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

17. Ｈ and V comprising the amino acid sequence SEQ ID NO: 29 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

29. Ｌ , (iv) V comprising the amino acid sequence SEQ ID NO: 18 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

18. Ｈ and V comprising the amino acid sequence SEQ ID NO: 29 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

29. Ｌ , (v) V comprising the amino acid sequence SEQ ID NO: 19 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

19. Ｈ and V comprising the amino acid sequence SEQ ID NO: 29 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

29. Ｌ , (vi) V comprising the amino acid sequence SEQ ID NO: 20 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

20. Ｈ and V comprising the amino acid sequence SEQ ID NO: 29 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

29. Ｌ , (vii) V comprising the amino acid sequence SEQ ID NO: 16 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

16. Ｈ and V comprising the amino acid sequence SEQ ID NO: 30 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

30. Ｌ , (viii) V comprising the amino acid sequence SEQ ID NO: 17 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

17. Ｈ and V comprising the amino acid sequence SEQ ID NO: 30 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

30. Ｌ , (ix) V comprising the amino acid sequence SEQ ID NO: 18 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

18. Ｈ and V comprising the amino acid sequence SEQ ID NO: 30 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

30. Ｌ , (x) V comprising the amino acid sequence SEQ ID NO: 19 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

19. Ｈ and V comprising the amino acid sequence SEQ ID NO: 30 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

30. Ｌ , (xi) V comprising the amino acid sequence SEQ ID NO: 20 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

20. Ｈ and V comprising the amino acid sequence SEQ ID NO: 30 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

30. Ｌ , (xii) V comprising the amino acid sequence SEQ ID NO: 16 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

16. Ｈ and V comprising the amino acid sequence SEQ ID NO: 31 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

31. Ｌ , (xiii) V comprising the amino acid sequence SEQ ID NO: 17 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

17. Ｈ and V comprising the amino acid sequence SEQ ID NO: 31 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

31. Ｌ , (xiv) V comprising the amino acid sequence SEQ ID NO: 18 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

18. Ｈ and V comprising the amino acid sequence SEQ ID NO: 31 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

31. Ｌ , (xv) V comprising the amino acid sequence SEQ ID NO: 19 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

19. Ｈ and V comprising the amino acid sequence SEQ ID NO: 31 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

31. Ｌ , (xvi) V comprising the amino acid sequence SEQ ID NO: 20 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

20. Ｈ and V comprising the amino acid sequence SEQ ID NO: 31 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

31. Ｌ ,or (xvii) V comprising the amino acid sequence SEQ ID NO: 21 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

21. Ｈ and V comprising the amino acid sequence SEQ ID NO: 32 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

32. Ｌ , including An isolated antibody or antigen-binding fragment that specifically binds to TRAIL according to claim 4 or 5.

7. the antibody or antigen-binding fragment comprises an Fc fragment; An isolated antibody or antigen-binding fragment that specifically binds to TRAIL according to claims 1 to 6.

8. the antibody or antigen-binding fragment is a full-length IgG antibody; An isolated antibody or antigen-binding fragment that specifically binds to TRAIL according to claim 7.

9. the antibody or antigen-binding fragment is a full-length IgG1, IgG2, IgG3, or IgG4 antibody; 9. An isolated antibody or antigen-binding fragment that specifically binds to TRAIL according to claim 8.

10. the antibody or antigen-binding fragment is a chimeric, humanized, or fully human antibody; An isolated antibody or antigen-binding fragment that specifically binds to TRAIL according to any one of claims 1 to 9.

11. The antigen-binding fragment may be Fab, Fab', or F(ab)' ２ , Fab'-SH, single chain antibody (scFv), Fv fragment, dAb, Fd, nanobody, double chain antibody (diabody) and linear antibody, An isolated antibody or antigen-binding fragment that specifically binds to TRAIL according to any one of claims 1 to 6.

12. a first antigen-binding domain that specifically binds to TRAIL and a second antigen-binding domain that specifically binds to FasL; Bispecific antibodies.

13. The first antigen-binding domain (i) V comprising HC-CDR1 having the amino acid sequence SEQ ID NO: 1, HC-CDR2 having the amino acid sequence SEQ ID NO: 3, and HC-CDR3 having the amino acid sequence SEQ ID NO:

5. Ｈ , and, V comprising an LC-CDR1 having the amino acid sequence SEQ ID NO: 7, an LC-CDR2 having the amino acid sequence SEQ ID NO: 9, and an LC-CDR3 having the amino acid sequence SEQ ID NO:

11. Ｌ ,or (ii) V comprising HC-CDR1 having the amino acid sequence SEQ ID NO: 2, HC-CDR2 having the amino acid sequence SEQ ID NO: 4, and HC-CDR3 having the amino acid sequence SEQ ID NO:

6. Ｈ , and, V comprising an LC-CDR1 having the amino acid sequence SEQ ID NO: 8, an LC-CDR2 having the amino acid sequence SEQ ID NO: 10, and an LC-CDR3 having the amino acid sequence SEQ ID NO:

12. Ｌ ,or (iii) V comprising HC-CDR1 having the amino acid sequence SEQ ID NO: 2, HC-CDR2 having the amino acid sequence SEQ ID NO: 161, and HC-CDR3 having the amino acid sequence SEQ ID NO:

6. Ｈ , and, V comprising an LC-CDR1 having the amino acid sequence SEQ ID NO: 8, an LC-CDR2 having the amino acid sequence SEQ ID NO: 10, and an LC-CDR3 having the amino acid sequence SEQ ID NO:

12. Ｌ , including The bispecific antibody of claim 12.

14. The first antigen-binding domain (i) a V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 13 and 33 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 13 and 33; Ｈ and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 22 and 41 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 22 and 41. Ｌ , (ii) a V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 14 and 34 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 14 and 34; Ｈ and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 23 and 42 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 23 and 42. Ｌ , (iii) a V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 14 and 34 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 14 and 34; Ｈ and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 24 and 43 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 24 and 43. Ｌ , (iv) V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 15 and 35 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 15 and 35. Ｈ and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 28 and 47 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 28 and 47. Ｌ , (v) V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 20 and 40 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 20 and 40. Ｈ and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 30 and 49 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 30 and 49. Ｌ , (vi) a V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 16 and 36 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 16 and 36; Ｈ and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 31 and 50 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 31 and 50. Ｌ , (vii) V comprising the amino acid sequence set forth in SEQ ID NO: 164 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in SEQ ID NO:

164. Ｈ and V comprising the amino acid sequence set forth in SEQ ID NO: 168 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in SEQ ID NO:

168. Ｌ ,or (viii) V comprising the amino acid sequence set forth in SEQ ID NO: 166 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in SEQ ID NO:

166. Ｈ and V comprising the amino acid sequence set forth in SEQ ID NO: 170 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in SEQ ID NO:

170. Ｌ , including A bispecific antibody according to claim 12 or 13.

