Anti-tissue factor antibody-drug conjugate and related methods

Abstract

Provided herein are antibodies that specifically bind to human tissue factor (TF), anti-TF antibody-drug conjugates (ADCs), and compositions comprising the antibodies or ADCs. Also provided herein are methods of making the antibodies or ADCs, as well as methods of using them, including therapeutic and diagnostic methods. TIFF2022538908000214.tif76151

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit and priority of U.S. Provisional Patent Application No. 62 / 870,644, filed on July 3, 2019, the entire contents of which are incorporated herein by reference.

Background Art

[0002] Blood coagulation is associated with a series of complex processes that lead to blood clotting. Tissue factor (TF) plays an important role in these clotting processes. TF is a cell - surface receptor for serine protease factor VIIa (FVIIa). The TF / FVIIa complex catalyzes the conversion of inactive protease factor X (FX) to active protease factor Xa (FXa). FXa and its co - factor FVa form the prothrombinase complex, which generates thrombin from prothrombin. Thrombin converts soluble fibrinogen into insoluble fibrin strands and catalyzes many other clot - related processes.

[0003] TF is overexpressed in multiple types of solid tumors. TF / FVIIa signaling in cancer can assist angiogenesis, tumor progression, and metastasis.

Summary of the Invention

[0004] This specification provides anti - TF antibody - drug conjugates and related methods.

[0005] This specification provides an antibody - drug conjugate, which is: a. an antigen - binding protein (Ab), that is, an antigen - binding protein that binds to the extracellular domain (SEQ ID NO: 810) of human tissue factor (TF), and the Ab includes VH - CDR1, VH - CDR2, VH - CDR3, VL - CDR1, VL - CDR2, and VL - CDR3, where i. the VH-CDR1 comprises SEQ ID NO: 872, the VH-CDR2 comprises SEQ ID NO: 873, the VH-CDR3 comprises SEQ ID NO: 874, the VL-CDR1 comprises SEQ ID NO: 875, the VL-CDR2 comprises SEQ ID NO: 876, and the VL-CDR3 comprises SEQ ID NO: 877; or ii. the VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 are derived from an antibody designated 25A3; or iii. the VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 are derived from an antibody designated 25A; or iv. the VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 are derived from an antibody designated 25A5; v. the VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 are derived from an antibody designated 25A5-T; or vi. the VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 are derived from an antibody designated 25G1; the antigen-binding protein; and b.Formula IV: comprising one or more linker-toxin moieties represented by TIFF0007709636000001.tif40128; During the ceremony: X is * -C(O)NHCH(CH2(R 2 ))- + where: * and + represent the respective points of attachment shown in formula IV or X is absent; L is a linker; represents the point of attachment of L to the Ab, where L is attached to the Ab via a covalent bond; R 1 teeth, selected from the group consisting of TIFF0007709636000002.tif42128, wherein # and % each represent the respective attachment points shown in Formula IV; and R 2 is phenyl.

[0006] In some embodiments, R 1 is selected from the group consisting of TIFF0007709636000003.tif23128.

[0007] In some embodiments, X is absent.

[0008] In some embodiments, the linker-toxin moiety of Formula IV is of Formula V: represented by TIFF0007709636000004.tif53128.

[0009] In some embodiments, R 1 is selected from the group consisting of TIFF0007709636000005.tif23128.

[0010] In some embodiments, R 1 is selected from the group consisting of TIFF0007709636000006.tif22128.

[0011] In some embodiments, R 1 is TIFF0007709636000007.tif20128.

[0012] In some embodiments, L is a cleavable linker.

[0013] In some embodiments, L is a peptide-containing linker.

[0014] In some embodiments, L is a linker cleavable by a protease.

[0015] In some embodiments, L is a linker selected from one of N-(β-maleimidopropyloxy)-N-hydroxysuccinimide ester (BMPS), N-(ε-maleimidocaproyl-oxy) succinimide ester (EMCS), N-[γ-maleimidobutyryloxy] succinimide ester (GMBS), 1,6-hexane-bis-vinylsulfone (HBVS), succinimidyl 4-(N-maleimidomethyl) cyclohexane-1-carboxy-(6-amidocaproate) (LC-SMCC), m-maleimidobenzoyl-N-hydroxysuccinimide ester (MBS), 4-(4-N-maleimidophenyl) butyric acid hydrazide (MPBH), succinimidyl 3-(bromoacetamido) propionate (SBAP), succinimidyl iodoacetate (SIA), succinimidyl (4-iodoacetyl) aminobenzoate (SIAB), N-succinimidyl-3-(2-pyridyldithio) propionate (SPDP), N-succinimidyl-4-(2-pyridylthio) pentanoate (SPP), succinimidyl 4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC), succinimidyl 4-(p-maleimidophenyl) butyrate (SMPB), succinimidyl 6-[(β-maleimidopropionamide) hexanoate] (SMPH), iminothiolane (IT), sulfo-EMCS, sulfo-GMBS, sulfo-KMUS, sulfo-MBS, sulfo-SIAB, sulfo-SMCC, sulfo-SMPB, and succinimidyl-(4-vinylsulfone) benzoate (SVSB).

[0016] In some embodiments, L is of the formula: including a poly(ethylene) glycol chain of TIFF0007709636000008.tif23128, wherein g is an integer from 1 to 20.

[0017] In some embodiments, g is 3.

[0018] As used herein, formula VI: Provided is an antibody-drug conjugate of TIFF0007709636000009.tif60128, wherein: Ab represents a tissue factor (TF) antibody; n is an integer of 1 or more; X is * -C(O)NHCH(CH2(R 2 ))- + wherein * and + each represent the respective binding points shown in Formula VI, or X is absent; L is a linker; R 1 is selected from the group consisting of TIFF0007709636000010.tif42128, wherein # and % each represent the respective binding points shown in Formula VI; and R 2 is phenyl; and wherein the Ab includes VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, where i. the VH-CDR1 includes SEQ ID NO: 872, the VH-CDR2 includes SEQ ID NO: 873, the VH-CDR3 includes SEQ ID NO: 874, the VL-CDR1 includes SEQ ID NO: 875, the VL-CDR2 includes SEQ ID NO: 876, and the VL-CDR3 includes SEQ ID NO: 877, or ii. the VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 are derived from an antibody named 25A3, iii. the VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 are derived from an antibody named 25A, iv. the VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 are derived from an antibody named 25A5, v. wherein the VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 are derived from an antibody named 25A5-T, or vi. wherein the VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 are derived from an antibody named 25G1.

[0019] In some embodiments, R 1 is selected from the group consisting of TIFF0007709636000011.tif23128.

[0020] In some embodiments, X is absent.

[0021] In some embodiments, R 1 is selected from the group consisting of TIFF0007709636000012.tif22128.

[0022] In some embodiments, R 1 is TIFF0007709636000013.tif20128.

[0023] In some embodiments, L is a cleavable linker.

[0024] In some embodiments, L is a peptide-containing linker.

[0025] In some embodiments, L is a linker cleavable by a protease.

[0026] In some embodiments, L is a linker selected from one of N-(β-maleimidopropyloxy)-N-hydroxysuccinimide ester (BMPS), N-(ε-maleimidocaproyl-oxy) succinimide ester (EMCS), N-[γ-maleimidobutyryloxy] succinimide ester (GMBS), 1,6-hexane-bis-vinylsulfone (HBVS), succinimidyl 4-(N-maleimidomethyl) cyclohexane-1-carboxy-(6-amidocaproate) (LC-SMCC), m-maleimidobenzoyl-N-hydroxysuccinimide ester (MBS), 4-(4-N-maleimidophenyl) butyric acid hydrazide (MPBH), succinimidyl 3-(bromoacetamido) propionate (SBAP), succinimidyl iodoacetate (SIA), succinimidyl (4-iodoacetyl) aminobenzoate (SIAB), N-succinimidyl-3-(2-pyridyldithio) propionate (SPDP), N-succinimidyl-4-(2-pyridylthio) pentanoate (SPP), succinimidyl 4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC), succinimidyl 4-(p-maleimidophenyl) butyrate (SMPB), succinimidyl 6-[(β-maleimidopropionamido) hexanoate] (SMPH), iminothiolane (IT), sulfo-EMCS, sulfo-GMBS, sulfo-KMUS, sulfo-MBS, sulfo-SIAB, sulfo-SMCC, sulfo-SMPB, and succinimidyl-(4-vinylsulfone) benzoate (SVSB).

[0027] In some embodiments, L is of the formula: including a poly(ethylene) glycol chain of TIFF0007709636000014.tif23128, wherein g is an integer from 1 to 20.

[0028] In some embodiments, g is 3.

[0029] In some embodiments, L is of formula VII: It is represented by TIFF0007709636000015.tif28128, wherein: Z represents a functional group that binds to the target group of the TF antibody; D represents a binding point for the amino group shown in Formula VI; Str is a spacer; AA1 and AA2 are each independently an amino acid, where AA1-[AA2] m forms a protease cleavage site; X1 is a self-destructive group; s is an integer selected from 0 and 1; m is an integer selected from the group consisting of 1, 2, 3, and 4; o is an integer selected from 0, 1, and 2.

[0030] In some embodiments, n is an integer selected from the group consisting of 1, 2, 3, 4, and 5.

[0031] In some embodiments, [Str] s is selected from the group consisting of an alkylene, a fatty acid-based spacer, a fatty aliphatic dibasic acid-based spacer, a fatty aliphatic amine-based spacer, and a fatty aliphatic diamine-based spacer.

[0032] In some embodiments, [Str] s is selected from the group consisting of a diglycolic acid-based spacer, a malonic acid-based spacer, a caproic acid-based spacer, and a caproamide-based spacer.

[0033] In some embodiments, [Str] s is selected from the group consisting of a glycine-based spacer, a polyethylene glycol-based spacer, and a monomethoxy polyethylene glycol-based spacer.

[0034] In some embodiments, [Str] s is TIFF0007709636000016.tif22128, and wherein h is an integer from 1 to 20, CC refers to the junction point to AA1; and DD refers to the junction point to Z.

[0035] In some embodiments, [Str] s is selected from TIFF0007709636000017.tif64129, wherein: EE and FF respectively represent the junction points to Z and AA1; R is selected from hydrogen and C1-C6 alkyl; each of the described p is independently an integer from 2 to 10; and each of the described q is independently an integer from 1 to 10.

[0036] In some embodiments, [Str] s is selected from TIFF0007709636000018.tif21153, wherein: EE and FF respectively represent the junction points to Z and AA1; each of the described p is independently an integer from 2 to 10; and each of the described q is independently an integer from 1 to 10.

[0037] In some embodiments, [Str] s is selected from TIFF0007709636000019.tif20128, wherein: EE and FF respectively represent the junction points to Z and AA1; each of the described p is independently an integer from 2 to 6; and q is an integer from 2 to 8.

[0038] In some embodiments, AA1 - [AA2] m is Val - Lys, Ala - Lys, Phe - Lys, Val - Cit, Phe - Cit, Leu - Cit, Ile - Cit, Trp - Cit, Phe - Arg, Ala - Phe, Val - Ala, Met - Lys, Asn - Lys, Ile - Pro, Ile - Val, Asp - Val, His - Val, Met - (D)Lys, Asn - (D)Lys, Val - (D)Asp, NorVal - (D)Asp, Ala - (D)Asp, Me3Lys - Pro, phenyl Gly - (D)Lys, Met - (D)Lys, Asn - (D)Lys, Pro - (D)Lys, Met - (D)Lys, Met - Cit - Val, Gly - Cit - Val, (D)Phe - Phe - Lys, (D)Ala - Phe - Lys, Gly - Phe - Leu - Gly (Accession No. 922) , and Ala - Leu - Ala - Leu (Accession No. 923) is selected from.

[0039] In some embodiments, m is selected from 1, 2, and 3.

[0040] In some embodiments, m is 1.

[0041] In some embodiments, AA1 - [AA2] m is a dipeptide selected from Val - Lys, Ala - Lys, Phe - Lys, Val - Cit, Phe - Cit, Leu - Cit, Ile - Cit, and Trp - Cit.

[0042] In some embodiments, each X1 is independently selected from p - aminobenzyloxycarbonyl (PABC), p - aminobenzyl ether (PABE), and methylated ethylenediamine (MED).

[0043] In some embodiments, s is 1 and h is 3.

[0044] In some embodiments, s is 1.

[0045] In some embodiments, o is 0.

[0046] As used herein, Formula VIII: provides an antibody-drug conjugate comprising a linker-toxin moiety of TIFF0007709636000020.tif48161, wherein ## represents the point of attachment of the linker-toxin moiety to the TF antibody, and the linker-toxin moiety is attached to the TF antibody via a covalent bond.

[0047] As used herein, Formula IX: provides an antibody-drug conjugate of TIFF0007709636000021.tif64145, wherein: Ab is a tissue factor (TF) antibody, where the Ab comprises VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, where i. the VH-CDR1 comprises SEQ ID NO: 872, the VH-CDR2 comprises SEQ ID NO: 873, the VH-CDR3 comprises SEQ ID NO: 874, the VL-CDR1 comprises SEQ ID NO: 875, the VL-CDR2 comprises SEQ ID NO: 876, and the VL-CDR3 comprises SEQ ID NO: 877, or ii. the VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 are derived from an antibody named 25A3, iii. the VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 are derived from an antibody named 25A, iv. the VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 are derived from an antibody named 25A5, v. where the VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 are derived from an antibody named 25A5-T, or vi. where the VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 are derived from an antibody named 25G1, n is an integer of 1 or more, and the succinimidyl group is bound to the Ab via a covalent bond.

[0048] In some embodiments, n is selected from the group consisting of 1, 2, 3, 4, and 5.

[0049] In some embodiments, n is selected from the group consisting of 2, 3, and 4.

[0050] As used herein, formula X: provides an antibody-drug conjugate comprising a linker represented by TIFF0007709636000022.tif47128, wherein: ## is a binding point to the antibody, and the succinimidyl group is bound to the antibody via a covalent bond; Y is one or more additional linker elements or is absent; and D1 is a binding point to a cytotoxic agent, and wherein the Ab comprises VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, where i. the VH-CDR1 comprises SEQ ID NO: 872, the VH-CDR2 comprises SEQ ID NO: 873, the VH-CDR3 comprises SEQ ID NO: 874, the VL-CDR1 comprises SEQ ID NO: 875, the VL-CDR2 comprises SEQ ID NO: 876, and the VL-CDR3 comprises SEQ ID NO: 877, or ii. the VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 are derived from an antibody named 25A3, or iii. whether the VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 are derived from an antibody named 25A, iv. whether the VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 are derived from an antibody named 25A5, v. whether the VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 are derived from an antibody named 25A5-T, or vi. the VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 are derived from an antibody named 25G1.

[0051] As used herein, Formula XI: provides an antibody-drug conjugate comprising a linker represented by TIFF0007709636000023.tif47128, wherein: ## is a binding site for the antibody, and the succinimidyl group is bound to the antibody via a covalent bond; Y is one or more additional linker elements or is absent; and D1 is a binding site for a cytotoxic agent, and wherein the Ab comprises VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, where i. the VH-CDR1 comprises SEQ ID NO: 872, the VH-CDR2 comprises SEQ ID NO: 873, the VH-CDR3 comprises SEQ ID NO: 874, the VL-CDR1 comprises SEQ ID NO: 875, the VL-CDR2 comprises SEQ ID NO: 876, and the VL-CDR3 comprises SEQ ID NO: 877, or ii. the VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 are derived from an antibody named 25A3, iii. whether the VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 are derived from an antibody named 25A, iv. whether the VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 are derived from an antibody named 25A5, v. whether the VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 are derived from an antibody named 25A5-T, or vi. the VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 are derived from an antibody named 25G1.

[0052] In some embodiments, the cytotoxic agent is selected from the group consisting of a diagnostic agent, a metal chelating agent, an enzyme, a fluorescent compound, a bioluminescent compound, or a chemiluminescent compound.

[0053] In some embodiments, the cytotoxic agent is a cytotoxic payload having an improved safety profile.

[0054] In some embodiments, the Ab is: a. a VH sequence of SEQ ID NO: 868 and a VL sequence of SEQ ID NO: 869, b. a VH sequence of SEQ ID NO: 151 and a VL sequence of SEQ ID NO: 152, c. a VH sequence of SEQ ID NO: 113 and a VL sequence of SEQ ID NO: 114, d. a VH sequence of SEQ ID NO: 189 and a VL sequence of SEQ ID NO: 190, e. a VH sequence of SEQ ID NO: 836 and a VL sequence of SEQ ID NO: 837, or f. includes a VH sequence of SEQ ID NO: 265 and a VL sequence of SEQ ID NO: 266.

[0055] In some embodiments, the Ab is a. a heavy chain sequence: QVQLVQSGAEVKKPGASVKVSCKASGYTFDx[V / A]YGISWVRQAPGQGLEWMGWIAPYx[N / S]GNTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARDAGTYSPFGYGMDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (Accession No. 924) and Light chain sequence: DIQMTQSPSTLSASVGDRVTITCx[R / Q]ASx[Q / E]SIx[S / N]x[S / N]WLAWYQQKPGKAPKLLIYKAx[S / Y]x[S / N]LEx[S / Y]GVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQx[Q / L]FQx[S / K]LPPFTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (Accession No. 925) , b. Heavy chain sequence: QVQLVQSGAEVKKPGASVKVSCKASGYTFDVYGISWVRQAPGQGLEWMGWIAPYSGNTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARDAGTYSPFGYGMDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (Accession No. 926) and Light chain sequence: DIQMTQSPSTLSASVGDRVTITCQASQSINNWLAWYQQKPGKAPKLLIYKAYNLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQLFQSLPPFTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (Accession No. 927) , c. Heavy chain sequence: QVQLVQSGAEVKKPGASVKVSCKASGYTFDVYGISWVRQAPGQGLEWMGWIAPYSGNTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARDAGTYSPFGYGMDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (Accession No. 926) and Light chain sequence: DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYKASSLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQFQSLPPFTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (Accession No. 928) , d. Heavy chain sequence: QVQLVQSGAEVKKPGASVKVSCKASGYTFDAYGISWVRQAPGQGLEWMGWIAPYSGNTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARDAGTYSPFGYGMDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (Accession No. 929) and Light chain sequence: DIQMTQSPSTLSASVGDRVTITCRASESISNWLAWYQQKPGKAPKLLIYKAYSLEYGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQFQKLPPFTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (Accession No. 930) , e. Heavy chain sequence: QVQLVQSGAEVKKPGASVKVSCKASGYTFRSYGISWVRQAPGQGLEWMGWVAPYSGNTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARDAGTYSPYGYGMDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (Accession No. 931) and Light chain sequence: DIQMTQSPSTLSASVGDRVTITCRASHSIDSWLAWYQQKPGKAPKLLIYKASYLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQLFQSLPPFTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (Accession No. 932) or f. Heavy chain sequence: QVQLVQSGAEVKKPGASVKVSCKASGYTFDVYGISWVRQAPGQGLEWMGWIAPYSGNTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARDAGTYSPFGYGMDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (Accession No. 926) and Light chain sequence: DIQMTQSPSTLSASVGDRVTITCRASESISNWLAWYQQKPGKAPKLLIYKAYSLEYGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQFQKLPPFTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (Accession No. 930) comprises

[0056] In this specification, formula IX: provides an antibody-drug conjugate of TIFF0007709636000024.tif64145 wherein: Ab is a tissue factor (TF) antibody, and the Ab comprises VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 derived from the antibody named 25A3; and n is an integer of 1 or more.

[0057] In some embodiments, n is selected from the group consisting of 1, 2, 3, 4, and 5.

[0058] In some embodiments, n is selected from the group consisting of 2, 3, and 4.

[0059] In some embodiments, Ab comprises a VH sequence of SEQ ID NO: 151 and a VL sequence of SEQ ID NO: 152.

[0060] In some embodiments, Ab is TIFF0007709636000025.tif55160 (Accession No. 926) a complete heavy chain sequence that is TIFF0007709636000026.tif26160 (Accession No. 927) and a light chain sequence that is

[0061] As used herein, Formula IX: provides an antibody-drug conjugate of TIFF0007709636000027.tif64145, wherein: Ab is a tissue factor (TF) antibody, and the Ab comprises a heavy chain sequence TIFF0007709636000028.tif63147 (Accession No. 926) and a light chain sequence TIFF0007709636000029.tif33139 (Accession No. 927) and n is an integer of 1 or more.

[0062] In some embodiments, n is selected from the group consisting of 1, 2, 3, 4, and 5.

[0063] In some embodiments, n is selected from the group consisting of 2, 3, and 4.

[0064] As used herein, an antibody (Ab) and the following structure: Provided is an antibody-drug conjugate comprising one or more linker-toxins of TIFF0007709636000030.tif36157, wherein: Ab is a tissue factor (TF) antibody, and the Ab comprises VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 derived from the antibody named 25A3; one or more of the linker-toxins are bound to the Ab via a covalent bond; and ## represents the binding point of the linker-toxin to the Ab.

[0065] Provided herein is an antibody-drug conjugate composition comprising the antibody-drug conjugate disclosed herein, the composition comprising various drug-antibody ratio (DAR) species, and the average DAR of the composition being 2 to 4.

[0066] Provided herein is an antibody-drug conjugate comprising an antibody (Ab) and one or more linker-toxins of the following structure: TIFF0007709636000031.tif36157, wherein: Ab is a tissue factor (TF) antibody, and the Ab comprises a heavy chain sequence: TIFF0007709636000032.tif63147 (Accession No. 926) and a light chain sequence: TIFF0007709636000033.tif31138 (Accession No. 927) and one or more of the linker-toxins are bound to the Ab via a covalent bond; and ## represents the binding point of the linker-toxin to the Ab.

[0067] Provided herein is an antibody-drug conjugate composition comprising the antibody-drug conjugate disclosed herein, the composition comprising various drug-antibody ratio (DAR) species, and the average DAR of the composition being 2 to 4.

[0068] In some embodiments, Ab is multispecific.

[0069] In some embodiments, Ab is a Fab, Fab’, F(ab’)2, Fv, scFv, (scFv)2, single-chain antibody molecule, bispecific variable domain antibody, single variable domain antibody, linear antibody, or V domain antibody.

[0070] In some embodiments, the antibody comprises a scaffold, optionally the scaffold is Fc, and optionally human Fc.

[0071] In some embodiments, the antibody comprises a heavy chain constant region of a class selected from IgG, IgA, IgD, IgE, and IgM.

[0072] In some embodiments, the antibody comprises a heavy chain constant region of class IgG, and the heavy chain constant region is derived from a subclass selected from IgG1, IgG2, IgG3, and IgG4.

[0073] In some embodiments, the antibody comprises a heavy chain constant region of IgG1.

[0074] In some embodiments, Fc comprises one or more modifications that result in an extended half-life, enhanced antibody-dependent cellular cytotoxicity (ADCC), enhanced antibody-dependent cellular phagocytosis (ADCP), enhanced complement-dependent cytotoxicity (CDC), or reduced effector function as compared to Fc without one or more such modifications.

[0075] Provided herein is a pharmaceutical composition comprising an antibody-drug conjugate disclosed herein and a pharmaceutically acceptable carrier.

[0076] Provided herein is a method of treating or preventing a disease or condition in a subject in need thereof, the method comprising administering to the subject an effective amount of an antibody-drug conjugate disclosed herein or a pharmaceutical composition disclosed herein.

[0077] In some embodiments, the disease or condition is cancer.

[0078] In some embodiments, the cancer is selected from the group consisting of head and neck cancer, ovarian cancer, gastric cancer, esophageal cancer, cervical cancer, prostate cancer, pancreatic cancer, estrogen receptor negative (ER-) breast cancer, progesterone receptor negative (PR-) breast cancer, HER2 negative (HER2-) triple negative breast cancer, glioblastoma, lung cancer, bladder cancer, melanoma, and kidney cancer.

[0079] In some embodiments, the disease or condition is associated with angiogenesis.

[0080] In some embodiments, the disease or condition associated with angiogenesis is cancer.

[0081] In some embodiments, the disease or condition is associated with vascular inflammation.

[0082] In some embodiments, the method further comprises administering one or more additional therapeutic agents to the subject.

[0083] In some embodiments, the composition further comprises one or more additional therapeutic agents.

[0084] In some embodiments, the additional therapeutic agents are formulated in different pharmaceutical compositions.

[0085] In some embodiments, the additional therapeutic agent is administered before the composition.

[0086] In some embodiments, the additional therapeutic agent is administered after the composition.

[0087] In some embodiments, the additional therapeutic agent is administered simultaneously with the composition.

[0088] In some embodiments, the subject is a human subject.

[0089] This specification provides a method (process) for preparing an antibody-drug conjugate, the method comprising: (A) reacting a nucleophilic or electrophilic group in an antigen-binding protein (Ab) that binds to the extracellular domain (SEQ ID NO: 810) of human tissue factor (TF) with a bifunctional linker to form an Ab-linker intermediate, and reacting the Ab-linker intermediate with the -NH2 group of a compound of general formula I: TIFF0007709636000034.tif50128 to provide an antibody-drug conjugate, wherein: In the formula: X is * -C(O)NHCH(CH2(R 2 ))- + wherein, * and + represent the respective binding points shown in formula I, or X is absent; R 1 is TIFF0007709636000035.tif42128 selected from the group consisting of, wherein # and % represent the respective binding points shown in formula I; and R 2 is phenyl, the step; or (B) reacting the -NH2 group of a compound of general formula I with a bifunctional linker to form a linker-toxin intermediate, and reacting the linker-toxin intermediate with a nucleophilic or electrophilic group in an antigen-binding protein (Ab) that binds to the extracellular domain (SEQ ID NO: 810) of human tissue factor (TF) to provide an antibody-drug conjugate comprising, wherein in (A) or (B), (a) the Ab comprises VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, wherein i. the VH-CDR1 comprises SEQ ID NO: 872, the VH-CDR2 comprises SEQ ID NO: 873, the VH-CDR3 comprises SEQ ID NO: 874, the VL-CDR1 comprises SEQ ID NO: 875, the VL-CDR2 comprises SEQ ID NO: 876, and the VL-CDR3 comprises SEQ ID NO: 877, or ii. whether the VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 are derived from an antibody named 25A3, iii. whether the VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 are derived from an antibody named 25A, iv. whether the VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 are derived from an antibody named 25A5, v. whether the VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 are derived from an antibody named 25A5-T, or vi. whether the VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 are derived from an antibody named 25G1; and (b) the antibody-drug conjugate comprises one or more moieties represented by Formula IV: TIFF0007709636000036.tif52138, wherein: X is * -C(O)NHCH(CH2(R 2 ))- + and wherein * and + represent the respective attachment points shown in Formula IV, or X is absent; L is a linker; ! represents the attachment point of L to the Ab, where L is attached to the Ab via a covalent bond; R 1 is selected from the group consisting of TIFF0007709636000037.tif42128, wherein # and % represent the respective attachment points shown in Formula IV; and R 2 is phenyl.

[0090] This specification provides a method for preparing an antibody-drug conjugate, the method comprising: (A) reacting a nucleophilic or electrophilic group of an antigen-binding protein (Ab) that binds to the extracellular domain (SEQ ID NO: 810) of human tissue factor (TF) with a first linker element of a bifunctional linker comprising two or more linker elements, and subsequently adding the remaining linker elements sequentially to form an Ab-linker intermediate, the Ab-linker intermediate being reacted with the -NH2 group of a compound of general formula I: TIFF0007709636000038.tif50128 to provide an antibody-drug conjugate, wherein In the formula: X is * -C(O)NHCH(CH2(R 2 ))- + wherein * and + each represent the respective bond points shown in formula I, or X is absent; R 1 is TIFF0007709636000039.tif42128 selected from the group consisting of, wherein # and % each represent the respective bond points shown in formula I; and R 2 is phenyl, the step; or (B) reacting the -NH2 group of a compound of general formula I with a first linker element of a bifunctional linker comprising two or more linker elements, and subsequently adding the remaining linker elements sequentially to form a linker-toxin intermediate, the linker-toxin intermediate being reacted with a nucleophilic or electrophilic group in an antigen-binding protein (Ab) that binds to the extracellular domain (SEQ ID NO: 810) of human tissue factor (TF) to provide an antibody-drug conjugate comprising, wherein in (A) or (B), (a) the Ab comprises VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, wherein i. where the VH-CDR1 contains SEQ ID NO: 872, the VH-CDR2 contains SEQ ID NO: 873, the VH-CDR3 contains SEQ ID NO: 874, the VL-CDR1 contains SEQ ID NO: 875, the VL-CDR2 contains SEQ ID NO: 876, and the VL-CDR3 contains SEQ ID NO: 877, or ii. the VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 are derived from an antibody named 25A3, or iii. the VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 are derived from an antibody named 25A, or iv. the VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 are derived from an antibody named 25A5, or v. the VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 are derived from an antibody named 25A5-T, or vi. the VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 are derived from an antibody named 25G1; and (b) the antibody-drug conjugate comprises one or more moieties represented by Formula IV: TIFF0007709636000040.tif52138 wherein: X is * -C(O)NHCH(CH2(R 2 ))- + wherein * and + represent the respective attachment points shown in Formula IV, or X is absent; L is a linker; ! represents the attachment point of L to the Ab, where L is attached to the Ab via a covalent bond; R 1 is selected from the group consisting of TIFF0007709636000041.tif42128, In the formula, # and % represent the respective bonding points shown in Formula IV; and R 2 is phenyl.

[0091] In some embodiments, the nucleophilic or electrophilic group in the Ab is a thiol or an amine.

[0092] In some embodiments, the method further comprises treating the Ab with a reducing agent to reduce one or more disulfide bonds in the Ab to provide a nucleophilic thiol group.

[0093] In some embodiments, L is represented by TIFF0007709636000042.tif23128, wherein: Z represents a functional group that binds to the target group of the Ab; D represents a bonding point for the amino group shown in Formula X; Str is a spacer; AA1 and AA2 are each independently an amino acid, where AA1-[AA2] m forms a protease cleavage site; X is a self-destructive group; s is an integer selected from 0 and 1; m is an integer selected from the group consisting of 1, 2, 3, and 4; and o is an integer selected from 0, 1, and 2.