15. The second antigen-binding domain is (i) V comprising HC-CDR1 having the amino acid sequence SEQ ID NO: 51, HC-CDR2 having the amino acid sequence SEQ ID NO: 53, and HC-CDR3 having the amino acid sequence SEQ ID NO:

55. Ｈ , and, V comprising an LC-CDR1 having the amino acid sequence SEQ ID NO: 57, an LC-CDR2 having the amino acid sequence SEQ ID NO: 59, and an LC-CDR3 having the amino acid sequence SEQ ID NO:

61. Ｌ ,or (ii) V comprising HC-CDR1 having the amino acid sequence SEQ ID NO: 52, HC-CDR2 having the amino acid sequence SEQ ID NO: 54, and HC-CDR3 having the amino acid sequence SEQ ID NO:

56. Ｈ , and, V comprising an LC-CDR1 having the amino acid sequence SEQ ID NO: 58, an LC-CDR2 having the amino acid sequence SEQ ID NO: 60, and an LC-CDR3 having the amino acid sequence SEQ ID NO:

62. Ｌ ,or (iii) V comprising HC-CDR1 having the amino acid sequence SEQ ID NO: 52, HC-CDR2 having the amino acid sequence SEQ ID NO: 54, and HC-CDR3 having the amino acid sequence SEQ ID NO:

56. Ｈ , and, LC-CDR1 comprising the amino acid sequence SEQ ID NO: 162, LC-CDR2 comprising the amino acid sequence SEQ ID NO: 60, and LC-CDR3 comprising the amino acid sequence SEQ ID NO:

62. Ｌ , including The bispecific antibody according to any one of claims 12 to 14.

16. The second antigen-binding domain is (i) a V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 63 and 80 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 63 and 80; Ｈ and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 73 and 89 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 73 and 89. Ｌ , (ii) a V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 64 and 81 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 64 and 81; Ｈ and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 74 and 90 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 74 and 90. Ｌ , (iii) a V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 66 and 82 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 66 and 82; Ｈ and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 76 and 92 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 76 and 92. Ｌ , (iv) a V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 70 and 86 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 70 and 86; Ｈ and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 78 and 94 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 78 and 94. Ｌ , (v) V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 69 and 85 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 69 and 85. Ｈ and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 79 and 95 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 79 and 95. Ｌ , (vi) V comprising the amino acid sequence set forth in SEQ ID NO: 163 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in SEQ ID NO:

163. Ｈ and V comprising the amino acid sequence set forth in SEQ ID NO: 167 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in SEQ ID NO:

167. Ｌ ,or (vii) V comprising the amino acid sequence set forth in SEQ ID NO: 165 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in SEQ ID NO:

165. Ｈ and V comprising the amino acid sequence set forth in SEQ ID NO: 169 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in SEQ ID NO:

169. Ｌ , including The bispecific antibody according to any one of claims 12 to 15.

17. a) the first antigen-binding domain is V Ｈ and V Ｌ and V Ｈ comprises an HC-CDR1 having the amino acid sequence SEQ ID NO: 1, an HC-CDR2 having the amino acid sequence SEQ ID NO: 3, and an HC-CDR3 having the amino acid sequence SEQ ID NO: 5, Ｌ comprises an LC-CDR1 comprising the amino acid sequence SEQ ID NO: 7, an LC-CDR2 comprising the amino acid sequence SEQ ID NO: 9, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO: 11; and the second antigen-binding domain is V Ｈ and V Ｌ and V Ｈ comprises an HC-CDR1 comprising the amino acid sequence SEQ ID NO: 51, an HC-CDR2 comprising the amino acid sequence SEQ ID NO: 53, and an HC-CDR3 comprising the amino acid sequence SEQ ID NO: 55, Ｌ comprises an LC-CDR1 comprising the amino acid sequence SEQ ID NO: 57, an LC-CDR2 comprising the amino acid sequence SEQ ID NO: 59, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO: 61; b) the first antigen-binding domain is V Ｈ and V Ｌ and V Ｈ comprises an HC-CDR1 having the amino acid sequence SEQ ID NO: 1, an HC-CDR2 having the amino acid sequence SEQ ID NO: 3, and an HC-CDR3 having the amino acid sequence SEQ ID NO: 5, Ｌ comprises an LC-CDR1 comprising the amino acid sequence SEQ ID NO: 7, an LC-CDR2 comprising the amino acid sequence SEQ ID NO: 9, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO: 11; and the second antigen-binding domain is V Ｈ and V Ｌ and V Ｈ comprises an HC-CDR1 comprising the amino acid sequence SEQ ID NO: 52, an HC-CDR2 comprising the amino acid sequence SEQ ID NO: 54, and an HC-CDR3 comprising the amino acid sequence SEQ ID NO: 56, Ｌ comprises an LC-CDR1 comprising the amino acid sequence SEQ ID NO: 58, an LC-CDR2 comprising the amino acid sequence SEQ ID NO: 60, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO: 62; c) the first antigen-binding domain is V Ｈ and V Ｌ and V Ｈ comprises an HC-CDR1 having the amino acid sequence SEQ ID NO: 2, an HC-CDR2 having the amino acid sequence SEQ ID NO: 4, and an HC-CDR3 having the amino acid sequence SEQ ID NO: 6, Ｌ comprises an LC-CDR1 comprising the amino acid sequence SEQ ID NO: 8, an LC-CDR2 comprising the amino acid sequence SEQ ID NO: 10, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO: 12; and the second antigen-binding domain is V Ｈ and V Ｌ and V Ｈ comprises an HC-CDR1 comprising the amino acid sequence SEQ ID NO: 51, an HC-CDR2 comprising the amino acid sequence SEQ ID NO: 53, and an HC-CDR3 comprising the amino acid sequence SEQ ID NO: 55, Ｌ comprises an LC-CDR1 comprising the amino acid sequence SEQ ID NO: 57, an LC-CDR2 comprising the amino acid sequence SEQ ID NO: 59, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO: 61; d) the first antigen-binding domain is V Ｈ and V Ｌ and V Ｈ comprises an HC-CDR1 having the amino acid sequence SEQ ID NO: 2, an HC-CDR2 having the amino acid sequence SEQ ID NO: 4, and an HC-CDR3 having the amino acid sequence SEQ ID NO: 6, Ｌ comprises an LC-CDR1 comprising the amino acid sequence SEQ ID NO: 8, an LC-CDR2 comprising the amino acid sequence SEQ ID NO: 10, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO: 12; and the second antigen-binding domain is V Ｈ and V Ｌ and V Ｈ comprises an HC-CDR1 comprising the amino acid sequence SEQ ID NO: 52, an HC-CDR2 comprising the amino acid sequence SEQ ID NO: 54, and an HC-CDR3 comprising the amino acid sequence SEQ ID NO: 56, Ｌ comprises an LC-CDR1 comprising the amino acid sequence SEQ ID NO: 58, an LC-CDR2 comprising the amino acid sequence SEQ ID NO: 60, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO: 62, or e) the first antigen-binding domain is V Ｈ and V Ｌ and V Ｈ comprises an HC-CDR1 comprising the amino acid sequence SEQ ID NO: 2, an HC-CDR2 comprising the amino acid sequence SEQ ID NO: 161, and an HC-CDR3 comprising the amino acid sequence SEQ ID NO: 6, Ｌ comprises an LC-CDR1 comprising the amino acid sequence SEQ ID NO: 8, an LC-CDR2 comprising the amino acid sequence SEQ ID NO: 10, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO: 12; and the second antigen-binding domain is V Ｈ and V Ｌ and V Ｈ comprises an HC-CDR1 comprising the amino acid sequence SEQ ID NO: 52, an HC-CDR2 comprising the amino acid sequence SEQ ID NO: 54, and an HC-CDR3 comprising the amino acid sequence SEQ ID NO: 56, Ｌ comprises an LC-CDR1 comprising the amino acid sequence SEQ ID NO: 162, an LC-CDR2 comprising the amino acid sequence SEQ ID NO: 60, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO: 62; The bispecific antibody according to any one of claims 12 to 13 and 15.