[0094] Provided herein is a kit comprising an antibody-drug conjugate disclosed herein or a pharmaceutical composition disclosed herein and instructions for use. [Invention 1001] An antibody-drug conjugate comprising: a. An antigen-binding protein (Ab) that binds to the extracellular domain of human tissue factor (TF) (Accession No. 810), wherein the Ab comprises VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, where i. The VH-CDR1 comprises Accession No. 872, the VH-CDR2 comprises Accession No. 873, the VH-CDR3 comprises Accession No. 874, the VL-CDR1 comprises Accession No. 875, the VL-CDR2 comprises Accession No. 876, and the VL-CDR3 comprises Accession No. 877, or ii. The VH-CDR1, the VH-CDR2, the VH-CDR3, the VL-CDR1, the VL-CDR2, and the VL-CDR3 are derived from an antibody named 25A3, or iii. The VH-CDR1, the VH-CDR2, the VH-CDR3, the VL-CDR1, the VL-CDR2, and the VL-CDR3 are derived from an antibody named 25A, or iv. The VH-CDR1, the VH-CDR2, the VH-CDR3, the VL-CDR1, the VL-CDR2, and the VL-CDR3 are derived from an antibody named 25A5, or v. The VH-CDR1, the VH-CDR2, the VH-CDR3, the VL-CDR1, the VL-CDR2, and the VL-CDR3 are derived from an antibody named 25A5-T, or vi. The VH-CDR1, the VH-CDR2, the VH-CDR3, the VL-CDR1, the VL-CDR2, and the VL-CDR3 are derived from an antibody named 25G1, the antigen-binding protein (Ab); and b. One or more linker-toxin moieties represented by Formula IV: TIFF0007709636000043.tif40128 wherein: X is -C(O)NHCH(CH * wherein, 2 (R 2 ))- + and + represent the respective attachment points shown in Formula IV, or X is absent; * ​ L is a linker; ! represents the attachment point of L to said Ab, where L is attached to said Ab via a covalent bond; R 1 is TIFF0007709636000044.tif42128 selected from the group consisting of wherein # and % represent the respective attachment points shown in Formula IV; and R 2 is phenyl, said linker-toxin moiety. [Inventive Item 1002] R 1 is TIFF0007709636000045.tif23128 an antibody-drug conjugate of Inventive Item 1001 selected from the group consisting of [Inventive Item 1003] an antibody-drug conjugate of Inventive Item 1001 or Inventive Item 1002 in which X is absent. [Inventive Item 1004] said linker-toxin moiety of Formula IV is of Formula V: TIFF0007709636000046.tif53128 an antibody-drug conjugate of any one of Inventive Items 1001 to 1003, represented by [Inventive Item 1005] R 1 is TIFF0007709636000047.tif23128 an antibody-drug conjugate of Inventive Item 1004 selected from the group consisting of [Inventive Item 1006] R 1 is TIFF0007709636000048.tif22128 an antibody-drug conjugate of Inventive Item 1004 or Inventive Item 1005 selected from the group consisting of [Inventive Item 1007] R 1 is TIFF0007709636000049.tif20128 an antibody-drug conjugate of any one of Inventive Items 1004 to 1006, which is [Inventive Item 1008] an antibody-drug conjugate of any of the prior inventive items, wherein L is a cleavable linker. [Inventive Item 1009] an antibody-drug conjugate of any of the prior inventive items, wherein L is a peptide-containing linker. [Inventive Item 1010] an antibody-drug conjugate of any of the prior inventive items, wherein L is a linker cleavable by a protease. [Inventive Item 1011] The antibody-drug conjugate of any one of the present inventions 1001 to 1007, wherein L is a linker selected from one of N-(β-maleimidopropyloxy)-N-hydroxysuccinimide ester (BMPS), N-(ε-maleimidocaproyl- oxy) succinimide ester (EMCS), N-[γ-maleimidobutyryloxy] succinimide ester (GMBS), 1,6-hexane-bis-vinylsulfone (HBVS), succinimidyl 4-(N-maleimidomethyl) cyclohexane-1-carboxy- (6-amidocaproate) (LC-SMCC), m-maleimidobenzoyl-N-hydroxysuccinimide ester (MBS), 4-(4-N-maleimidophenyl) butyric acid hydrazide (MPBH), succinimidyl 3-(bromoacetamido) propionate (SBAP), succinimidyl iodoacetate (SIA), succinimidyl (4-iodoacetyl) aminobenzoate (SIAB), N-succinimidyl-3-(2-pyridyldithio) propionate (SPDP), N-succinimidyl-4-(2-pyridylthio) pentanoate (SPP), succinimidyl 4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC), succinimidyl 4-(p-maleimidophenyl) butyrate (SMPB), succinimidyl 6-[(β-maleimidopropionamide) hexanoate] (SMPH), iminothiolane (IT), sulfo-EMCS, sulfo-GMBS, sulfo-KMUS, sulfo-MBS, sulfo-SIAB, sulfo-SMCC, sulfo-SMPB, and succinimidyl-(4-vinylsulfone) benzoate (SVSB). [The present invention 1012] L contains a poly(ethylene) glycol chain of the formula: TIFF0007709636000050.tif23128 wherein g is an integer from 1 to 20, The antibody-drug conjugate of any one of the present inventions 1001 to 1007. [The present invention 1013] The antibody-drug conjugate of the present invention 1012, wherein g is 3. [The present invention 1014] An antibody-drug conjugate of formula VI: wherein: TIFF0007709636000051.tif60128 Ab represents a tissue factor (TF) antibody; n is an integer of 1 or more; X is -C(O)NHCH(CH wherein * and + represent the respective binding points shown in formula VI, or X is absent; 2 (R 2))- + L is a linker; * is selected from the group consisting of R 1 ​ TIFF0007709636000052.tif42128 ​ In the formula, # and % represent each of the binding points shown in Formula VI; and R 2 is phenyl; and the Ab includes VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, i. the VH-CDR1 includes SEQ ID NO: 872, the VH-CDR2 includes SEQ ID NO: 873, the VH-CDR3 includes SEQ ID NO: 874, the VL-CDR1 includes SEQ ID NO: 875, the VL-CDR2 includes SEQ ID NO: 876, and the VL-CDR3 includes SEQ ID NO: 877, or ii. the VH-CDR1, the VH-CDR2, the VH-CDR3, the VL-CDR1, the VL-CDR2, and the VL-CDR3 are derived from an antibody named 25A3, iii. the VH-CDR1, the VH-CDR2, the VH-CDR3, the VL-CDR1, the VL-CDR2, and the VL-CDR3 are derived from an antibody named 25A, iv. the VH-CDR1, the VH-CDR2, the VH-CDR3, the VL-CDR1, the VL-CDR2, and the VL-CDR3 are derived from an antibody named 25A5, v. the VH-CDR1, the VH-CDR2, the VH-CDR3, the VL-CDR1, the VL-CDR2, and the VL-CDR3 are derived from an antibody named 25A5-T, or vi. the VH-CDR1, the VH-CDR2, the VH-CDR3, the VL-CDR1, the VL-CDR2, and the VL-CDR3 are derived from an antibody named 25G1, the antibody-drug conjugate. [Invention 1015] R 1 is TIFF0007709636000053.tif23128 an antibody-drug conjugate of Invention 1014 selected from the group consisting of. [Invention 1016] An antibody-drug conjugate of Invention 1014 or Invention 1015 in which X is absent. [Invention 1017] R 1 is TIFF0007709636000054.tif22128 an antibody-drug conjugate of Invention 1015 or Invention 1016 selected from the group consisting of. [Invention 1018] R 1 is TIFF0007709636000055.tif20128 an antibody-drug conjugate of any one of Inventions 1015 to 1017 which is. [Invention 1019] An antibody-drug conjugate of any one of Inventions 1016 to 1017 in which L is a cleavable linker. [Invention 1020] An antibody-drug conjugate of any one of Inventions 1014 to 1019 in which L is a peptide-containing linker. [Invention 1021] An antibody-drug conjugate according to any one of aspects 1014 to 1019 of the present invention, wherein L is a linker cleavable by a protease. [Aspect 1022] An antibody-drug conjugate according to any one of aspects 1014 to 1019 of the present invention, wherein L is a linker selected from one of N-(β-maleimidopropyloxy)-N-hydroxysuccinimide ester (BMPS), N-(ε-maleimidocaproyl- oxy)succinimide ester (EMCS), N-[γ-maleimidobutyryloxy]succinimide ester (GMBS), 1,6-hexane-bis-vinylsulfone (HBVS), succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxy-(6-aminocaproate) (LC-SMCC), m-maleimidobenzoyl-N-hydroxysuccinimide ester (MBS), 4-(4-N-maleimidophenyl)butyric acid hydrazide (MPBH), succinimidyl 3-(bromoacetamido)propionate (SBAP), succinimidyl iodoacetate (SIA), succinimidyl (4-iodoacetyl)aminobenzoate (SIAB), N-succinimidyl-3-(2-pyridyldithio)propionate (SPDP), N-succinimidyl-4-(2-pyridylthio)pentanoate (SPP), succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC), succinimidyl 4-(p-maleimidophenyl)butyrate (SMPB), succinimidyl 6-[(β-maleimidopropionamido)hexanoate] (SMPH), iminothiolane (IT), sulfo-EMCS, sulfo-GMBS, sulfo-KMUS, sulfo-MBS, sulfo-SIAB, sulfo-SMCC, sulfo-SMPB, and succinimidyl-(4-vinylsulfone)benzoate (SVSB). [Aspect 1023] L comprises a poly(ethylene) glycol chain of the formula: TIFF0007709636000056.tif23128 wherein g is an integer from 1 to 20, An antibody-drug conjugate according to any one of aspects 1014 to 1019 of the present invention. [Aspect 1024] An antibody-drug conjugate according to aspect 1023, wherein g is 3. [Aspect 1025] L is represented by formula VII: wherein: TIFF0007709636000057.tif27128 Z represents a functional group that binds to the target group of the TF antibody; D represents a point of attachment to the amino group shown in formula VI; ​ ​ Str is a stretcher; AA 1 and AA 2 are each independently an amino acid, where AA 1 -[AA 2 ] m forms a protease cleavage site; X 1 is a self-destructive group; s is an integer selected from 0 and 1; m is an integer selected from the group consisting of 1, 2, 3, and 4; o is an integer selected from 0, 1, and 2, The antibody-drug conjugate of the present invention 1014. [The present invention 1026] The antibody-drug conjugate of the present invention 1025, wherein n is an integer selected from the group consisting of 1, 2, 3, 4, and 5. [The present invention 1027] [Str] s is selected from the group consisting of an alkylene, a fatty acid-based stretcher, an aliphatic dibasic acid-based stretcher, an aliphatic amine-based stretcher, and an aliphatic diamine-based stretcher, for the antibody-drug conjugate of the present invention 1025 or the present invention 1026. [The present invention 1028] [Str]s is selected from the group consisting of a diglycolic acid-based stretcher, a malonic acid-based stretcher, a caproic acid-based stretcher, and a caproamide-based stretcher, for the antibody-drug conjugate of any one of the present inventions 1025 to 1027. [The present invention 1029] [Str] s is selected from the group consisting of a glycine-based stretcher, a polyethylene glycol-based stretcher, and a monomethoxypolyethylene glycol-based stretcher, for the antibody-drug conjugate of the present invention 1025 or the present invention 1026. [The present invention 1030] [Str] s is TIFF0007709636000058.tif22128 wherein in the formula h is an integer from 1 to 20, CC refers to the binding point to AA 1 and; and DD refers to the binding point to Z, for the antibody-drug conjugate of the present invention 1025 or the present invention 1026. [The present invention 1031] [Str] s is TIFF0007709636000059.tif64129 selected from wherein: EE and FF each represent the binding points to Z and AA 1 respectively; R is selected from hydrogen and C 1 -C 6 alkyl; each p as described is independently an integer from 2 to 10; and each q as described is independently an integer from 1 to 10, for the antibody-drug conjugate of the present invention 1025 or the present invention 1026. [The present invention 1032] [Str] s is TIFF0007709636000060.tif21153 selected from the group consisting of wherein: EE and FF each represent the binding points to Z and AA 1 respectively; Each p described is, independently, an integer from 2 to 10; and each q described is, independently, an integer from 1 to 10. An antibody-drug conjugate of the present invention 1025, the present invention 1026, or the present invention 1031. [The present invention 1033] [Str] s is TIFF0007709636000061.tif20128 selected from wherein: EE and FF each represent a bonding point to Z and AA 1 respectively; each p described is, independently, an integer from 2 to 6; and q is an integer from 2 to 8. An antibody-drug conjugate of the present invention 1025, the present invention 1026, the present invention 1031, or the present invention 1032. [The present invention 1034] AA 1 -[AA 2 ] m is selected from Val-Lys, Ala-Lys, Phe-Lys, Val-Cit, Phe-Cit, Leu-Cit, Ile-Cit, Trp-Cit, Phe-Arg, Ala-Phe, Val-Ala, Met-Lys, Asn-Lys, Ile-Pro, Ile-Val, Asp-Val, His-Val, Met-(D)Lys, Asn-(D)Lys, Val-(D)Asp, NorVal-(D)Asp, Ala-(D)Asp, Me 3 Lys-Pro, phenyl Gly-(D)Lys, Met-(D)Lys, Asn-(D)Lys, Pro-(D)Lys, Met-(D)Lys, Met-Cit-Val, Gly-Cit-Val, (D)Phe-Phe-Lys, (D)Ala-Phe-Lys, Gly-Phe-Leu-Gly, and Ala-Leu-Ala-Leu, and is an antibody-drug conjugate of any one of the present inventions 1025 to 1033. [The present invention 1035] m is selected from 1, 2, and 3, and is an antibody-drug conjugate of any one of the present inventions 1025 to 1034. [The present invention 1036] m is 1, and is an antibody-drug conjugate of any one of the present inventions 1025 to 1035. [The present invention 1037] AA 1 -[AA 2 ] m is a dipeptide selected from Val-Lys, Ala-Lys, Phe-Lys, Val-Cit, Phe-Cit, Leu-Cit, Ile-Cit, and Trp-Cit, and is an antibody-drug conjugate of any one of the present inventions 1025 to 1036. [The present invention 1038] Each X 1 is, independently, an antibody-drug conjugate of any one of 1025 to 1037 of the present invention selected from p-aminobenzyloxycarbonyl (PABC), p-aminobenzyl ether (PABE), and methylated ethylenediamine (MED). [1039 of the present invention] The antibody-drug conjugate of 1030 of the present invention, wherein s is 1 and h is 3. [1040 of the present invention] The antibody-drug conjugate of any one of 1025 to 1039 of the present invention, wherein s is 1. [1041 of the present invention] The antibody-drug conjugate of any one of 1025 to 1040 of the present invention, wherein o is 0. [1042 of the present invention] Formula VIII: TIFF0007709636000062.tif48161 An antibody-drug conjugate comprising a linker-toxin moiety of wherein ## represents the binding point of the linker-toxin moiety to the TF antibody, and the linker-toxin moiety is covalently bound to the TF antibody. [1043 of the present invention] Formula IX: TIFF0007709636000063.tif64145 An antibody-drug conjugate of wherein: Ab is a tissue factor (TF) antibody, where the Ab comprises VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, where i. the VH-CDR1 comprises SEQ ID NO: 872, the VH-CDR2 comprises SEQ ID NO: 873, the VH-CDR3 comprises SEQ ID NO: 874, the VL-CDR1 comprises SEQ ID NO: 875, the VL-CDR2 comprises SEQ ID NO: 876, and the VL-CDR3 comprises SEQ ID NO: 877, or ii. the VH-CDR1, the VH-CDR2, the VH-CDR3, the VL-CDR1, the VL-CDR2, and the VL-CDR3 are derived from an antibody named 25A3, or iii. the VH-CDR1, the VH-CDR2, the VH-CDR3, the VL-CDR1, the VL-CDR2, and the VL-CDR3 are derived from an antibody named 25A, or iv. the VH-CDR1, the VH-CDR2, the VH-CDR3, the VL-CDR1, the VL-CDR2, and the VL-CDR3 are derived from an antibody named 25A5, or v. the VH-CDR1, the VH-CDR2, the VH-CDR3, the VL-CDR1, the VL-CDR2, and the VL-CDR3 are derived from an antibody named 25A5-T, or vi. The VH-CDR1, the VH-CDR2, the VH-CDR3, the VL-CDR1, the VL-CDR2, and the VL-CDR3 are derived from an antibody named 25G1, n is an integer of 1 or more, and the succinimidyl group is bonded to the Ab via a covalent bond, the antibody-drug conjugate. [Invention 1044] The antibody-drug conjugate of Invention 1043, wherein n is selected from the group consisting of 1, 2, 3, 4, and 5. [Invention 1045] The antibody-drug conjugate of Invention 1043 or 1044, wherein n is selected from the group consisting of 2, 3, and 4. [Invention 1046] Formula X: TIFF0007709636000064.tif47128 An antibody-drug conjugate comprising a linker represented by: Wherein: # is a binding point to the antibody, and the succinimidyl group is bonded to the antibody via a covalent bond; Y is one or more additional linker elements or does not exist; and D 1 is a binding point to a cytotoxic agent, and the Ab comprises VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, where i. the VH-CDR1 comprises SEQ ID NO: 872, the VH-CDR2 comprises SEQ ID NO: 873, the VH-CDR3 comprises SEQ ID NO: 874, the VL-CDR1 comprises SEQ ID NO: 875, the VL-CDR2 comprises SEQ ID NO: 876, and the VL-CDR3 comprises SEQ ID NO: 877, or ii. the VH-CDR1, the VH-CDR2, the VH-CDR3, the VL-CDR1, the VL-CDR2, and the VL-CDR3 are derived from an antibody named 25A3, or iii. the VH-CDR1, the VH-CDR2, the VH-CDR3, the VL-CDR1, the VL-CDR2, and the VL-CDR3 are derived from an antibody named 25A, or iv. the VH-CDR1, the VH-CDR2, the VH-CDR3, the VL-CDR1, the VL-CDR2, and the VL-CDR3 are derived from an antibody named 25A5, or v. the VH-CDR1, the VH-CDR2, the VH-CDR3, the VL-CDR1, the VL-CDR2, and the VL-CDR3 are derived from an antibody named 25A5-T, or vi. The VH-CDR1, the VH-CDR2, the VH-CDR3, the VL-CDR1, the VL-CDR2, and the VL-CDR3 are derived from an antibody named 25G1, the antibody-drug conjugate. [Inventive concept 1047] Formula XI: TIFF0007709636000065.tif47128 An antibody-drug conjugate comprising a linker represented by wherein: # is a binding point to the antibody, and the succinimidyl group is bound to the antibody via a covalent bond; Y is one or more additional linker elements or is absent; and D 1 is a binding point to a cytotoxic agent, and the Ab comprises VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, where i. the VH-CDR1 comprises SEQ ID NO: 872, the VH-CDR2 comprises SEQ ID NO: 873, the VH-CDR3 comprises SEQ ID NO: 874, the VL-CDR1 comprises SEQ ID NO: 875, the VL-CDR2 comprises SEQ ID NO: 876, and the VL-CDR3 comprises SEQ ID NO: 877, or ii. the VH-CDR1, the VH-CDR2, the VH-CDR3, the VL-CDR1, the VL-CDR2, and the VL-CDR3 are derived from an antibody named 25A3, or iii. the VH-CDR1, the VH-CDR2, the VH-CDR3, the VL-CDR1, the VL-CDR2, and the VL-CDR3 are derived from an antibody named 25A, or iv. the VH-CDR1, the VH-CDR2, the VH-CDR3, the VL-CDR1, the VL-CDR2, and the VL-CDR3 are derived from an antibody named 25A5, or v. the VH-CDR1, the VH-CDR2, the VH-CDR3, the VL-CDR1, the VL-CDR2, and the VL-CDR3 are derived from an antibody named 25A5-T, or vi. the VH-CDR1, the VH-CDR2, the VH-CDR3, the VL-CDR1, the VL-CDR2, and the VL-CDR3 are derived from an antibody named 25G1, the antibody-drug conjugate. [Inventive concept 1048] The antibody-drug conjugate of the present invention 1046 or the present invention 1047, wherein the cytotoxic agent is selected from the group consisting of a diagnostic agent, a metal chelating agent, an enzyme, a fluorescent compound, a bioluminescent compound, or a chemiluminescent compound. [The present invention 1049] The antibody-drug conjugate of the present invention 1046 or the present invention 1047, wherein the cytotoxic agent is a cytotoxic payload having an improved safety profile. [The present invention 1050] The Ab is a. a VH sequence that is SEQ ID NO: 868 and a VL sequence that is SEQ ID NO: 869, b. a VH that is SEQ ID NO: 151 and a VL sequence that is SEQ ID NO: 152, c. a VH sequence that is SEQ ID NO: 113 and a VL sequence that is SEQ ID NO: 114, d. a VH sequence that is SEQ ID NO: 189 and a VL sequence that is SEQ ID NO: 190, e. a VH sequence that is SEQ ID NO: 836 and a VL sequence that is SEQ ID NO: 837, or f. a VH sequence that is SEQ ID NO: 265 and a VL sequence that is SEQ ID NO: 266 The antibody-drug conjugate of any of the prior inventions. [The present invention 1051] The Ab is a. Heavy chain sequence: QVQLVQSGAEVKKPGASVKVSCKASGYTFDx[V / A]YGISWVRQAPGQGLEWMGWIAPYx[N / S]GNTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARDAGTYSPFGYGMDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG, and Light chain sequence: DIQMTQSPSTLSASVGDRVTITCx[R / Q]ASx[Q / E]SIx[S / N]x[S / N]WLAWYQQKPGKAPKLLIYKAx[S / Y]x[S / N]LEx[S / Y]GVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQx[Q / L]FQx[S / K]LPPFTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC、 b. Heavy chain sequence: QVQLVQSGAEVKKPGASVKVSCKASGYTFDVYGISWVRQAPGQGLEWMGWIAPYSGNTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARDAGTYSPFGYGMDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG, and c. Light chain sequence: DIQMTQSPSTLSASVGDRVTITCQASQSINNWLAWYQQKPGKAPKLLIYKAYNLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQLFQSLPPFTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC、 c. Heavy chain sequence: QVQLVQSGAEVKKPGASVKVSCKASGYTFDVYGISWVRQAPGQGLEWMGWIAPYSGNTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARDAGTYSPFGYGMDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG, and Light chain sequence: DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYKASSLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQFQSLPPFTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC, d. Heavy chain sequence: QVQLVQSGAEVKKPGASVKVSCKASGYTFDAYGISWVRQAPGQGLEWMGWIAPYSGNTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARDAGTYSPFGYGMDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG, and Light chain sequence: DIQMTQSPSTLSASVGDRVTITCRASESISNWLAWYQQKPGKAPKLLIYKAYSLEYGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQFQKLPPFTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC e. Heavy chain sequence: QVQLVQSGAEVKKPGASVKVSCKASGYTFRSYGISWVRQAPGQGLEWMGWVAPYSGNTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARDAGTYSPYGYGMDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG, and Light chain sequence: DIQMTQSPSTLSASVGDRVTITCRASHSIDSWLAWYQQKPGKAPKLLIYKASYLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQLFQSLPPFTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC, or f. Heavy chain sequence: QVQLVQSGAEVKKPGASVKVSCKASGYTFDVYGISWVRQAPGQGLEWMGWIAPYSGNTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARDAGTYSPFGYGMDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG, and Light chain sequence: DIQMTQSPSTLSASVGDRVTITCRASESISNWLAWYQQKPGKAPKLLIYKAYSLEYGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQFQKLPPFTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Any antibody-drug conjugate of the prior invention comprising [Inventive Article 1052] Formula IX: TIFF0007709636000066.tif64145 An antibody-drug conjugate of Wherein: Ab is a tissue factor (TF) antibody, said Ab comprising VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 derived from the antibody named 25A3; and n is an integer of 1 or more Said antibody-drug conjugate [Inventive Article 1053] The antibody-drug conjugate of Inventive Article 1052, wherein n is selected from the group consisting of 1, 2, 3, 4, and 5 [Inventive Article 1054] The antibody-drug conjugate of Inventive Article 1052, wherein n is selected from the group consisting of 2, 3, and 4 [Inventive Article 1055] The antibody-drug conjugate according to any one of the present inventions 1052 to 1054, wherein the Ab comprises a VH sequence of SEQ ID NO: 151 and a VL sequence of SEQ ID NO: 152. [The present invention 1056] wherein the Ab is TIFF0007709636000067.tif63159 the complete heavy chain sequence of, and TIFF0007709636000068.tif26160 the light chain sequence of, the antibody-drug conjugate according to any one of the present inventions 1052 to 1055. [The present invention 1057] Formula IX: TIFF0007709636000069.tif64145 An antibody-drug conjugate, wherein In the formula: Ab is a tissue factor (TF) antibody, and the Ab TIFF0007709636000070.tif63147 comprises a heavy chain sequence of, and TIFF0007709636000071.tif33146 a light chain sequence of, and n is an integer of 1 or more, the antibody-drug conjugate. [The present invention 1058] The antibody-drug conjugate according to the present invention 1057, wherein n is selected from the group consisting of 1, 2, 3, 4, and 5. [The present invention 1059] The antibody-drug conjugate according to the present invention 1057, wherein n is selected from the group consisting of 2, 3, and 4. [The present invention 1060] An antibody-drug conjugate comprising an antibody (Ab) and one or more linker-toxins having the following structure: TIFF0007709636000072.tif36157 wherein In the formula: Ab is a tissue factor (TF) antibody, and the Ab comprises VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 derived from the antibody named 25A3; the one or more linker-toxins are bound to the Ab via a covalent bond; and ## represents the binding point of the linker-toxin to the Ab, the antibody-drug conjugate. [The present invention 1061] An antibody-drug conjugate composition comprising the antibody-drug conjugate according to the present invention 1060, wherein the composition comprises various drug-antibody ratio (DAR) species, and the average DAR of the composition is 2 to 4. [The present invention 1062] An antibody-drug conjugate comprising an antibody (Ab) and one or more linker-toxins having the following structure: TIFF0007709636000073.tif36157 wherein In the formula: Ab is a tissue factor (TF) antibody, and the Ab TIFF0007709636000074.tif63147 comprises a heavy chain sequence of, and TIFF0007709636000075.tif33146 a light chain sequence of, and the one or more linker-toxins are bound to the Ab via a covalent bond; and ## represents the binding point of the linker-toxin to the Ab, the antibody-drug conjugate. [The present invention 1063] An antibody-drug conjugate composition comprising the antibody-drug conjugate according to the present invention 1062, wherein the composition comprises various drug-antibody ratio (DAR) species, and the average DAR of the composition is 2 to 4. [The present invention 1064] Any antibody-drug conjugate of the prior invention, wherein the Ab is multispecific. [The present invention 1065] Any antibody-drug conjugate of the prior invention, wherein the Ab is Fab, Fab’, F(ab’) 2 , Fv, scFv, (scFv) 2 , single-chain antibody molecule, diabody, single variable domain antibody, linear antibody, or V domain antibody. [The present invention 1066] Any antibody-drug conjugate of the prior invention, wherein the antibody comprises a scaffold, optionally the scaffold is Fc, and optionally the Fc is human Fc. [The present invention 1067] Any antibody-drug conjugate of the prior invention, wherein the antibody comprises a heavy chain constant region of a class selected from IgG, IgA, IgD, IgE, and IgM. [The present invention 1068] The antibody-drug conjugate of the present invention 1067, wherein the antibody comprises a heavy chain constant region of class IgG, and the heavy chain constant region is derived from a subclass selected from IgG1, IgG2, IgG3, and IgG4. [The present invention 1069] The antibody-drug conjugate of the present invention 1068, wherein the antibody comprises a heavy chain constant region of IgG1. [The present invention 1070] The antibody-drug conjugate of the present invention 1066, wherein the Fc comprises one or more modifications that result in an extended half-life, enhanced antibody-dependent cell cytotoxicity (ADCC), enhanced antibody-dependent cell phagocytosis (ADCP), enhanced complement-dependent cytotoxicity (CDC), or reduced effector function as compared to the Fc without the one or more modifications. [The present invention 1071] Any antibody-drug conjugate of the present invention 1001 - 1070, which, when administered to a subject bearing a tumor, reduces tumor volume or inhibits tumor growth. [The present invention 1072] Any antibody-drug conjugate of the present invention 1001 - 1071, which, when administered to a subject bearing a tumor, reduces tumor volume by at least about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 99%. [The present invention 1073] When the antibody-drug conjugate is administered to a subject bearing a tumor, it inhibits tumor growth by at least about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 99%. The antibody-drug conjugate of any one of the present inventions 1001 to 1072. [The present invention 1074] When the antibody-drug conjugate is administered to a subject, the antibody-drug conjugate does not cause measurable skin toxicity. The antibody-drug conjugate of any one of the present inventions 1001 to 1073. [The present invention 1075] When the antibody-drug conjugate is administered to a subject, the antibody-drug conjugate results in a reduction in skin toxicity as compared to different anti-TF ADCs. The antibody-drug conjugate of any one of the present inventions 1001 to 1073. [The present invention 1076] Administration of the antibody-drug conjugate to a subject does not require administration of one or more anti-inflammatory agents. The antibody-drug conjugate of any one of the present inventions 1001 to 1075. [The present invention 1077] Administration of the antibody-drug conjugate to a subject reduces the need for one or more anti-inflammatory agents as compared to different anti-TF ADCs. The antibody-drug conjugate of any one of the present inventions 1001 to 1075. [The present invention 1078] The one or more anti-inflammatory agents include at least one of a topical steroid and a systemic steroid. The antibody-drug conjugate of the present invention 1076 or 1077. [The present invention 1079] When the antibody-drug conjugate is administered to a subject, the antibody-drug conjugate results in a reduction or elimination of neutropenia in the subject as compared to the baseline level. The antibody-drug conjugate of any one of the present inventions 1001 to 1078. [The present invention 1080] When the antibody-drug conjugate is administered to a subject, the antibody-drug conjugate does not change, increase, or decrease the number of monocytes in the subject as compared to the baseline level. The antibody-drug conjugate of any one of the present inventions 1001 to 1078. [The present invention 1081] The different anti-TF ADC is identical to the antibody-drug conjugate except that it is conjugated to MMAE. The antibody-drug conjugate of any one of the present inventions 1075 to 1080. [The present invention 1082] A pharmaceutical composition comprising any antibody-drug conjugate of the prior invention and a pharmaceutically acceptable carrier. [The present invention 1083] A method for treating or preventing the disease or condition in a subject in need thereof, the method comprising administering to the subject an effective amount of any antibody-drug conjugate of the present invention 1001-1081 or the pharmaceutical composition of the present invention 1082. [The present invention 1084] A method for treating the cancer or delaying the onset of cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of any antibody-drug conjugate of the present invention 1001-1081. [The present invention 1085] The method of the present invention 1083, wherein the disease or condition is cancer. [The present invention 1086] The method of the present invention 1084 or 1085, wherein the cancer is selected from the group consisting of head and neck cancer, ovarian cancer, gastric cancer, esophageal cancer, cervical cancer, prostate cancer, pancreatic cancer, estrogen receptor negative (ER-) breast cancer, progesterone receptor negative (PR-) breast cancer, HER2 negative (HER2-) triple negative breast cancer, glioblastoma, lung cancer, bladder cancer, melanoma, and renal cancer. [The present invention 1087] The method of the present invention 1083, wherein the disease or condition is associated with angiogenesis. [The present invention 1088] The method of the present invention 1087, wherein the disease or condition associated with angiogenesis is cancer. [The present invention 1089] The method of the present invention 1083, wherein the disease or condition is associated with vascular inflammation. [The present invention 1090] The method of any of the present invention 1083-1089, further comprising administering to the subject one or more additional therapeutic agents. [The present invention 1091] The method of the present invention 1090, wherein the composition further comprises the one or more additional therapeutic agents. [The present invention 1092] The method of the present invention 1090, wherein the additional therapeutic agent is formulated in a different pharmaceutical composition. [The present invention 1093] The method of the present invention 1090, wherein the additional therapeutic agent is administered before administering the composition. [The present invention 1094] The method of the present invention 1090, wherein the additional therapeutic agent is administered after administering the composition. [The present invention 1095] The method of the present invention 1090, wherein the additional therapeutic agent is administered simultaneously with the composition. [The present invention 1096] Any method of the prior invention, wherein the subject is a human subject. [The present invention 1097] A method for killing cancer cells, comprising contacting the cancer cells with an effective amount of any one of antibodies-drug conjugates of the present invention from 1001 to 1081, said method. [The present invention 1098] A method for preparing an antibody-drug conjugate, comprising: (A) Reacting a nucleophilic or electrophilic group in an antigen-binding protein (Ab) that binds to the extracellular domain (SEQ ID NO: 810) of human tissue factor (TF) with a bifunctional linker to form an Ab-linker intermediate, and reacting the Ab-linker intermediate with the -NH TIFF0007709636000076.tif50128 group of a compound of general formula I: 2 to provide the antibody-drug conjugate, wherein: In the formula: X is *-C(O)NHCH(CH 2 (R 2 ))- + and in the formula, * and + represent the respective binding points shown in formula I, or X does not exist; R 1 is TIFF0007709636000077.tif42128 selected from the group consisting of wherein # and % represent the respective binding points shown in formula I; and R 2 is phenyl, the step; or (B) Reacting the -NH 2 group of a compound of general formula I with a bifunctional linker to form a linker-toxin intermediate, and reacting the linker-toxin intermediate with a nucleophilic or electrophilic group in an antigen-binding protein (Ab) that binds to the extracellular domain (SEQ ID NO: 810) of the human tissue factor (TF) to provide the antibody-drug conjugate wherein in (A) or (B), (a) The Ab comprises VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, wherein i. The VH-CDR1 comprises SEQ ID NO: 872, the VH-CDR2 comprises SEQ ID NO: 873, the VH-CDR3 comprises SEQ ID NO: 874, the VL-CDR1 comprises SEQ ID NO: 875, the VL-CDR2 comprises SEQ ID NO: 876, and the VL-CDR3 comprises SEQ ID NO: 877, or ii. The VH-CDR1, the VH-CDR2, the VH-CDR3, the VL-CDR1, the VL-CDR2, and the VL-CDR3 are derived from an antibody named 25A3, or iii. The VH-CDR1, the VH-CDR2, the VH-CDR3, the VL-CDR1, the VL-CDR2, and the VL-CDR3 are derived from an antibody named 25A iv. The VH-CDR1, the VH-CDR2, the VH-CDR3, the VL-CDR1, the VL-CDR2, and the VL-CDR3 are derived from an antibody named 25A5, v. The VH-CDR1, the VH-CDR2, the VH-CDR3, the VL-CDR1, the VL-CDR2, and the VL-CDR3 are derived from an antibody named 25A5-T, or vi. The VH-CDR1, the VH-CDR2, the VH-CDR3, the VL-CDR1, the VL-CDR2, and the VL-CDR3 are derived from an antibody named 25G1; and (b) The antibody-drug conjugate comprises one or more moieties represented by Formula IV: TIFF0007709636000078.tif52138 wherein: X is -C(O)NHCH(CH * wherein 2 (R 2 ))- + and + represent the respective attachment points shown in Formula IV, or X is absent; * L is a linker; ! represents the attachment point of L to the Ab, where L is attached to the Ab via a covalent bond; is R 1 selected from the group consisting of TIFF0007709636000079.tif42128 wherein # and % represent the respective attachment points shown in Formula IV; and is phenyl, the method. R 2 [Invention No. 1099] A method for preparing an antibody-drug conjugate, comprising: (A) Reacting a nucleophilic or electrophilic group of an antigen-binding protein (Ab) that binds to the extracellular domain (SEQ ID NO: 810) of human tissue factor (TF) with a first linker element of a bifunctional linker comprising two or more linker elements, and subsequently adding the remaining linker elements sequentially to form an Ab-linker intermediate, and reacting the Ab-linker intermediate with the -NH group of a compound of general formula I: TIFF0007709636000080.tif50128 to provide the antibody-drug conjugate, 2 wherein: X is -C(O)NHCH(CH * wherein 2 (R 2 ))- + and + represent the respective attachment points shown in Formula I, or X is absent; * is R 1 selected from the group consisting of TIFF0007709636000081.tif42128 wherein # and % represent the respective attachment points shown in Formula I; and R is phenyl, the step; or 2 (B) The -NH of a compound of general formula I ​ 2 Reacting a base with a first linker element of a bifunctional linker comprising two or more linker elements, and subsequently adding the remaining linker elements sequentially to form a linker-toxin intermediate, and reacting the linker-toxin intermediate with a nucleophilic or electrophilic group in an antigen-binding protein (Ab) that binds to the extracellular domain (SEQ ID NO: 810) of the human tissue factor (TF) to provide the antibody-drug conjugate comprising, wherein in (A) or (B), (a) the Ab comprises VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, wherein i. the VH-CDR1 comprises SEQ ID NO: 872, the VH-CDR2 comprises SEQ ID NO: 873, the VH-CDR3 comprises SEQ ID NO: 874, the VL-CDR1 comprises SEQ ID NO: 875, the VL-CDR2 comprises SEQ ID NO: 876, and the VL-CDR3 comprises SEQ ID NO: 877, or ii. the VH-CDR1, the VH-CDR2, the VH-CDR3, the VL-CDR1, the VL-CDR2, and the VL-CDR3 are derived from an antibody named 25A3, or iii. the VH-CDR1, the VH-CDR2, the VH-CDR3, the VL-CDR1, the VL-CDR2, and the VL-CDR3 are derived from an antibody named 25A, or iv. the VH-CDR1, the VH-CDR2, the VH-CDR3, the VL-CDR1, the VL-CDR2, and the VL-CDR3 are derived from an antibody named 25A5, or v. the VH-CDR1, the VH-CDR2, the VH-CDR3, the VL-CDR1, the VL-CDR2, and the VL-CDR3 are derived from an antibody named 25A5-T, or vi. the VH-CDR1, the VH-CDR2, the VH-CDR3, the VL-CDR1, the VL-CDR2, and the VL-CDR3 are derived from an antibody named 25G1; and (b) the antibody-drug conjugate comprises one or more moieties represented by Formula IV: TIFF0007709636000082.tif52138 wherein: X is -C(O)NHCH(CH * and + represent the respective attachment points shown in Formula IV, or X is absent; 2 (R 2 ))- + L is a linker; * ! represents the attachment point of L to the Ab, wherein L is attached to the Ab via a covalent bond; is ​ R 1 ​ TIFF0007709636000083.tif42128 selected from the group consisting of; wherein # and % each represent the respective attachment points shown in Formula IV; and R 2 is phenyl, said method. [Inventive Concept 1100] The method of Inventive Concept 1098 or Inventive Concept 1099, wherein the nucleophilic group or the electrophilic group in the Ab is a thiol or an amine. [Inventive Concept 1101] The method of Inventive Concept 1100, further comprising treating the Ab with a reducing agent to reduce one or more disulfide bonds in the Ab to provide the nucleophilic thiol group. [Inventive Concept 1102] L is TIFF0007709636000084.tif23128 represented by wherein: Z represents a functional group that binds to the target group of the Ab; D represents the attachment point to the amino group shown in Formula I; Str is a spacer; AA 1 and AA 2 are each independently an amino acid, where AA 1 -[AA 2 ] m forms a protease cleavage site; X is a self-destructive group; s is an integer selected from 0 and 1; m is an integer selected from the group consisting of 1, 2, 3, and 4; and o is an integer selected from 0, 1, and 2, The method according to any one of Inventive Concepts 1098 to 1101. [Inventive Concept 1103] A kit comprising any antibody-drug conjugate of Inventive Concepts 1001 to 1081 or the pharmaceutical composition of Inventive Concept 1082, and an instruction manual.