18. a) the first antigen-binding domain comprises an amino acid sequence set forth in any one of SEQ ID NOs: 14 and 34, or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 14 and 34; Ｈ and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 23 and 42 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 23 and 42. Ｌ Including, and the second antigen-binding domain comprises an amino acid sequence set forth in any one of SEQ ID NOs: 64 and 81 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 64 and 81. Ｈ and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 74 and 90 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 74 and 90. Ｌ Including, b) the first antigen-binding domain comprises an amino acid sequence set forth in any one of SEQ ID NOs: 14 and 34 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 14 and 34; Ｈ and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 24 and 43 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 24 and 43. Ｌ Including, and the second antigen-binding domain comprises an amino acid sequence set forth in any one of SEQ ID NOs: 64 and 81 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 64 and 81. Ｈ and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 74 and 90 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 74 and 90. Ｌ Including, c) the first antigen-binding domain comprises an amino acid sequence set forth in any one of SEQ ID NOs: 15 and 35 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 15 and 35; Ｈ and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 28 and 47 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 28 and 47. Ｌ Including, and the second antigen-binding domain comprises an amino acid sequence set forth in any one of SEQ ID NOs: 66 and 82 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 66 and 82. Ｈ and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 76 and 92 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 76 and 92. Ｌ Including, d) the first antigen-binding domain comprises an amino acid sequence set forth in any one of SEQ ID NOs: 16 and 36 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 16 and 36; Ｈ and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 31 and 50 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 31 and 50. Ｌ Including, and the second antigen-binding domain comprises an amino acid sequence set forth in any one of SEQ ID NOs: 66 and 82 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 66 and 82. Ｈ and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 76 and 92 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 76 and 92. Ｌ Including, e) the first antigen-binding domain comprises an amino acid sequence set forth in any one of SEQ ID NOs: 16 and 36 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 16 and 36; Ｈ and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 31 and 50 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 31 and 50. Ｌ Including, and the second antigen-binding domain comprises an amino acid sequence set forth in any one of SEQ ID NOs: 69 and 85 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 69 and 85. Ｈ and V comprising the amino acid sequence set forth in any one of SEQ ID NOs: 79 and 95 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in any one of SEQ ID NOs: 79 and 95. Ｌ Including, f) the first antigen-binding domain comprises the amino acid sequence set forth in SEQ ID NO: 164 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in SEQ ID NO: 164; Ｈ , and V comprising the amino acid sequence set forth in SEQ ID NO: 168 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in SEQ ID NO:

168. Ｌ Including, and the second antigen-binding domain comprises the amino acid sequence set forth in SEQ ID NO: 163 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in SEQ ID NO:

163. Ｈ and V comprising the amino acid sequence set forth in SEQ ID NO: 167 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in SEQ ID NO:

167. Ｌ contains, or g) the first antigen-binding domain comprises the amino acid sequence set forth in SEQ ID NO: 166 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in SEQ ID NO: 166; Ｈ , and V comprising the amino acid sequence set forth in SEQ ID NO: 170 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in SEQ ID NO:

170. Ｌ Including, and the second antigen-binding domain comprises the amino acid sequence set forth in SEQ ID NO: 165 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in SEQ ID NO:

165. Ｈ and V comprising the amino acid sequence set forth in SEQ ID NO: 169 or a variant thereof having at least about 80% sequence identity with the amino acid sequence set forth in SEQ ID NO:

169. Ｌ Including, The bispecific antibody according to any one of claims 12 to 17.

19. comprising an Fc selected from an IgG1, IgG2, IgG3, IgG4, IgA, IgM, IgE, or IgD Fc; A bispecific molecule according to any one of claims 12 to 18.

20. Fc includes Fc variants; 20. The bispecific molecule of claim 19.

21. Fc variants comprise substitutions at one or more of positions 228, 239, 282, 289, 297, 312, 324, 330, 335, 337, 339, 356, 359, 361, 383, 384, 398, 400, 440, 422 and 442, EU numbering; 21. The bispecific molecule of claim 20.

22. The Fc region is glycosylated, A bispecific molecule according to any one of claims 19 to 21.

23. The Fc region is deglycosylated. A bispecific molecule according to any one of claims 19 to 21.

24. the Fc region is hypofucosylated or afucosylated; A bispecific molecule according to any one of claims 19 to 23.

25. The structure is selected from DVD-IgG, Bs4Ab, Hetero H, CrossMab, IgG-(scFv)2, scFv-Fab IgG, etc. The bispecific antibody according to any one of claims 12 to 24.

26. comprising four polypeptide chains, Two of these polypeptide chains are V from the N-terminus to the C-terminus. Ｈ 1-L-V Ｈ 2-C Ｈ 1 structure, provided that V Ｈ 1 is a heavy chain variable region that specifically binds to TRAIL, and V Ｈ 2 is a heavy chain variable region that specifically binds to FasL, L is a linker peptide, and C Ｈ 1 is heavy chain constant region C Ｈ 1 domain, provided that the polypeptide chain is C Ｈ 2 and C Ｈ further comprising an Fc comprising three domains, and The other two polypeptide chains are both V Ｌ 1-L-V Ｌ 2-C Ｌ The structure includes, where V Ｌ 1 is a light chain variable region that specifically binds to TRAIL, and V Ｌ 2 is a light chain variable region that specifically binds to FasL, L is a linker peptide, and C Ｌ is the light chain constant region, A bispecific antibody according to any one of claims 12 to 25.

27. comprising four polypeptide chains, Both polypeptide chains are V Ｈ 1-L-V Ｈ 2-C Ｈ 1 structure, provided that V Ｈ 1 is a heavy chain variable region that specifically binds to FasL, and V Ｈ 2 is a heavy chain variable region that specifically binds to TRAIL, L is a linker peptide, and C Ｈ 1 is heavy chain constant region C Ｈ 1 domain, provided that the polypeptide chain is C Ｈ 2 and C Ｈ further comprising an Fc comprising three domains, and The other two polypeptide chains are both V Ｌ 1-L-V Ｌ 2-C Ｌ The structure includes, where V Ｌ 1 is a light chain variable region that specifically binds to FasL, and V Ｌ 2 is a light chain variable region that specifically binds to TRAIL, L is a linker peptide, and C Ｌ is the light chain constant region, A bispecific antibody according to any one of claims 12 to 25.