Brief Description of the Drawings

[0095] These features, aspects, and advantages of the present invention, as well as other features, aspects, and advantages, will be better understood from the following description and the accompanying drawings.

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[0113] DETAILED DESCRIPTION 1. Definitions Unless defined otherwise, all technical terms, notations, and other scientific terms used herein are intended to have the meaning commonly understood by one of ordinary skill in the art. In some instances, terms with commonly understood meanings are defined herein for clarity and / or for ready reference, and inclusion of such definitions herein should not be construed as necessarily indicating a substantial difference from the meaning commonly understood in the art. The techniques and procedures described herein or referenced herein are matters of general knowledge, and one of ordinary skill in the art routinely uses conventional methods such as the molecular cloning techniques described in Sambrook et al., Molecular Cloning: A Laboratory Manual 4th ed. (2012) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY. Procedures, including the use of commercially available kits and reagents, are generally carried out according to the protocols and conditions indicated by the manufacturer, unless otherwise specified.

[0114] As used herein, the terms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. The terms "include," "such as," and the like are intended to convey the meaning of incorporating without limitation unless otherwise indicated.

[0115] As used herein, the term "comprising" also specifically encompasses, unless otherwise indicated, embodiments "consisting of" the recited elements and embodiments "consisting essentially of" the recited elements.

[0116] The term "about" indicates and encompasses the recited numerical value, as well as the range before and after that numerical value. In certain embodiments, the term "about" indicates the specified numerical value ±10%, ±5%, or ±1%. In certain embodiments, where applicable, the term "about" indicates the specified numerical value ± one standard deviation of that numerical value.

[0117] The terms "tissue factor", "TF", "platelet tissue factor", "factor III", "thromboplastin", and "CD142" are used interchangeably herein and refer to TF, or any variant of TF (e.g., splice variant and allelic variant), isoform, and species homolog, which are expressed either natively by cells or by cells transfected with the TF gene. In some aspects, the TF protein is a TF protein that is natively expressed in primates (e.g., monkeys or humans), rodents (e.g., mice or rats), dogs, camels, cats, cows, goats, horses, pigs, or sheep. In some aspects, the TF protein is human TF (hTF, SEQ ID NO: 809). In some aspects, the TF protein is cynomolgus monkey TF (cTF, SEQ ID NO: 813). In some aspects, the TF protein is mouse TF (mTF, SEQ ID NO: 817). In some aspects, the TF protein is porcine TF (pTF, SEQ ID NO: 824). TF is a cell surface receptor for serine protease factor VIIa. It is constitutively expressed by certain cells surrounding blood vessels and often constitutively expressed in some disease situations.

[0118] The term "antibody-drug conjugate" or "ADC" optionally refers to a conjugate comprising an antibody conjugated to one or more cytotoxic agents via one or more linkers. The term "anti-TF antibody-drug conjugate" or "anti-TF ADC" optionally refers to a conjugate comprising an anti-TF antibody conjugated to one or more cytotoxic agents via one or more linkers.

[0119] As used herein, the terms "TF antibody" and "anti-TF antibody" are synonyms.

[0120] As used herein, the term "cytotoxic agent" refers to a substance that inhibits or blocks cell function and / or causes cell death or cell destruction. Cytotoxic agents can be angiogenesis inhibitors, apoptosis promoters, mitosis inhibitors, kinase inhibitors, alkylating agents, hormones, hormone agonists, hormone antagonists, chemokines, drugs, prodrugs, toxins, enzymes, antimetabolites, antibiotics, alkaloids, or radioisotopes. Representative cytotoxic agents include calicheamicin, camptothecin, carboplatin, irinotecan, SN-38, carboplatin, camptothecin, cyclophosphamide, cytarabine, dacarbazine, docetaxel, dactinomycin, daunorubicin, doxorubicin, doxorubicin, etoposide, idarubicin, topotecan, vinca alkaloids, maytansinoids, maytansinoid analogs, pyrrolobenzodiazepines, taxoids, duocarmycin, dolastatin, auristatin, and derivatives thereof.

[0121] "Linker" refers to a molecule that binds one composition to another composition, for example, a molecule that binds an antibody to an agent. The linkers described herein can conjugate an antibody to a cytotoxic agent. Representative linkers include labile linkers, acid-labile linkers, photo-labile linkers, charged linkers, disulfide-containing linkers, peptidase-sensitive linkers, □-glucuronide-linkers, dimethyl linkers, thio-ether linkers, and hydrophilic linkers. The linker can be cleavable or non-cleavable.

[0122] The term "immunoglobulin" generally refers to a class of structurally related proteins that includes two pairs of polypeptide chains, a pair of light (L) chains and a pair of heavy (H) chains. In "intact immunoglobulin", all four of these chains are linked to each other by disulfide bonds. The structure of immunoglobulins is very well characterized. See, for example, Paul, Fundamental Immunology 7th ed., Ch.5 (2013) Lippincott Williams & Wilkins, Philadelphia, PA. Briefly, each heavy chain generally includes a heavy chain variable region (V H ) and a heavy chain constant region (C H ). The heavy chain constant region generally includes three domains abbreviated as C H1 , C H2 , and C H3 . Each light chain generally includes a light chain variable region (V L ) and a light chain constant region. The light chain constant region generally includes one domain abbreviated as C L .

[0123] The term "antibody" is used herein in the broadest sense and includes certain types of immunoglobulin molecules that include one or more antigen-binding domains that specifically bind to an antigen or epitope. Specific examples of antibodies include intact antibodies (e.g., intact immunoglobulins), antibody fragments, and multispecific antibodies.

[0124] The term "alternative scaffold" refers to a molecule in which one or more regions can be diversified to generate one or more antigen-binding domains that specifically bind to an antigen or epitope. In some embodiments, the antigen-binding domain binds to an antigen or epitope with specificity and affinity similar to that of an antibody. Representative alternative scaffolds include those derived from fibronectin (e.g., Adnectins™), β-sandwich (e.g., iMab), lipocalin (e.g., Anticalins®), EETI-II / AGRP, BPTI / LACI-D1 / ITI-D2 (e.g., Kunitz domain), thioredoxin peptide aptamer, protein A (e.g., Affibody®), ankyrin repeat (e.g., DARPin), gamma-B-crystallin / ubiquitin (e.g., Affilins), CTLD3 (e.g., tetranectin), Fynomers, and (LDLR-A module) (e.g., Avimers). Further information regarding alternative scaffolds is provided in Binz et al., Nat. Biotechnol., 2005 23:1257-1268, Skerra, Current Opin. in Biotech., 2007 18:295-304, and Silacci et al., J. Biol. Chem., 2014, 289:14392-14398, each of which is hereby incorporated by reference in its entirety.

[0125] The term "antigen-binding domain" means the portion of an antibody that can specifically bind to an antigen or epitope. An example of an antigen-binding domain is the antigen-binding domain formed by the V H -V L dimer of an antibody. Another example of an antigen-binding domain is an antigen-binding domain formed by diversifying a specific loop from the 10th fibronectin type III domain of Adnectin. Antigen-binding domains can be found in various contexts, such as antibodies and chimeric antigen receptors (CARs), e.g., CARs derived from antibody fragments such as antibodies or scFvs.

[0126] The terms "full-length antibody", "intact antibody", and "whole antibody" are used interchangeably herein and refer to an antibody having a structure substantially similar to a naturally occurring antibody structure and having a heavy chain that includes an Fc region. For example, when used to refer to an IgG molecule, a "full-length antibody" is an antibody that includes two heavy chains and two light chains.

[0127] The term "Fc region" means the C-terminal region of an immunoglobulin heavy chain that interacts with certain proteins of the Fc receptor and complement system in a naturally occurring antibody. The structures of the Fc regions of various immunoglobulins and the glycosylation sites contained therein are known in the art. See Schroeder and Cavacini, J. Allergy Clin. Immunol., 2010, 125: S41-52, which is incorporated by reference in its entirety. The Fc region can be a naturally occurring Fc region or an Fc region modified as described in the art or elsewhere in this disclosure.

[0128] V H and V L regions can be further subdivided into regions of hypervariability (the "hypervariable region (HVR)"; also known as "complementary determining region" (CDR)) interspersed with regions of conserved residues. These regions of conserved residues are referred to as framework regions (FR). Each V H and V L generally includes three CDRs and four FRs arranged in the following order (from N-terminus to C-terminus): FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4. The CDRs are involved in antigen binding and affect the antigen specificity and binding affinity of the antibody. See Kabat et al., Sequences of Proteins of Immunological Interest 5th ed. (1991) Public Health Service, National Institutes of Health, Bethesda, MD, which is incorporated by reference in its entirety.

[0129] "Complementary determining region (CDR)" refers to one of three hypervariable regions (H1, H2, or H3) within the non-framework region of the VH β-sheet framework of an immunoglobulin (Ig or antibody), or one of three hypervariable regions (L1, L2, or L3) within the non-framework region of the VL β-sheet framework of an antibody. CDRs are variable region sequences interspersed within the framework region sequences. CDRs are well recognized in the art and are defined, for example, by Kabat as the regions having the greatest hypervariability within the antibody variable (V) domain. See Kabat et al., J Biol Chem, 1977, 252:6609-6616 and Kabat, Adv Protein Chem, 1978, 32:1-75, each of which is hereby incorporated by reference in its entirety. Also, CDRs are structurally defined by Chothia as residues that are not part of the conserved β-sheet framework, i.e., residues adaptable to various conformations. See Chothia and Lesk, J Mol Biol, 1987, 196:901-917, which is hereby incorporated by reference in its entirety. Both the Kabat and Chothia nomenclatures are well known in the art. AbM, Contact, and IMGT have also defined CDRs. The positions of CDRs in classical antibody variable domains have been determined by comparing numerous structures. See Morea et al., Methods, 2000, 20:267-279, and Al-Lazikani et al., J Mol Biol, 1997, 273:927-48, each of which is hereby incorporated by reference in its entirety. Since the number of residues within the hypervariable regions varies for each antibody, additional residues relative to the classical positions are customarily numbered a, b, c, etc., adjacent to the residue numbers in the numbering scheme of the classical variable domain (Al-Lazikani et al., supra). Such terminology is well known to those skilled in the art.