28. a) the amino acid sequence SEQ ID NO: 104 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 104, and / or the amino acid sequence SEQ ID NO: 105 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 105; b) the amino acid sequence SEQ ID NO: 104 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 104, and / or the amino acid sequence SEQ ID NO: 106 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 106; c) the amino acid sequence SEQ ID NO: 107 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 107, and / or the amino acid sequence SEQ ID NO: 108 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 108; d) the amino acid sequence SEQ ID NO: 107 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 107, and / or the amino acid sequence SEQ ID NO: 109 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 109; e) the amino acid sequence SEQ ID NO: 110 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 110, and / or the amino acid sequence SEQ ID NO:111 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:111; or f) the amino acid sequence SEQ ID NO: 172 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 172, and / or the amino acid sequence SEQ ID NO: 174 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 174, The bispecific antibody according to any one of claims 26 to 27.

29. a) the amino acid sequence SEQ ID NO: 131 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 131, and / or the amino acid sequence SEQ ID NO: 105 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 105; b) the amino acid sequence SEQ ID NO: 131 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 131, and / or the amino acid sequence SEQ ID NO: 106 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 106; c) the amino acid sequence SEQ ID NO: 132 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 132, and / or the amino acid sequence SEQ ID NO: 108 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 108; d) the amino acid sequence SEQ ID NO: 132 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 132, and / or the amino acid sequence SEQ ID NO: 109 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 109; e) the amino acid sequence SEQ ID NO: 133 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 133, and / or the amino acid sequence SEQ ID NO:111 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:111; or f) the amino acid sequence SEQ ID NO: 176 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 176, and / or the amino acid sequence SEQ ID NO: 174 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 174, The bispecific antibody according to any one of claims 26 to 27.

30. comprising four polypeptide chains, Two polypeptide chains are V from N-terminus to C-terminus Ｈ 1-C Ｈ 1-L1-V Ｈ 2-L3-V Ｌ 2 structure or V Ｈ 1-C Ｈ 1-L1-V Ｌ 2-L3-V Ｈ 2 structure, provided that V Ｈ 1 is a heavy chain variable region that specifically binds to TRAIL, and V Ｈ 2 is a heavy chain variable region that specifically binds to FasL, and V Ｌ 2 is a light chain variable region that specifically binds to FasL, L1 and L3 are linker peptides, and C Ｈ 1 is heavy chain constant region C Ｈ 1 domain, provided that the polypeptide chain is C Ｈ 2 and C Ｈ further comprising an Fc comprising three domains, and The other two polypeptide chains are V from N-terminus to C-terminus Ｌ 1-C Ｌ The structure includes, where V Ｌ 1 is a light chain variable region that specifically binds to TRAIL, and C Ｌ is the light chain constant region, A bispecific antibody according to any one of claims 12 to 25.

31. comprising four polypeptide chains, Two polypeptide chains are V from N-terminus to C-terminus Ｈ 1-C Ｈ 1-L1-V Ｈ 2-L3-V Ｌ 2 structure or V Ｈ 1-C Ｈ 1-L1-V Ｌ 2-L3-V Ｈ 2 structure, provided that V Ｈ 1 is a heavy chain variable region that specifically binds to FasL, and V Ｈ 2 is a heavy chain variable region that specifically binds to TRAIL, and V Ｌ 2 is a light chain variable region that specifically binds to TRAIL, L1 and L3 are linker peptides, and C Ｈ 1 is heavy chain constant region C Ｈ 1 domain, provided that the polypeptide chain is C Ｈ 2 and C Ｈ further comprising an Fc comprising three domains, and The other two polypeptide chains are V from N-terminus to C-terminus Ｌ 1-C Ｌ structure, but V Ｌ 1 is a light chain variable region that specifically binds to FasL, and C Ｌ is the light chain constant region, A bispecific antibody according to any one of claims 12 to 25.

32. a) the amino acid sequence SEQ ID NO: 112 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 112, and / or the amino acid sequence SEQ ID NO: 113 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 113; b) the amino acid sequence SEQ ID NO: 114 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 114, and / or the amino acid sequence SEQ ID NO: 115 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 115; c) the amino acid sequence SEQ ID NO: 116 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 116, and / or the amino acid sequence SEQ ID NO: 119 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 119; d) the amino acid sequence SEQ ID NO: 117 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 117, and / or the amino acid sequence SEQ ID NO: 119 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 119; e) the amino acid sequence SEQ ID NO: 118 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 118, and / or the amino acid sequence SEQ ID NO: 119 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 119; f) the amino acid sequence SEQ ID NO: 120 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 120, and / or the amino acid sequence SEQ ID NO: 121 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 121; g) the amino acid sequence SEQ ID NO: 120 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 120, and / or the amino acid sequence SEQ ID NO: 122 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 122; h) the amino acid sequence SEQ ID NO: 123 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 123, and / or the amino acid sequence SEQ ID NO: 124 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 124, or i) the amino acid sequence SEQ ID NO: 171 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 171, and / or the amino acid sequence SEQ ID NO: 173 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 173; The bispecific antibody according to any one of claims 30 to 31.

33. a) the amino acid sequence SEQ ID NO: 134 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 134, and / or the amino acid sequence SEQ ID NO: 113 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 113; b) the amino acid sequence SEQ ID NO: 135 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 135, and / or the amino acid sequence SEQ ID NO: 113 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 113; c) the amino acid sequence SEQ ID NO: 136 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 136, and / or the amino acid sequence SEQ ID NO: 115 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 115; d) the amino acid sequence SEQ ID NO: 137 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 137, and / or the amino acid sequence SEQ ID NO: 115 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 115; e) the amino acid sequence SEQ ID NO: 138 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 138, and / or the amino acid sequence SEQ ID NO: 119 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 119; f) the amino acid sequence SEQ ID NO: 139 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 139, and / or the amino acid sequence SEQ ID NO: 119 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 119; g) the amino acid sequence SEQ ID NO: 140 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 140, and / or the amino acid sequence SEQ ID NO: 119 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 119; h) the amino acid sequence SEQ ID NO: 141 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 141, and / or the amino acid sequence SEQ ID NO: 121 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 121; i) the amino acid sequence SEQ ID NO: 141 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 141, and / or the amino acid sequence SEQ ID NO: 122 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 122; j) the amino acid sequence SEQ ID NO: 142 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 142, and / or the amino acid sequence SEQ ID NO: 124 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 124, or k) comprising the amino acid sequence SEQ ID NO: 175 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 175, and / or the amino acid sequence SEQ ID NO: 173 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 173; The bispecific antibody according to any one of claims 30 to 31.