[0130] The boundaries of several hypervariable regions are used and are described herein. Kabat CDRs are based on sequence variability and are the most commonly used. See Kabat et al. (1992) Sequences of Proteins of Immunological Interest, DIANE Publishing: 2719, which is incorporated herein by reference in its entirety. Chothia looks at things differently and focuses on structural loop regions (Chothia and Lesk, supra). The AbM hypervariable regions represent a compromise between Kabat CDRs and Chothia structural loops and are used in Oxford Molecular's AbM antibody modeling software. Contact hypervariable regions are based on the analysis of available complex crystal structures. The residues of each of these hypervariable regions are listed in Table 1.

[0131] More recently, the ImMunoGeneTics (IMGT) Information System™, a universal numbering system, has been developed and widely used. See Lefranc et al., Dev Comp Immunol, 2003, 27:55-77, which is incorporated herein by reference in its entirety. IMGT is an integrated information system specialized for immunoglobulins (IG), T cell receptors (TR), and major histocompatibility complexes (MHC) of humans and other vertebrates. IMGT CDRs are referenced from both the amino acid sequence and the location within the light or heavy chain. The "location" of the CDRs within the structure of the immunoglobulin variable domain is conserved between species and exists in a structure called a loop, so the CDRs and framework residues can be readily identified by using a numbering system that aligns the variable domain sequences according to structural features. The correspondence between the Kabat, Chothia, and IMGT numbering methods is also well known in the art (Lefranc et al., supra). The representative system shown herein combines the Kabat and Chothia CDR definitions.

[0132] (Table 1) TIFF0007709636000085.tif39162

[0133] Light chains from all vertebrate species can be assigned to one of two types, called kappa (κ) and lambda (λ), based on the sequence of their constant domains.

[0134] Heavy chains from all vertebrate species can be assigned to one of five different classes (or isotypes): IgA, IgD, IgE, IgG, and IgM. These classes are also denoted as α, δ, ε, γ, and μ, respectively. The IgG and IgA classes are further divided into subclasses based on differences in sequence and function. Humans express the following subclasses: IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2.

[0135] The terms "constant region" or "constant domain" refer to the carboxy-terminal portions of the light and heavy chains that do not directly participate in the binding of the antibody to the antigen but exhibit various effector functions such as interaction with Fc receptors. These terms refer to portions of the immunoglobulin molecule that have a conserved amino acid sequence compared to the other portion of the immunoglobulin, i.e., the variable domain containing the antigen-binding site. The constant domain is the C H1 、C H2 、and C H3 domains of the heavy chain and the C L domain of the light chain.

[0136] The "EU numbering scheme" is generally used when referring to residues in the constant region of the heavy chain of an antibody (e.g., as reported by Kabat et al., supra). Unless otherwise specified, the EU numbering scheme is used to refer to residues in the constant region of the heavy chain of the antibodies described herein.

[0137] "Antibody fragment" includes a part of an intact antibody such as the antigen-binding region or variable region of an intact antibody. Examples of antibody fragments include Fv fragment, Fab fragment, F(ab')2 fragment, Fab' fragment, scFv (sFv) fragment, and scFv-Fc fragment.

[0138] The "Fv" fragment includes a dimer in which one heavy-chain variable domain and one light-chain variable domain are non-covalently bound.

[0139] The "Fab" fragment includes, in addition to the heavy-chain and light-chain variable domains, the constant domains of the light chain and the first constant domain (C H1 ) of the heavy chain. The Fab fragment can be produced, for example, by recombinant methods or by papain digestion of a full-length antibody.

[0140] The "F(ab')2" fragment includes two Fab' fragments joined by a disulfide bond near the hinge region. The F(ab')2 fragment can be produced, for example, by recombinant methods or by pepsin digestion of an intact antibody. The F(ab') fragment can be dissociated, for example, by treatment with β-mercaptoethanol.

[0141] The "single-chain Fv" or "sFv" or "scFv" antibody fragment includes V H domains and V L domains in a single polypeptide chain. V H and V L are generally linked by a peptide linker. See Pluckthun A. (1994). Any suitable linker can be used. In some embodiments, the linker is (GGGGS) n(Accession number 823). In some embodiments, n = 1, 2, 3, 4, 5, or 6. See Escherichia coli-derived antibodies in Rosenberg M. & Moore G.P. (Eds.), The Pharmacology of Monoclonal Antibodies vol. 113 (pp. 269-315). Springer-Verlag, New York, which is incorporated by reference in its entirety.

[0142] The "scFv-Fc" fragment comprises an scFv bound to an Fc domain. For example, the Fc domain can be bound to the C-terminus of the scFv. The Fc domain can follow V H -V L or V L -V H depending on the orientation of the variable domains in the scFv (i.e., V H or V L ). Any suitable Fc domain known in the art or described herein can be used.

[0143] The term "single domain antibody" refers to a molecule in which one variable domain of an antibody specifically binds to an antigen even in the absence of the other variable domain. Single domain antibodies and their fragments are described in Arabi Ghahroudi et al., FEBS Letters, 1998, 414:521-526 and Muyldermans et al., Trends in Biochem. Sci., 2001, 26:230-245, each of which is incorporated by reference in its entirety. Single domain antibodies are also known as sdAbs or nanobodies.

[0144] A "multispecific antibody" is an antibody that contains two or more different antigen-binding domains that specifically bind jointly to two or more different epitopes. These two or more different epitopes can be epitopes on the same antigen (e.g., a single TF molecule expressed by a cell), or epitopes on different antigens (e.g., a TF molecule and a non-TF molecule). In some embodiments, the multispecific antibody binds to two different epitopes (i.e., a "bispecific antibody"). In some embodiments, the multispecific antibody binds to three different epitopes (i.e., a "trispecific antibody"). In some embodiments, the multispecific antibody binds to four different epitopes (i.e., a "tetraspecific antibody"). In some embodiments, the multispecific antibody binds to five different epitopes (i.e., a "pentaspecific antibody"). In some embodiments, the multispecific antibody binds to six, seven, eight, or more different epitopes. Each binding specificity can exist with any suitable valence. Examples of multispecific antibodies are provided elsewhere in this disclosure.

[0145] A "monospecific antibody" is an antibody that contains one or more binding sites that specifically bind to a single epitope. Examples of monospecific antibodies are naturally occurring IgG molecules that are bivalent (i.e., have two antigen-binding domains) but recognize the same epitope with each of the two antigen-binding domains. The binding specificity can exist with any suitable valence.

[0146] The term "monoclonal antibody" refers to an antibody that is derived from a population of substantially homogeneous antibodies. A population of substantially homogeneous antibodies is substantially similar, excluding variants that may occur normally during the production process of monoclonal antibodies, and includes antibodies that bind to the same epitope. Such variants generally exist only in small amounts. Monoclonal antibodies are generally obtained by a process that includes selecting a single antibody from a plurality of antibodies. For example, the selection process can be the selection of a unique clone from a plurality of clones, such as a pool of hybridoma clones, phage clones, yeast clones, bacterial clones, or other recombinant DNA clones. The selected antibody can be further modified, for example, to improve its affinity for the target ("affinity maturation"), to humanize the antibody, to improve its production in cell culture, and / or to suppress its immunogenicity in a subject.

[0147] The term "chimeric antibody" refers to an antibody in which a portion of the heavy chain and / or light chain is derived from a particular source or species, while the remaining portion of the heavy chain and / or light chain is derived from a different source or species.

[0148] The "humanized" form of a non-human antibody is a chimeric antibody that contains minimal sequences derived from non-human antibodies. Humanized antibodies generally replace residues derived from one or more CDRs in a human antibody (recipient antibody) with residues derived from one or more CDRs of a non-human antibody (donor antibody). The donor antibody can be any suitable non-human antibody, such as a mouse, rat, rabbit, chicken, or non-human primate antibody, that has the desired specificity, affinity, or biological effect. In some examples, residues in selected framework regions of the recipient antibody are replaced with corresponding residues from the framework regions of the donor antibody. A humanized antibody can also contain residues not found in either the recipient or donor antibody. Such modifications can be made to further improve antibody function. For further details, see Jones et al., Nature, 1986, 321:522-525, Riechmann et al., Nature, 1988, 332:323-329, and Presta, Curr. Op. Struct. Biol., 1992, 2:593-596, each of which is incorporated by reference in its entirety.

[0149] A "human antibody" is an amino acid sequence of an antibody produced by a human or human cell, or an amino acid sequence corresponding to the amino acid sequence of an antibody derived from a non-human source, having an amino acid sequence that utilizes a repertoire of human antibodies or a human antibody coding sequence (e.g., obtained from a human source or newly designed). A human antibody is distinct from a humanized antibody.

[0150] "Isolated antibody" or "isolated nucleic acid" refers to an antibody or nucleic acid that has been separated from and / or recovered from components of its natural environment. Components of the natural environment include enzymes, hormones, and other proteinaceous or non-proteinaceous materials. In some embodiments, an isolated antibody is purified to a sufficient extent to obtain at least 15 residues of the N-terminal amino acid sequence or an internal amino acid sequence, for example, using a spinning cup sequenator. In some embodiments, an isolated antibody is purified to homogeneity by gel electrophoresis (e.g., SDS-PAGE) under reducing or non-reducing conditions using detection by Coomassie blue or silver staining. In some embodiments, an isolated antibody may contain the antibody in situ within a recombinant cell because at least one component of the antibody in its natural environment is absent. In some aspects, an isolated antibody or isolated nucleic acid is prepared in at least one purification step. In some embodiments, an isolated antibody or isolated nucleic acid is purified to at least 80 wt%, 85 wt%, 90 wt%, 95 wt%, or 99 wt%. In some embodiments, an isolated antibody or isolated nucleic acid is purified to at least 80 vol%, 85 vol%, 90 vol%, 95 vol%, or 99 vol%. In some embodiments, an isolated antibody or isolated nucleic acid is provided as a solution containing at least 85 wt%, 90 wt%, 95 wt%, 98 wt%, 99 wt% to 100 wt% of the antibody or nucleic acid. In some embodiments, an isolated antibody or isolated nucleic acid is provided as a solution containing at least 85 vol%, 90 vol%, 95 vol%, 98 vol%, 99 vol% to 100 vol% of the antibody or nucleic acid.

[0151] "Affinity" refers to the sum of the strengths of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen or epitope). Unless otherwise indicated, "affinity" as used herein refers to the intrinsic binding affinity that reflects a 1:1 interaction between members of a binding pair (e.g., an antibody and an antigen or epitope). The affinity that molecule X exhibits for its partner Y is the dissociation equilibrium constant (K D) can be represented by. The kinetic components contributing to the dissociation equilibrium constant are further detailed below. Affinity can be measured by common methods known in the art, including the methods described herein, such as surface plasmon resonance (SPR) techniques (e.g., BIACORE®), or biolayer interferometry (e.g., FORTEBIO®).

[0152] With respect to the binding of an antibody to a target molecule, the terms "bind", "specific binding", "specifically binds to", "specific for", "selectively binds", and "selective for" refer to a particular antigen (e.g., a polypeptide target) or an epitope within a particular antigen, and mean binding that differs to a measurable degree from non-specific or non-selective interactions (e.g., with non-target molecules). Specific binding can be measured, for example, by measuring binding to the target molecule and comparing it to binding to non-target molecules. Specific binding can also be determined by competition with a control molecule that mimics the epitope recognized by the target molecule. In that example, if the binding of an antibody to the target molecule is competitively inhibited by the control molecule, it is considered specific binding. In some embodiments, the affinity of the TF antibody for non-target molecules is less than about 50% of the affinity for TF. In some embodiments, the affinity of the TF antibody for non-target molecules is less than about 40% of the affinity for TF. In some embodiments, the affinity of the TF antibody for non-target molecules is less than about 30% of the affinity for TF. In some embodiments, the affinity of the TF antibody for non-target molecules is less than about 20% of the affinity for TF. In some embodiments, the affinity of the TF antibody for non-target molecules is less than about 10% of the affinity for TF. In some embodiments, the affinity of the TF antibody for non-target molecules is less than about 1% of the affinity for TF. In some embodiments, the affinity of the TF antibody for non-target molecules is less than about 0.1% of the affinity for TF.

[0153] As used herein, the term "k d " (seconds -1 ) refers to the dissociation rate constant of a particular antibody-antigen interaction. This value is also referred to as the k off value.

[0154] As used herein, the term "k a」(M -1 × seconds -1 ) refers to the association rate constant of a specific antibody-antigen interaction. This value is also referred to as the k on value.

[0155] As used herein, the term "K D 」(M) refers to the dissociation equilibrium constant of a specific antibody-antigen interaction. K D = k d / k a . In some embodiments, the affinity of an antibody is expressed as K D for the interaction between such antibody and its antigen. For clarity, as is known in the art, a low K D value indicates a strong affinity interaction, while a high K D value indicates a weak affinity interaction.

[0156] As used herein, the term "K A 」(M -1 ) refers to the association equilibrium constant of a specific antibody-antigen interaction. K A = k a / k d .

[0157] An "affinity matured" antibody has one or more modifications (e.g., in one or more CDRs or FRs) compared to a parental antibody (i.e., the antibody from which the modified antibody is derived or the antibody that is the design material for the modified antibody), and as a result, the affinity of the antibody for its antigen is improved compared to the parental antibody that does not have such modification. In some embodiments, the affinity matured antibody has a nanomolar or picomolar affinity for the target antigen. Affinity matured antibodies can be produced using various methods known in the art. For example, Marks et al. (Bio / Technology, 1992, 10:779-783, incorporated herein by reference in its entirety) describe methods for generating antibodies with improved affinity by mutagenizing the V H and V LDescribes affinity maturation by domain shuffling. Random mutagenesis of CDR and / or framework residues is described, for example, by Barbas et al., Proc. Nat. Acad. Sci. U.S.A., 1994, 91:3809-3813, Schier et al., Gene, 1995, 169:147-155, Yelton et al., J. Immunol., 1995, 155:1994-2004, Jackson et al., J. Immunol., 1995, 154:3310-33199, and Hawkins et al, J. Mol. Biol., 1992, 226:889-896, each of which is hereby incorporated by reference in its entirety.

[0158] "Fc effector function" refers to the biological activities mediated by the Fc region of an antibody, and the activities can vary depending on the isotype of the antibody. Examples of antibody effector functions include C1q binding that activates complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), and Fc receptor binding that activates antibody-dependent cell phagocytosis (ADCP).

[0159] As used herein in connection with two or more antibodies, the terms "compete with" or "cross-compete with" indicate that two or more antibodies compete for binding to an antigen (e.g., TF). In one representative assay, TF is coated on a surface and contacted with a first TF antibody, and then a second TF antibody is added. In another representative assay, a first TF antibody is coated on a surface and contacted with TF, and then a second TF antibody is added. In either assay, if the presence of the first TF antibody inhibits the binding of the second TF antibody, those antibodies compete with each other. The term "compete with" includes antibody combinations where one antibody inhibits the binding of another antibody, but no competition is observed when these antibodies are added in the reverse order. However, in some embodiments, the first and second antibodies inhibit each other's binding regardless of the order in which they are added. In some embodiments, one antibody inhibits the binding of another antibody to its antigen by at least 25%, at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, or at least 95%. One of ordinary skill in the art can select the concentration of antibodies to use in a competition assay based on the affinity of the antibodies for TF and the avidity of the antibodies. The assays described in this definition are exemplary, and one of ordinary skill in the art can use any suitable assay to determine whether antibodies compete with each other. Suitable assays are described, for example, in Cox et al., "Immunoassay Methods," in Assay Guidance Manual [Internet], updated December 24, 2014 (www.ncbi.nlm.nih.gov / books / NBK92434 / , accessed September 29, 2015), Silman et al., Cytometry, 2001, 44:30-37, and Finco et al., J. Pharm. Biomed. Anal., 2011, 54:351-358, each of which is incorporated by reference in its entirety.As provided in Example 8 of PCT / US2019 / 12427, filed on January 4, 2019, the antibodies of Group 25 and the antibodies of Group 43 compete with each other for binding to human TF, while the antibodies from Groups 1, 29, 39, and 54 do not compete with the antibodies of Groups 25 and 43 for binding to human TF.