34. comprising four polypeptide chains, One of the polypeptide chains is V from the N-terminus to the C-terminus. Ｈ 1-C Ｈ 1 structure, provided that V Ｈ 1 is a heavy chain variable region that specifically binds to TRAIL, and C Ｈ 1 is heavy chain constant region C Ｈ 1 domain, provided that the polypeptide chain is C Ｈ 2 and C Ｈ further comprising an Fc comprising three domains, and A single polypeptide chain is V from the N-terminus to the C-terminus. Ｌ 1-C Ｌ , where V Ｌ 1 is a light chain variable region that specifically binds to TRAIL, and C Ｌ is the light chain constant region, and A single polypeptide chain is V from the N-terminus to the C-terminus. Ｈ 2-C Ｌ , where V Ｈ 2 is a heavy chain variable region that specifically binds to FasL, and C Ｌ is a light chain constant region, provided that said polypeptide chain is C Ｈ 2 and C Ｈ further comprising an Fc comprising three domains, and A single polypeptide chain is V from the N-terminus to the C-terminus. Ｌ 2-C Ｈ 1, provided that V Ｌ 2 is a light chain variable region that specifically binds to FasL, and C Ｈ 1 is heavy chain constant region C Ｈ One domain, A bispecific antibody according to any one of claims 12 to 25.

35. comprising four polypeptide chains, A single polypeptide chain is V from the N-terminus to the C-terminus. Ｈ 1-C Ｈ 1 structure, provided that V Ｈ 1 is a heavy chain variable region that specifically binds to FasL, and C Ｈ 1 is heavy chain constant region C Ｈ 1 domain, provided that the polypeptide chain is C Ｈ 2 and C Ｈ further comprising an Fc comprising three domains, and A single polypeptide chain is V from the N-terminus to the C-terminus. Ｌ 1-C Ｌ , where V Ｌ 1 is a light chain variable region that specifically binds to FasL, and C Ｌ is the light chain constant region, and A single polypeptide chain is V from the N-terminus to the C-terminus. Ｈ 2-C Ｌ , where V Ｈ 2 is a heavy chain variable region that specifically binds to TRAIL, and C Ｌ is a light chain constant region, provided that said polypeptide chain is C Ｈ 2 and C Ｈ further comprising an Fc comprising three domains, and A single polypeptide chain is V from the N-terminus to the C-terminus. Ｌ 2-C Ｈ 1, provided that V Ｌ 2 is a light chain variable region that specifically binds to TRAIL, and C Ｈ 1 is heavy chain constant region C Ｈ One domain, A bispecific antibody according to any one of claims 12 to 25.

36. a) the amino acid sequence SEQ ID NO: 125 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 125, and / or the amino acid sequence SEQ ID NO: 126 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 126, and / or the amino acid sequence SEQ ID NO: 127 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 127, and / or the amino acid sequence SEQ ID NO: 129 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 129; or b) the amino acid sequence SEQ ID NO: 125 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 125, and / or the amino acid sequence SEQ ID NO: 130 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 130, and / or the amino acid sequence SEQ ID NO: 128 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 128, and / or the amino acid sequence SEQ ID NO: 129 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 129, A bispecific antibody according to any one of claims 34 to 35.

37. a) the amino acid sequence SEQ ID NO: 143 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 143, and / or the amino acid sequence SEQ ID NO: 126 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 126, and / or the amino acid sequence SEQ ID NO: 144 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 144, and / or the amino acid sequence SEQ ID NO: 129 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 129; or b) the amino acid sequence SEQ ID NO: 145 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 145, and / or the amino acid sequence SEQ ID NO: 130 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 130, and / or the amino acid sequence SEQ ID NO: 146 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 146, and / or the amino acid sequence SEQ ID NO: 129 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 129, A bispecific antibody according to any one of claims 34 to 35.

38. Encoding an antibody or antigen-binding fragment that specifically binds to TRAIL according to any one of claims 1 to 11, or a bispecific antibody according to any one of claims 12 to 37. Nucleic acid molecule.

39. 39. The nucleic acid molecule of claim 38, vector.

40. The antibody or antigen-binding fragment that specifically binds to TRAIL according to any one of claims 1 to 11, or the bispecific antibody according to any one of claims 12 to 37, the nucleic acid molecule according to claim 38, or the vector according to claim 39. Isolated host cells.

41. A method for preparing an antibody or antigen-binding fragment that specifically binds to TRAIL according to any one of claims 1 to 11, or a bispecific antibody according to any one of claims 12 to 37, comprising: A) culturing the host cell of claim 40 under conditions that allow for effective expression of the antibody; b) obtaining the expressed antibody from the host cell; method.

42. An antibody or antigen-binding fragment that specifically binds to TRAIL according to any one of claims 1 to 11, a bispecific antibody according to any one of claims 12 to 37, a nucleic acid molecule according to claim 38, a vector according to claim 39, an isolated host cell according to claim 40, or an antibody prepared by the method according to claim 41, and a pharmaceutically acceptable vector or auxiliary material. Pharmaceutical compositions.

43. 1. A method of treating a disease or condition in an individual in need thereof, comprising:

40. A method for treating TRAIL comprising administering to an individual an effective amount of an antibody or antigen-binding fragment thereof that specifically binds to TRAIL according to any one of claims 1 to 11, a bispecific antibody according to any one of claims 12 to 37, a nucleic acid molecule according to claim 38, a vector according to claim 39, an isolated host cell according to claim 40, or an antibody prepared by the method according to claim 41, or a pharmaceutical composition according to claim 42. method.

44. A pharmaceutical composition comprising an antibody or antigen-binding fragment that specifically binds to TRAIL and an antibody or antigen-binding fragment that specifically binds to FasL, wherein the antibody or antigen-binding fragment that specifically binds to TRAIL is a) V Ｈ or the V Ｈ and mutants of V Ｌ or the V Ｌ and a variant of The V Ｈ comprises an HC-CDR1 comprising the amino acid sequence SEQ ID NO: 1, an HC-CDR2 comprising the amino acid sequence SEQ ID NO: 3, and an HC-CDR3 comprising the amino acid sequence SEQ ID NO: 5; The V Ｈ wherein the variant comprises at most about five amino acid substitutions in its HC-CDRs, The V Ｌ comprises an LC-CDR1 comprising the amino acid sequence SEQ ID NO: 7, an LC-CDR2 comprising the amino acid sequence SEQ ID NO: 9, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO: 11; The V Ｌ The variant of comprises at most about five amino acid substitutions in its LC-CDRs, or b) V Ｈ or the V Ｈ and mutants of V Ｌ or the V Ｌ and a variant of The V Ｈ comprises an HC-CDR1 comprising the amino acid sequence SEQ ID NO: 2, an HC-CDR2 comprising the amino acid sequence SEQ ID NO: 4, and an HC-CDR3 comprising the amino acid sequence SEQ ID NO: 6; The V Ｈ wherein the variant comprises at most about five amino acid substitutions in its HC-CDRs, The V Ｌ comprises an LC-CDR1 comprising the amino acid sequence SEQ ID NO: 8, an LC-CDR2 comprising the amino acid sequence SEQ ID NO: 10, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO: 12; The V Ｌ The variant of comprises at most about five amino acid substitutions in its LC-CDRs, Pharmaceutical compositions.

45. 1. A method for treating and / or preventing a disease or condition in an individual in need thereof, comprising administering to the individual an effective amount of an antibody or antigen-binding fragment that specifically binds to TRAIL and an antibody or antigen-binding fragment that specifically binds to FasL, or a pharmaceutical composition comprising said antibody or antigen-binding fragment that specifically binds to TRAIL and said antibody or antigen-binding fragment that specifically binds to FasL, The antibody or antigen-binding fragment that specifically binds to TRAIL is a) V Ｈ or the V Ｈ and mutants of V Ｌ or the V Ｌ and a variant of The V Ｈ comprises an HC-CDR1 comprising the amino acid sequence SEQ ID NO: 1, an HC-CDR2 comprising the amino acid sequence SEQ ID NO: 3, and an HC-CDR3 comprising the amino acid sequence SEQ ID NO: 5; The V Ｈ wherein the variant comprises at most about five amino acid substitutions in its HC-CDRs, The V Ｌ comprises an LC-CDR1 comprising the amino acid sequence SEQ ID NO: 7, an LC-CDR2 comprising the amino acid sequence SEQ ID NO: 9, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO: 11; The V Ｌ The variant of comprises at most about five amino acid substitutions in its LC-CDRs, or b) V Ｈ or the V Ｈ and mutants of V Ｌ or the V Ｌ and a variant of The V Ｈ comprises an HC-CDR1 comprising the amino acid sequence SEQ ID NO: 2, an HC-CDR2 comprising the amino acid sequence SEQ ID NO: 4, and an HC-CDR3 comprising the amino acid sequence SEQ ID NO: 6; The V Ｈ wherein the variant comprises at most about five amino acid substitutions in its HC-CDRs, The V Ｌ comprises an LC-CDR1 comprising the amino acid sequence SEQ ID NO: 8, an LC-CDR2 comprising the amino acid sequence SEQ ID NO: 10, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO: 12; The V Ｌ The variant of comprises at most about five amino acid substitutions in its LC-CDRs, method.

46. The antibody or antigen-binding fragment that specifically binds to TRAIL is (i) a V comprising the amino acid sequence SEQ ID NO: 13 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO: 13; Ｈ and V comprising the amino acid sequence SEQ ID NO: 22 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

22. Ｌ , (ii) V comprising the amino acid sequence SEQ ID NO: 14 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

14. Ｈ and V comprising the amino acid sequence SEQ ID NO: 23 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

23. Ｌ , (iii) V comprising the amino acid sequence SEQ ID NO: 14 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

14. Ｈ and V comprising the amino acid sequence SEQ ID NO: 24 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

24. Ｌ , (iv) V comprising the amino acid sequence SEQ ID NO: 15 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

15. Ｈ and V comprising the amino acid sequence SEQ ID NO: 28 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

28. Ｌ , (v) V comprising the amino acid sequence SEQ ID NO: 20 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

20. Ｈ and V comprising the amino acid sequence SEQ ID NO: 30 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

30. Ｌ ,or (vi) V comprising the amino acid sequence SEQ ID NO: 16 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

16. Ｈ and V comprising the amino acid sequence SEQ ID NO: 31 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

31. Ｌ , including 46. ​​The pharmaceutical composition of claim 44, or the method of claim 45.

47. The antibody or antigen-binding fragment that specifically binds to FasL is a) V Ｈ or the V Ｈ and mutants of V Ｌ or the V Ｌ and a variant of The V Ｈ comprises an HC-CDR1 comprising the amino acid sequence SEQ ID NO: 51, an HC-CDR2 comprising the amino acid sequence SEQ ID NO: 53, and an HC-CDR3 comprising the amino acid sequence SEQ ID NO: 55; The V Ｈ wherein the variant comprises at most about five amino acid substitutions in its HC-CDRs, The V Ｌ comprises an LC-CDR1 comprising the amino acid sequence SEQ ID NO: 57, an LC-CDR2 comprising the amino acid sequence SEQ ID NO: 59, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO: 61; The V Ｌ The variant of comprises at most about five amino acid substitutions in its LC-CDRs, or b) V Ｈ or the V Ｈ and mutants of V Ｌ or the V Ｌ and a variant of The V Ｈ comprises an HC-CDR1 comprising the amino acid sequence SEQ ID NO: 52, an HC-CDR2 comprising the amino acid sequence SEQ ID NO: 54, and an HC-CDR3 comprising the amino acid sequence SEQ ID NO: 56; The V Ｈ wherein the variant comprises at most about five amino acid substitutions in its HC-CDRs, The V Ｌ comprises an LC-CDR1 comprising the amino acid sequence SEQ ID NO: 58, an LC-CDR2 comprising the amino acid sequence SEQ ID NO: 60, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO: 62; The V Ｌ The variant of comprises at most about five amino acid substitutions in its LC-CDRs, A pharmaceutical composition according to any one of claims 44 and 46, or a method according to any one of claims 45 to 46.

48. The antibody or antigen-binding fragment that specifically binds to FasL is (i) a V comprising the amino acid sequence SEQ ID NO:63 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:63; Ｈ and V comprising the amino acid sequence SEQ ID NO: 73 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

73. Ｌ , (ii) V comprising the amino acid sequence SEQ ID NO:64 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

64. Ｈ and V comprising the amino acid sequence SEQ ID NO: 74 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

74. Ｌ , (iii) V comprising the amino acid sequence SEQ ID NO: 66 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

66. Ｈ and V comprising the amino acid sequence SEQ ID NO: 76 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

76. Ｌ , (iv) V comprising the amino acid sequence SEQ ID NO: 70 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

70. Ｈ and V comprising the amino acid sequence SEQ ID NO: 78 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

78. Ｌ ,or (v) V comprising the amino acid sequence SEQ ID NO: 69 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

69. Ｈ and V comprising the amino acid sequence SEQ ID NO: 79 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

79. Ｌ , including A pharmaceutical composition according to any one of claims 44, 46 to 47, or a method according to any one of claims 45 to 47.

49. A pharmaceutical composition comprising an antibody or antigen-binding fragment that specifically binds to TRAIL and an antibody or antigen-binding fragment that specifically binds to FasL, The antibody or antigen-binding fragment that specifically binds to FasL is a) V Ｈ or the V Ｈ and mutants of V Ｌ or the V Ｌ and a variant of The V Ｈ comprises an HC-CDR1 comprising the amino acid sequence SEQ ID NO: 51, an HC-CDR2 comprising the amino acid sequence SEQ ID NO: 53, and an HC-CDR3 comprising the amino acid sequence SEQ ID NO: 55; The V Ｈ wherein the variant comprises at most about five amino acid substitutions in its HC-CDRs, The V Ｌ comprises an LC-CDR1 comprising the amino acid sequence SEQ ID NO: 57, an LC-CDR2 comprising the amino acid sequence SEQ ID NO: 59, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO: 61; The V Ｌ The variant of comprises at most about five amino acid substitutions in its LC-CDRs, or b) V Ｈ or the V Ｈ and mutants of V Ｌ or the V Ｌ and a variant of The V Ｈ comprises an HC-CDR1 comprising the amino acid sequence SEQ ID NO: 52, an HC-CDR2 comprising the amino acid sequence SEQ ID NO: 54, and an HC-CDR3 comprising the amino acid sequence SEQ ID NO: 56; The V Ｈ wherein the variant comprises at most about five amino acid substitutions in its HC-CDRs, The V Ｌ comprises an LC-CDR1 comprising the amino acid sequence SEQ ID NO: 58, an LC-CDR2 comprising the amino acid sequence SEQ ID NO: 60, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO: 62; The V Ｌ The variant of comprises at most about five amino acid substitutions in its LC-CDRs, Pharmaceutical compositions.