[0160] Antibodies that specifically bind to a human antigen as used herein, if the K D value can be measured with a ForteBio Octet, are considered to bind to the same antigen of murine origin. Antibodies that specifically bind to a human antigen are considered to be "cross-reactive" with the same antigen of murine origin if the K D value is 20 times or less the corresponding K D value for each human antigen. For example, the antibodies M1593 described in U.S. Patent Nos. 8,722,044, 8,951,525, and 8,999,333, which are incorporated herein by reference in their entirety for all purposes, the humanized 5G9 antibody described in Ngo et al., 2007, Int J Cancer, 120(6):1261-1267, which is incorporated herein by reference in its entirety, and the chimeric ALT-836 antibody described in Hong et al, 2012, J Nucl Med, 53(11):1748-1754, which is incorporated herein by reference in its entirety, do not bind to murine TF. As provided in Examples 1 and 2 of PCT / US2019 / 12427, filed on January 4, 2019, the TF antibodies from Groups 25 and 43 bind to murine TF. For example, the TF antibodies 25G, 25G1, 25G9, and 43D8 are cross-reactive with murine TF.

[0161] Antibodies that specifically bind to a human antigen as used herein, if the K D value for the cynomolgus monkey antigen is, for each human antigen, the corresponding K DIf it is 15 times or less the value, it is regarded as having "cross-reactivity" with the same antigen of cynomolgus monkey origin. As provided in Example 1 of PCT / US2019 / 12427 filed on January 4, 2019, all antibodies tested from Groups 1, 25, 29, 39, 43, and 54 are cross-reactive with cynomolgus monkey TF.

[0162] The term "epitope" means a portion of an antigen to which an antibody specifically binds. Epitopes often include amino acid residues and / or sugar side chains that are accessible on the surface, and may have specific three-dimensional structural characteristics, as well as specific charge characteristics. Conformational epitopes and non-conformational epitopes are distinguished in that in the presence of a denaturing solvent, binding to the former can be lost, but binding to the latter cannot be lost. An epitope can include amino acid residues directly involved in binding and other amino acid residues not directly involved in binding. The epitope to which an antibody binds can be determined using known techniques for epitope determination, such as tests on antibody binding to TF variants having different point mutations, or chimeric TF variants.

[0163] The "percent identity" between a polypeptide sequence and a reference sequence is defined as the percentage of amino acid residues in the polypeptide sequence that are identical to the amino acid residues in the reference sequence, as observed after aligning these sequences to achieve the maximum percent sequence identity and introducing gaps as necessary. Alignment for determining the percent amino acid sequence identity can be achieved in a variety of ways within the skill of the art using commonly available computer software such as BLAST, BLAST-2, ALIGN, MEGALIGN (DNASTAR), CLUSTALW, CLUSTAL OMEGA, or MUSCLE software. One of ordinary skill in the art can determine appropriate parameters for aligning those sequences, such as any algorithm necessary to achieve the maximum alignment over the full length of the sequences being compared.

[0164] "Conservative substitution" or "conservative amino acid substitution" refers to substituting one amino acid with a chemically or functionally similar amino acid. Conservative substitution tables provide similar amino acids and are well known in the art. By way of example, the groups of amino acids provided in Tables 2-4 are considered to be conservative substitutions for one another in some embodiments.

[0165] (Table 2) Selected groups of amino acids considered to be conservative substitutions for one another in certain embodiments TIFF0007709636000086.tif27128

[0166] (Table 3) Further selected groups of amino acids considered to be conservative substitutions for one another in certain embodiments TIFF0007709636000087.tif27128

[0167] (Table 4) Further selected groups of amino acids considered to be conservative substitutions for one another in certain embodiments TIFF0007709636000088.tif36128

[0168] Further conservative substitutions can be found, for example, in Creighton, Proteins: Structures and Molecular Properties 2nd ed. (1993) W.H. Freeman & Co., New York, NY. Antibodies generated by making one or more conservative substitutions of the amino acid residues of the parent antibody are referred to as "conservative modified variants."

[0169] The term "amino acid" refers to the 20 common amino acids that occur naturally. The naturally occurring amino acids are alanine (Ala, A), arginine (Arg, R), asparagine (Asn, N), aspartic acid (Asp, D), cysteine (Cys, C), glutamic acid (Glu, E), glutamine (Gln, Q), glycine (Gly, G), histidine (His, H), isoleucine (Ile, I), leucine (Leu, L), lysine (Lys, K), methionine (Met, M), phenylalanine (Phe, F), proline (Pro, P), serine (Ser, S), threonine (Thr, T), tryptophan (Trp, W), tyrosine (Tyr, Y), and valine (Val, V).

[0170] As used herein, the term "vector" refers to a nucleic acid molecule capable of propagating another nucleic acid incorporated therein. This term includes vectors as self-replicating nucleic acid structures, as well as vectors incorporated into the genome of a host cell into which the vector has already been introduced. Certain vectors can direct the expression of nucleic acids operably linked thereto. Such vectors are referred to herein as "expression vectors".

[0171] The terms "host cell", "host cell line", and "host cell culture" are used interchangeably and refer to cells into which an exogenous nucleic acid has been introduced, and the progeny of such cells. Host cells include "transformants" (or "transformed cells") and "transfectants" (or "transfected cells"), which include, respectively, primary cells that have been transformed or transfected and progeny derived therefrom. Such progeny may not have the exact same nucleic acid content as the parental cell and may contain mutations.

[0172] The term "treating" (and its variations such as "treat" or "treatment") refers to a clinical intervention to effect a change in the natural course of a disease or condition in a subject in need thereof. Treatments can be administered both for prophylaxis and during clinical pathologic processes. Desirable effects of treatment include preventing the occurrence or recurrence of a disease, alleviating symptoms, reducing any direct or indirect pathologic consequences of the disease, preventing metastasis, decreasing the rate of disease progression, restoring or effecting primary alleviation of the condition, and improving remission or prognosis.

[0173] As used herein, the term "therapeutically effective amount" or "effective amount" refers to an amount of an antibody or pharmaceutical composition provided herein that is effective to treat a disease or disorder upon administration to a subject.

[0174] As used herein, the term "subject" means a mammalian subject. Representative subjects include humans, monkeys, dogs, cats, mice, rats, cows, horses, camels, goats, rabbits, pigs, and sheep. In certain embodiments, the subject is a human. In some embodiments, the subject has a disease or condition that can be treated with an antibody provided herein. In some aspects, the disease or condition is cancer. In some aspects, the disease or condition is associated with angiogenesis or vascular inflammation. In certain aspects, the disease or condition associated with angiogenesis is cancer.

[0175] The term "package insert" is used to refer to the instructions routinely included in the commercial package (e.g., kit) of a therapeutic or diagnostic product, which document contains information about the indications, usage, dosage, administration, combination therapies, contraindications, and / or warnings regarding the use of the therapeutic or diagnostic product.

[0176] "Chemotherapeutic agent" refers to a chemical substance useful in the treatment of cancer. Chemotherapeutic agents include "anti-hormonal agents" or "endocrine therapies" that act to modulate, attenuate, block, or inhibit the effects of hormones that can promote cancer growth.

[0177] The term "cell division inhibitor" refers to a compound or composition that halts cell growth either in vitro or in vivo. In some embodiments, the cell division inhibitor is an agent that reduces the percentage of cells in the S phase. In some embodiments, the cell division inhibitor reduces the percentage of cells in the S phase by at least about 20%, at least about 40%, at least about 60%, or at least about 80%.

[0178] The term "pharmaceutical composition" refers to a preparation in which the biological activity of the active ingredient therein renders it effective in treating a subject, and which contains no additional components, i.e., components that exhibit unacceptable toxicity to the subject in the amounts provided in the pharmaceutical composition.

[0179] The terms "modulate" and "modulation" refer to reducing or inhibiting, or in some cases, activating or increasing, the recited variable element.

[0180] The terms "increase" and "activate" refer to an increase of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 20-fold, 50-fold, 100-fold, or more of the recited variable element.

[0181] The terms "decrease" and "inhibit" refer to a decrease of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 20-fold, 50-fold, 100-fold, or more of the recited variable element.

[0182] The term "activate" refers to activating the signal transduction of a receptor to induce a biological response associated with the activation of the receptor. An "agonist" is an entity that binds to a receptor and activates it.

[0183] The term "antagonize" refers to inhibiting the signal transduction of a receptor and thereby inhibiting the biological responses associated with receptor activation. An "antagonist" is an entity that binds to a receptor and antagonizes it.

[0184] "Alkyl" refers to a radical of a straight-chain or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C 1-20 alkyl"). In some embodiments, the alkyl group has 1 to 12 carbon atoms ("C 1-12 alkyl"). In some embodiments, the alkyl group has 1 to 10 carbon atoms ("C 1-10 alkyl"). In some embodiments, the alkyl group has 1 to 9 carbon atoms ("C 1-9 alkyl"). In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C 1-8 alkyl"). In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C 1-7 alkyl"). In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C 1-6 alkyl"). In some embodiments, the alkyl group has 1 to 5 carbon atoms ("C 1-5 alkyl"). In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C 1-4 alkyl"). In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C 1-3 alkyl"). In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C 1-2 alkyl"). In some embodiments, the alkyl group has 1 carbon atom ("C1 alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C 2-6 alkyl"). C 1-6Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanil (C5), tertiary amyl (C5), and n-hexyl (C6). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise specified, each instance of an alkyl group is independently optional and substituted, i.e., unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents: for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkyl"). In certain embodiments, the alkyl group is unsubstituted C 1-10 alkyl (e.g., -CH3). In certain embodiments, the alkyl group is substituted C 1-10 alkyl. Common abbreviations for alkyl include Me (-CH3), Et (-CH2CH3), iPr (-CH(CH3)2), nPr (-CH2CH2CH3), n-Bu (-CH2CH2CH2CH3), or i-Bu (-CH2CH(CH3)2).

[0185] "Alkylene" refers to an alkyl group that removes two hydrogens to provide a divalent radical and that may be substituted or unsubstituted. Examples of unsubstituted alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2), etc. Exemplary substituted alkylene groups include, but are not limited to, those substituted with one or more alkyl (methyl) groups, such as substituted methylene (-CH(CH3)-, -C(CH3)2-), substituted ethylene (-CH)(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), etc.

[0186] "Halo" or "halogen" refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I). In certain embodiments, the halo group is either fluoro or chloro.

[0187] As used herein, the term "self-immolative group" provides a stable bond formation between two groups of a compound or conjugate, but becomes unstable upon activation (e.g., upon undergoing a nucleophilic attack), leading to rapid cleavage of a moiety or residue and separation of the two groups. The chemical nature of self-immolative groups is described, for example, in Alouane, A. et al., “Self-immolative spacers: kinetic aspects, structure-property relationships, and applications”, Angew. Chem. Int. Ed., 2015, 54, 7492-7509 and Kolakowski, R. V. et al., “The methylene alkoxy carbamate self-immolative unit: Utilization of the targeted delivery of alcohol-containing payloads with antibody-drug conjugates”, Angew. Chem. Int. Ed., 2016, 55, 7948-7951.

[0188] 2. TF antibody 2.1. TF binding The present specification provides an isolated antibody that specifically binds to TF. In some embodiments, TF is hTF (SEQ ID NO: 809). In some embodiments, TF is cTF (SEQ ID NO: 813). In some embodiments, TF is mTF (SEQ ID NO: 817). In some embodiments, TF is rabbit TF (SEQ ID NO: 832). In some embodiments, TF is pTF (SEQ ID NO: 824). In some embodiments, the antibody provided herein specifically binds to hTF (SEQ ID NO: 809), cTF (SEQ ID NO: 813), mTF (SEQ ID NO: 817), rabbit TF (SEQ ID NO: 832), and pTF (SEQ ID NO: 824). In some embodiments, the antibody provided herein specifically binds to hTF (SEQ ID NO: 809), cTF (SEQ ID NO: 813), mTF (SEQ ID NO: 817), and pTF (SEQ ID NO: 824). In some embodiments, the antibody provided herein specifically binds to hTF (SEQ ID NO: 809), cTF (SEQ ID NO: 813), and mTF (SEQ ID NO: 817). In some embodiments, the antibody provided herein specifically binds to hTF (SEQ ID NO: 809) and cTF (SEQ ID NO: 813). In some embodiments, the antibody provided herein does not bind to mTF (SEQ ID NO: 817). In some embodiments, the antibody provided herein does not bind to pTF (SEQ ID NO: 824). In some embodiments, the antibody provided herein does not bind to rabbit TF (SEQ ID NO: 832).

[0189] In various embodiments, the antibody provided herein specifically binds to the extracellular domain of human TF (SEQ ID NO: 810).

[0190] In some embodiments, the binding between the antibody provided herein and the extracellular domain of variant TF containing a mutation at amino acid residue 149 of the sequence shown in SEQ ID NO: 810 is less than 50% of the binding between the antibody provided herein and the extracellular domain of TF of the sequence shown in SEQ ID NO: 810, as determined by the median fluorescence intensity of the antibody compared to the isotype control in a live cell staining assay. In some embodiments, the mutation at amino acid residue 149 of the sequence shown in SEQ ID NO: 810 is K149N.

[0191] In some embodiments, the binding between the antibody provided herein and the extracellular domain of a variant TF comprising a mutation at amino acid residue 68 of the sequence shown in SEQ ID NO: 810 is, according to the median fluorescence intensity of the antibody compared to an isotype control in a live cell staining assay, more than 50% of the binding between the antibody provided herein and the extracellular domain of the TF of the sequence shown in SEQ ID NO: 810. In some embodiments, the mutation at amino acid residue 68 of the sequence shown in SEQ ID NO: 810 is K68N.

[0192] In some embodiments, the binding between the antibody provided herein and the extracellular domain of a variant TF comprising mutations at amino acid residues 171 and 197 of the sequence shown in SEQ ID NO: 810 is, according to the median fluorescence intensity of the antibody compared to an isotype control in a live cell staining assay, less than 50% of the binding between the antibody provided herein and the extracellular domain of the TF of the sequence shown in SEQ ID NO: 810. In some embodiments, the mutations at amino acid residues 171 and 197 of the sequence shown in SEQ ID NO: 810 are N171H and T197K.

[0193] In some embodiments, the binding between the antibody provided herein and the extracellular domain of human TF is, when amino acid residues 1-77 of the sequence shown in SEQ ID NO: 810 are replaced with amino acid residues 1-76 of the extracellular domain of rat TF of the sequence shown in SEQ ID NO: 838, according to the median fluorescence intensity of the antibody compared to an isotype control in a live cell staining assay, more than 50% of the binding between the antibody and the extracellular domain of the TF of the sequence shown in SEQ ID NO: 810.

[0194] In some embodiments, the binding between the antibody provided herein and the extracellular domain of human TF is, when amino acid residues 39-77 of the sequence shown in SEQ ID NO: 810 are replaced with amino acid residues 38-76 of the extracellular domain of rat TF of the sequence shown in SEQ ID NO: 838, according to the median fluorescence intensity of the antibody compared to an isotype control in a live cell staining assay, more than 50% of the binding between the antibody and the extracellular domain of the TF of the sequence shown in SEQ ID NO: 810.

[0195] In some embodiments, when the amino acid residues 94-107 of the sequence shown in SEQ ID NO: 810 are replaced with the amino acid residues 99-112 of the extracellular domain of rat TF of the sequence shown in SEQ ID NO: 838, the binding between the antibody provided herein and the extracellular domain of human TF is more than 50% of the binding between the antibody and the extracellular domain of TF of the sequence shown in SEQ ID NO: 810, as determined by the median fluorescence intensity of the antibody compared to the isotype control in a live cell staining assay.

[0196] In some embodiments, when the amino acid residues 146-158 of the sequence shown in SEQ ID NO: 810 are replaced with the amino acid residues 151-163 of the extracellular domain of rat TF of the sequence shown in SEQ ID NO: 838, the binding between the antibody provided herein and the extracellular domain of human TF is less than 50% of the binding between the antibody and the extracellular domain of TF of the sequence shown in SEQ ID NO: 810, as determined by the median fluorescence intensity of the antibody compared to the isotype control in a live cell staining assay.