50. 1. A method for treating and / or preventing a disease or condition in an individual in need thereof, comprising administering to the individual an effective amount of an antibody or antigen-binding fragment that specifically binds to TRAIL and an antibody or antigen-binding fragment that specifically binds to FasL, or a pharmaceutical composition comprising said antibody or antigen-binding fragment that specifically binds to TRAIL and said antibody or antigen-binding fragment that specifically binds to FasL, The antibody or antigen-binding fragment that specifically binds to FasL is a) V Ｈ or the V Ｈ and mutants of V Ｌ or the V Ｌ and a variant of The V Ｈ comprises an HC-CDR1 comprising the amino acid sequence SEQ ID NO: 51, an HC-CDR2 comprising the amino acid sequence SEQ ID NO: 53, and an HC-CDR3 comprising the amino acid sequence SEQ ID NO: 55; The V Ｈ wherein the variant comprises at most about five amino acid substitutions in its HC-CDRs, The V Ｌ comprises an LC-CDR1 comprising the amino acid sequence SEQ ID NO: 57, an LC-CDR2 comprising the amino acid sequence SEQ ID NO: 59, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO: 61; The V Ｌ The variant of comprises at most about five amino acid substitutions in its LC-CDRs, or b) V Ｈ or the V Ｈ and mutants of V Ｌ or the V Ｌ and a variant of The V Ｈ comprises an HC-CDR1 comprising the amino acid sequence SEQ ID NO: 52, an HC-CDR2 comprising the amino acid sequence SEQ ID NO: 54, and an HC-CDR3 comprising the amino acid sequence SEQ ID NO: 56; The V Ｈ wherein the variant comprises at most about five amino acid substitutions in its HC-CDRs, The V Ｌ comprises an LC-CDR1 comprising the amino acid sequence SEQ ID NO: 58, an LC-CDR2 comprising the amino acid sequence SEQ ID NO: 60, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO: 62; The V Ｌ The variant of comprises at most about five amino acid substitutions in its LC-CDRs, method.

51. The antibody or antigen-binding fragment that specifically binds to FasL is (i) a V comprising the amino acid sequence SEQ ID NO:63 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:63; Ｈ and V comprising the amino acid sequence SEQ ID NO: 73 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

73. Ｌ , (ii) V comprising the amino acid sequence SEQ ID NO:64 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

64. Ｈ and V comprising the amino acid sequence SEQ ID NO: 74 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

74. Ｌ , (iii) V comprising the amino acid sequence SEQ ID NO: 66 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

66. Ｈ and V comprising the amino acid sequence SEQ ID NO: 76 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

76. Ｌ , (iv) V comprising the amino acid sequence SEQ ID NO: 70 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

70. Ｈ and V comprising the amino acid sequence SEQ ID NO: 78 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

78. Ｌ ,or (v) V comprising the amino acid sequence SEQ ID NO: 69 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

69. Ｈ and V comprising the amino acid sequence SEQ ID NO: 79 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

79. Ｌ , including 51. The pharmaceutical composition of claim 49 or the method of claim 50.

52. a) The antibody or antigen-binding fragment that specifically binds to TRAIL is V Ｈ or the V Ｈ and mutants of V Ｌ or the V Ｌ and a variant of said V Ｈ comprises an HC-CDR1 having the amino acid sequence SEQ ID NO: 1, an HC-CDR2 having the amino acid sequence SEQ ID NO: 3, and an HC-CDR3 having the amino acid sequence SEQ ID NO: 5, Ｈ The variant of V contains at most about five amino acid substitutions in its HC-CDRs, Ｌ comprises an LC-CDR1 comprising the amino acid sequence SEQ ID NO: 7, an LC-CDR2 comprising the amino acid sequence SEQ ID NO: 9, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO: 11, Ｌ wherein the variant comprises at most about five amino acid substitutions in its LC-CDRs, and an antibody or antigen-binding fragment that specifically binds to FasL is V Ｈ or the V Ｈ and mutants of V Ｌ or the V Ｌ and a variant of said V Ｈ comprises an HC-CDR1 comprising the amino acid sequence SEQ ID NO: 51, an HC-CDR2 comprising the amino acid sequence SEQ ID NO: 53, and an HC-CDR3 comprising the amino acid sequence SEQ ID NO: 55, Ｈ The variant of V contains at most about five amino acid substitutions in its HC-CDRs, Ｌ comprises an LC-CDR1 comprising the amino acid sequence SEQ ID NO: 57, an LC-CDR2 comprising the amino acid sequence SEQ ID NO: 59, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO: 61, Ｌ wherein the variant comprises at most about five amino acid substitutions in its LC-CDRs, b) The antibody or antigen-binding fragment that specifically binds to TRAIL is V Ｈ or the V Ｈ and mutants of V Ｌ or the V Ｌ and a variant of said V Ｈ comprises an HC-CDR1 having the amino acid sequence SEQ ID NO: 2, an HC-CDR2 having the amino acid sequence SEQ ID NO: 4, and an HC-CDR3 having the amino acid sequence SEQ ID NO: 6, Ｈ The variant of V contains at most about five amino acid substitutions in its HC-CDRs, Ｌ comprises an LC-CDR1 comprising the amino acid sequence SEQ ID NO: 8, an LC-CDR2 comprising the amino acid sequence SEQ ID NO: 10, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO: 12, Ｌ wherein the variant comprises at most about five amino acid substitutions in its LC-CDRs, and an antibody or antigen-binding fragment that specifically binds to FasL is V Ｈ or the V Ｈ and mutants of V Ｌ or the V Ｌ and a variant of said V Ｈ comprises an HC-CDR1 comprising the amino acid sequence SEQ ID NO: 51, an HC-CDR2 comprising the amino acid sequence SEQ ID NO: 53, and an HC-CDR3 comprising the amino acid sequence SEQ ID NO: 55, Ｈ The variant of V contains at most about five amino acid substitutions in its HC-CDRs, Ｌ comprises an LC-CDR1 comprising the amino acid sequence SEQ ID NO: 57, an LC-CDR2 comprising the amino acid sequence SEQ ID NO: 59, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO: 61, Ｌ wherein the variant comprises at most about five amino acid substitutions in its LC-CDRs, c) The antibody or antigen-binding fragment that specifically binds to TRAIL is V Ｈ or the V Ｈ and mutants of V Ｌ or the V Ｌ and a variant of said V Ｈ comprises an HC-CDR1 having the amino acid sequence SEQ ID NO: 1, an HC-CDR2 having the amino acid sequence SEQ ID NO: 3, and an HC-CDR3 having the amino acid sequence SEQ ID NO: 5, Ｈ The variant of V contains at most about five amino acid substitutions in its HC-CDRs, Ｌ comprises an LC-CDR1 comprising the amino acid sequence SEQ ID NO: 7, an LC-CDR2 comprising the amino acid sequence SEQ ID NO: 9, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO: 11, Ｌ wherein the variant comprises at most about five amino acid substitutions in its LC-CDRs, and an antibody or antigen-binding fragment that specifically binds to FasL is V Ｈ or the V Ｈ and mutants of V Ｌ or the V Ｌ and a variant of said V Ｈ comprises an HC-CDR1 comprising the amino acid sequence SEQ ID NO: 52, an HC-CDR2 comprising the amino acid sequence SEQ ID NO: 54, and an HC-CDR3 comprising the amino acid sequence SEQ ID NO: 56, Ｈ The variant of V contains at most about five amino acid substitutions in its HC-CDRs, Ｌ comprises an LC-CDR1 comprising the amino acid sequence SEQ ID NO: 58, an LC-CDR2 comprising the amino acid sequence SEQ ID NO: 60, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO: 62, Ｌ The variant of comprises at most about five amino acid substitutions in its LC-CDRs, or d) The antibody or antigen-binding fragment that specifically binds to TRAIL is V Ｈ or the V Ｈ and mutants of V Ｌ or the V Ｌ and a variant of said V Ｈ comprises an HC-CDR1 having the amino acid sequence SEQ ID NO: 2, an HC-CDR2 having the amino acid sequence SEQ ID NO: 4, and an HC-CDR3 having the amino acid sequence SEQ ID NO: 6, Ｈ The variant of V contains at most about five amino acid substitutions in its HC-CDRs, Ｌ comprises an LC-CDR1 comprising the amino acid sequence SEQ ID NO: 8, an LC-CDR2 comprising the amino acid sequence SEQ ID NO: 10, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO: 12, Ｌ wherein the variant comprises at most about five amino acid substitutions in its LC-CDRs, and an antibody or antigen-binding fragment that specifically binds to FasL is V Ｈ or the V Ｈ and mutants of V Ｌ or the V Ｌ and a variant of said V Ｈ comprises an HC-CDR1 comprising the amino acid sequence SEQ ID NO: 52, an HC-CDR2 comprising the amino acid sequence SEQ ID NO: 54, and an HC-CDR3 comprising the amino acid sequence SEQ ID NO: 56, Ｈ The variant of V contains at most about five amino acid substitutions in its HC-CDRs, Ｌ comprises an LC-CDR1 comprising the amino acid sequence SEQ ID NO: 58, an LC-CDR2 comprising the amino acid sequence SEQ ID NO: 60, and an LC-CDR3 comprising the amino acid sequence SEQ ID NO: 62, Ｌ The variant of comprises at most about five amino acid substitutions in its LC-CDRs, A pharmaceutical composition according to any one of claims 44, 47, 49, a method according to any one of claims 45, 47, 50, or a use according to any one of claims 46-47, 49-50, 56-57.

53. a) The antibody or antigen-binding fragment that specifically binds to TRAIL comprises the amino acid sequence SEQ ID NO: 14 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

14. Ｈ and V comprising the amino acid sequence SEQ ID NO: 23 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

23. Ｌ Including, and an antibody or antigen-binding fragment that specifically binds to FasL, comprising the amino acid sequence SEQ ID NO:64 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

64. Ｈ and V comprising the amino acid sequence SEQ ID NO: 74 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

74. Ｌ Including, b) The antibody or antigen-binding fragment that specifically binds to TRAIL comprises the amino acid sequence SEQ ID NO: 14 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

14. Ｈ and V comprising the amino acid sequence SEQ ID NO: 24 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

24. Ｌ Including, and an antibody or antigen-binding fragment that specifically binds to FasL, comprising the amino acid sequence SEQ ID NO:64 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

64. Ｈ and V comprising the amino acid sequence SEQ ID NO: 74 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

74. Ｌ Including, c) The antibody or antigen-binding fragment that specifically binds to TRAIL comprises the amino acid sequence SEQ ID NO: 15 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

15. Ｈ and V comprising the amino acid sequence SEQ ID NO: 28 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

28. Ｌ Including, and an antibody or antigen-binding fragment that specifically binds to FasL, comprising the amino acid sequence SEQ ID NO:66 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

66. Ｈ and V comprising the amino acid sequence SEQ ID NO: 76 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

76. Ｌ Including, d) The antibody or antigen-binding fragment that specifically binds to TRAIL comprises the amino acid sequence SEQ ID NO: 16 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

16. Ｈ and V comprising the amino acid sequence SEQ ID NO: 31 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

31. Ｌ Including, and an antibody or antigen-binding fragment that specifically binds to FasL, comprising the amino acid sequence SEQ ID NO:66 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

66. Ｈ and V comprising the amino acid sequence SEQ ID NO: 76 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

76. Ｌ Including, e) An antibody or antigen-binding fragment that specifically binds to TRAIL comprises the amino acid sequence SEQ ID NO: 16 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

16. Ｈ and V comprising the amino acid sequence SEQ ID NO: 31 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

31. Ｌ Including, and an antibody or antigen-binding fragment that specifically binds to FasL, comprising the amino acid sequence SEQ ID NO:70 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

70. Ｈ and V comprising the amino acid sequence SEQ ID NO: 78 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

78. Ｌ contains, or f) An antibody or antigen-binding fragment that specifically binds to TRAIL comprises the amino acid sequence SEQ ID NO: 16 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

16. Ｈ and V comprising the amino acid sequence SEQ ID NO: 31 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

31. Ｌ Including, and an antibody or antigen-binding fragment that specifically binds to FasL, comprising the amino acid sequence SEQ ID NO:69 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

69. Ｈ and V comprising the amino acid sequence SEQ ID NO: 79 or a variant thereof having at least about 80% sequence identity with the amino acid sequence SEQ ID NO:

79. Ｌ Including, A pharmaceutical composition according to any one of claims 44, 46 to 49, 51, or a method according to any one of claims 45 to 48, 50 to 51.

54. The antibody or antigen-binding fragment that specifically binds to TRAIL and the antibody or antigen-binding fragment that specifically binds to FasL are administered to the individual simultaneously or sequentially; The method according to any one of claims 45 to 48 and 50 to 53.

55. The disease or condition is an inflammatory disease, autoimmune disease, transplant-related disease, liver disease, neurodegenerative disease or cancer related to the TRAIL and / or FasL signaling pathway; The method according to any one of claims 43, 45 to 48, and 50 to 53.

56. The disease or condition is selected from transplant rejection, graft-versus-host disease, liver damage, pulmonary arterial hypertension, Alzheimer's disease, acute lung injury, acute respiratory distress syndrome, myocardial infarction, myocardial disease, ischemia-reperfusion injury, diabetes, brain injury, spinal cord injury, acute viral hepatitis B, acute viral hepatitis C, chronic hepatitis C, chronic hepatitis B, alcoholic hepatitis, non-alcoholic steatohepatitis, cirrhosis, drug-induced liver injury / liver failure, autoimmune hepatitis, chronic kidney disease, acute kidney disease, diabetic kidney disease, and cancer.

56. The use or method of claim 55.

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