[0197] In some embodiments, when the amino acid residues 159-219 of the sequence shown in SEQ ID NO: 810 are replaced with the amino acid residues 164-224 of the extracellular domain of rat TF of the sequence shown in SEQ ID NO: 838, the binding between the antibody provided herein and the extracellular domain of human TF is less than 50% of the binding between the antibody and the extracellular domain of TF of the sequence shown in SEQ ID NO: 810, as determined by the median fluorescence intensity of the antibody compared to the isotype control in a live cell staining assay.

[0198] In some embodiments, when the amino acid residues 159-189 of the sequence shown in SEQ ID NO: 810 are replaced with the amino acid residues 164-194 of the extracellular domain of rat TF of the sequence shown in SEQ ID NO: 838, the binding between the antibody provided herein and the extracellular domain of human TF is less than 50% of the binding between the antibody and the extracellular domain of TF of the sequence shown in SEQ ID NO: 810, as determined by the median fluorescence intensity of the antibody compared to the isotype control in a live cell staining assay.

[0199] In some embodiments, when the amino acid residues 159-174 of the sequence shown in SEQ ID NO: 810 are replaced with the amino acid residues 164-179 of the extracellular domain of rat TF of the sequence shown in SEQ ID NO: 838, the binding between the antibody provided herein and the extracellular domain of human TF is less than 50% of the binding between the antibody and the extracellular domain of TF of the sequence shown in SEQ ID NO: 810, as determined by the median fluorescence intensity of the antibody compared to the isotype control in a live cell staining assay.

[0200] In some embodiments, when the amino acid residues 167-174 of the sequence shown in SEQ ID NO: 810 are replaced with the amino acid residues 172-179 of the extracellular domain of rat TF of the sequence shown in SEQ ID NO: 838, the binding between the antibody provided herein and the extracellular domain of human TF is less than 50% of the binding between the antibody and the extracellular domain of TF of the sequence shown in SEQ ID NO: 810, as determined by the median fluorescence intensity of the antibody compared to the isotype control in a live cell staining assay.

[0201] In some embodiments, when the amino acid residues 141-194 of the sequence shown in SEQ ID NO: 838 are replaced with the amino acid residues 136-189 of the extracellular domain of human TF of the sequence shown in SEQ ID NO: 810, the binding between the antibody provided herein and the extracellular domain of rat TF is more than 50% of the binding between the antibody provided herein and the extracellular domain of TF of the sequence shown in SEQ ID NO: 810, as determined by the median fluorescence intensity of the antibody compared to the isotype control in a live cell staining assay.

[0202] In some embodiments, according to the median fluorescence intensity of the antibody compared to the isotype control in a live cell staining assay, the binding between the antibody provided herein and the extracellular domain of the variant TF containing a mutation at amino acid residue 149 of the sequence shown in SEQ ID NO: 810 is less than 50% of the binding between the antibody provided herein and the extracellular domain of the TF of the sequence shown in SEQ ID NO: 810; the binding between the antibody provided herein and the extracellular domain of the variant TF containing a mutation at amino acid residue 68 of the sequence shown in SEQ ID NO: 810 is more than 50% of the binding between the antibody provided herein and the extracellular domain of the TF of the sequence shown in SEQ ID NO: 810; the binding between the antibody provided herein and the extracellular domain of human TF is more than 50% of the binding between the antibody and the extracellular domain of the TF of the sequence shown in SEQ ID NO: 810 when amino acid residues 1-77 of the sequence shown in SEQ ID NO: 810 are replaced with amino acid residues 1-76 of the extracellular domain of the rat TF of the sequence shown in SEQ ID NO: 838; the binding between the antibody provided herein and the extracellular domain of human TF is more than 50% of the binding between the antibody and the extracellular domain of the TF of the sequence shown in SEQ ID NO: 810 when amino acid residues 39-77 of the sequence shown in SEQ ID NO: 810 are replaced with amino acid residues 38-76 of the extracellular domain of the rat TF of the sequence shown in SEQ ID NO: 838; the binding between the antibody provided herein and the extracellular domain of human TF is more than 50% of the binding between the antibody and the extracellular domain of the TF of the sequence shown in SEQ ID NO: 810 when amino acid residues 94-107 of the sequence shown in SEQ ID NO: 810 are replaced with amino acid residues 99-112 of the extracellular domain of the rat TF of the sequence shown in SEQ ID NO: 838; the binding between the antibody provided herein and the extracellular domain of human TF is less than 50% of the binding between the antibody and the extracellular domain of the TF of the sequence shown in SEQ ID NO: 810 when amino acid residues 146-158 of the sequence shown in SEQ ID NO: 810 are replaced with amino acid residues 151-163 of the extracellular domain of the rat TF of the sequence shown in SEQ ID NO: 838;Moreover, when the binding between the antibody provided in this specification and the extracellular domain of rat TF is such that amino acid residues 141 to 194 of the sequence shown in SEQ ID NO: 838 are replaced with amino acid residues 136 to 189 of the extracellular domain of human TF of the sequence shown in SEQ ID NO: 810, it is more than 50% of the binding between the antibody provided in this specification and the extracellular domain of TF of the sequence shown in SEQ ID NO: 810. In some embodiments, the mutation at amino acid residue 149 of the sequence shown in SEQ ID NO: 810 is K149N; and the mutation at amino acid residue 68 of the sequence shown in SEQ ID NO: 810 is K68N.;

[0203] In some embodiments, according to the median fluorescence intensity of the antibody compared to the isotype control in the live cell staining assay, the binding between the antibody provided herein and the extracellular domain of the variant TF containing a mutation at amino acid residue 149 of the sequence shown in SEQ ID NO: 810 is less than 50% of the binding between the antibody provided herein and the extracellular domain of the TF of the sequence shown in SEQ ID NO: 810; the binding between the antibody provided herein and the extracellular domain of the variant TF containing a mutation at amino acid residue 68 of the sequence shown in SEQ ID NO: 810 is more than 50% of the binding between the antibody provided herein and the extracellular domain of the TF of the sequence shown in SEQ ID NO: 810; the binding between the antibody provided herein and the extracellular domain of the variant TF containing mutations at amino acid residues 171 and 197 of the sequence shown in SEQ ID NO: 810 is less than 50% of the binding between the antibody provided herein and the extracellular domain of the TF of the sequence shown in SEQ ID NO: 810; the binding between the antibody provided herein and the extracellular domain of human TF is more than 50% of the binding between the antibody and the extracellular domain of the TF of the sequence shown in SEQ ID NO: 810 when amino acid residues 1-77 of the sequence shown in SEQ ID NO: 810 are replaced with amino acid residues 1-76 of the extracellular domain of the rat TF of the sequence shown in SEQ ID NO: 838; the binding between the antibody provided herein and the extracellular domain of human TF is more than 50% of the binding between the antibody and the extracellular domain of the TF of the sequence shown in SEQ ID NO: 810 when amino acid residues 39-77 of the sequence shown in SEQ ID NO: 810 are replaced with amino acid residues 38-76 of the extracellular domain of the rat TF of the sequence shown in SEQ ID NO: 838; the binding between the antibody provided herein and the extracellular domain of human TF is more than 50% of the binding between the antibody and the extracellular domain of the TF of the sequence shown in SEQ ID NO: 810 when amino acid residues 94-107 of the sequence shown in SEQ ID NO: 810 are replaced with amino acid residues 99-112 of the extracellular domain of the rat TF of the sequence shown in SEQ ID NO: 838;The binding between the antibody provided herein and the extracellular domain of human TF is less than 50% of the binding between the antibody and the extracellular domain of TF of the sequence shown in SEQ ID NO: 810 when amino acid residues 146-158 of the sequence shown in SEQ ID NO: 810 are replaced with amino acid residues 151-163 of the extracellular domain of rat TF of the sequence shown in SEQ ID NO: 838; the binding between the antibody provided herein and the extracellular domain of human TF is less than 50% of the binding between the antibody and the extracellular domain of TF of the sequence shown in SEQ ID NO: 810 when amino acid residues 159-219 of the sequence shown in SEQ ID NO: 810 are replaced with amino acid residues 164-224 of the extracellular domain of rat TF of the sequence shown in SEQ ID NO: 838; the binding between the antibody provided herein and the extracellular domain of human TF is less than 50% of the binding between the antibody and the extracellular domain of TF of the sequence shown in SEQ ID NO: 810 when amino acid residues 159-189 of the sequence shown in SEQ ID NO: 810 are replaced with amino acid residues 164-194 of the extracellular domain of rat TF of the sequence shown in SEQ ID NO: 838; the binding between the antibody provided herein and the extracellular domain of human TF is less than 50% of the binding between the antibody and the extracellular domain of TF of the sequence shown in SEQ ID NO: 810 when amino acid residues 159-174 of the sequence shown in SEQ ID NO: 810 are replaced with amino acid residues 164-179 of the extracellular domain of rat TF of the sequence shown in SEQ ID NO: 838; the binding between the antibody provided herein and the extracellular domain of human TF is less than 50% of the binding between the antibody and the extracellular domain of TF of the sequence shown in SEQ ID NO: 810 when amino acid residues 167-174 of the sequence shown in SEQ ID NO: 810 are replaced with amino acid residues 172-179 of the extracellular domain of rat TF of the sequence shown in SEQ ID NO: 838; and the binding between the antibody provided herein and the extracellular domain of rat TF is more than 50% of the binding between the antibody provided herein and the extracellular domain of TF of the sequence shown in SEQ ID NO: 810 when amino acid residues 141-194 of the sequence shown in SEQ ID NO: 838 are replaced with amino acid residues 136-189 of the extracellular domain of human TF of the sequence shown in SEQ ID NO: 810. In some embodiments, the mutation at amino acid residue 149 of the sequence shown in SEQ ID NO: 810 is K149N;The mutation at amino acid residue 68 of the sequence shown in SEQ ID NO: 810 is K68N; and the mutations at amino acid residues 171 and 197 of the sequence shown in SEQ ID NO: 810 are N171H and T197K.

[0204] In some embodiments, the antibodies provided herein are inactive in inhibiting human thrombin generation according to a thrombin generation assay (TGA), compared to the reference antibody M1593, where the reference antibody M1593 has the V H sequence of SEQ ID NO: 821 and the V L sequence of SEQ ID NO: 822.

[0205] In some embodiments, the antibodies provided herein do not inhibit the generation of human thrombin according to a thrombin generation assay (TGA). In certain embodiments, the antibodies provided herein permit the generation of human thrombin according to a thrombin generation assay (TGA).

[0206] In some embodiments, the antibodies provided herein bind to human TF at a human TF binding site distinct from the human TF binding site to which human FX binds. In certain embodiments, the antibodies provided herein do not interfere with the ability of TF:FVIIa to convert FX to FXa.

[0207] In some embodiments, the antibodies provided herein bind to human TF at a human TF binding site distinct from the human TF binding site to which human FVIIa binds. In certain embodiments, the antibodies provided herein do not compete with human FVIIa for binding to human TF.

[0208] In some embodiments, the antibodies provided herein bind to human TF at a human TF binding site distinct from the human TF binding site to which human FVIIa binds, at a human TF binding site distinct from the human TF binding site to which human FX binds, at a human TF binding site in the extracellular domain of human TF, and permit the generation of human thrombin according to a thrombin generation assay (TGA).

[0209] In some embodiments, the antibodies provided herein bind to the extracellular domain of human TF, do not inhibit the generation of human thrombin according to the thrombin generation assay (TGA), do not interfere with the ability of TF:FVIIa to convert FX to FXa, and do not compete with human FVIIa for binding to human TF.

[0210] In some embodiments, the antibodies provided herein bind to the extracellular domain of human TF at a human TF binding site distinct from the human TF binding site to which human FVIIa binds, do not inhibit the generation of human thrombin according to the thrombin generation assay (TGA), allow the generation of human thrombin according to the thrombin generation assay (TGA), bind to human TF at a human TF binding site distinct from the human TF binding site to which human FX binds, do not interfere with the ability of TF:FVIIa to convert FX to FXa, and do not compete with human FVIIa for binding to human TF.

[0211] In some embodiments, the antibodies provided herein inhibit FVIIa-dependent TF signaling.

[0212] In some embodiments, the antibodies provided herein bind to the extracellular domain of human TF at a human TF binding site distinct from the human TF binding site to which human FVIIa binds, do not inhibit the generation of human thrombin according to the thrombin generation assay (TGA), allow the generation of human thrombin according to the thrombin generation assay (TGA), bind to human TF at a human TF binding site distinct from the human TF binding site to which human FX binds, do not interfere with the ability of TF:FVIIa to convert FX to FXa, do not compete with human FVIIa for binding to human TF, and bind to cynomolgus and mouse TF.

[0213] In some embodiments, the antibodies provided herein bind to the extracellular domain of human TF at a human TF binding site distinct from the human TF binding site to which human FVIIa binds, do not inhibit the generation of human thrombin according to a thrombin generation assay (TGA), allow the generation of human thrombin according to a thrombin generation assay (TGA), bind to human TF at a human TF binding site distinct from the human TF binding site to which human FX binds, do not interfere with the ability of TF:FVIIa to convert FX to FXa, do not compete with human FVIIa for binding to human TF, and bind to cynomolgus monkey, mouse, and porcine TF.

[0214] In some embodiments, the antibodies provided herein bind to the extracellular domain of human TF, inhibit FVIIa-dependent TF signaling, and bind to cynomolgus monkey TF.

[0215] 2.2. TF Antibody Sequences 2.2.1. Heavy Chain In some embodiments, the antibodies provided herein comprise a heavy chain sequence. Exemplary heavy chain sequences are shown in Table 22. The heavy chain sequence can be the heavy chain sequence from the antibody clone identified as 25A. The heavy chain sequence can be the heavy chain sequence from the antibody clone identified as 25A3. The heavy chain sequence can be the heavy chain sequence from the antibody clone identified as 25A5. The heavy chain sequence can be the heavy chain sequence from the antibody clone identified as 25A5T. The heavy chain sequence can be the heavy chain sequence from the antibody clone identified as 25G. The heavy chain sequence can be the heavy chain sequence from the antibody clone identified as 25G1. The heavy chain sequence can be the heavy chain sequence from the antibody clone identified as 25G9.

[0216] 2.2.2. Light Chain In some embodiments, the antibodies provided herein include a light chain sequence. Exemplary light chain sequences are shown in Table 22. The light chain sequence can be the light chain sequence derived from the antibody clone identified as 25A. The light chain sequence can be the light chain sequence derived from the antibody clone identified as 25A3. The light chain sequence can be the light chain sequence derived from the antibody clone identified as 25A5. The light chain sequence can be the light chain sequence derived from the antibody clone identified as 25A5T. The light chain sequence can be the light chain sequence derived from the antibody clone identified as 25G. The light chain sequence can be the light chain sequence derived from the antibody clone identified as 25G1. The light chain sequence can be the light chain sequence derived from the antibody clone identified as 25G9.

[0217] 2.2.3.V H Domain In some embodiments, the antibodies provided herein include a V selected from SEQ ID NOs: 113, 151, 189, 836, 227, 265, 303, 763, 868, and 870. H sequence. In some embodiments, the antibodies provided herein include the V of SEQ ID NO: 113. H sequence. In some embodiments, the antibodies provided herein include the V of SEQ ID NO: 151. H sequence. In some embodiments, the antibodies provided herein include the V of SEQ ID NO: 189. H sequence. In some embodiments, the antibodies provided herein include the V of SEQ ID NO: 836. H sequence. In some embodiments, the antibodies provided herein include the V of SEQ ID NO: 227. H sequence. In some embodiments, the antibodies provided herein include the V of SEQ ID NO: 265. H sequence. In some embodiments, the antibodies provided herein include the V of SEQ ID NO: 303. H sequence. In some embodiments, the antibodies provided herein include the V of SEQ ID NO: 763. H sequence. In some embodiments, the antibodies provided herein include the V of SEQ ID NO: 868. H sequence.

[0218] In some embodiments, the antibodies provided herein have exemplary V selected from SEQ ID NOs: 113, 151, 189, 836, 227, 265, 303, 763, 868, and 870 H sequences having at least about 50%, 60%, 70%, 80%, 90%, 95%, or 99% identity to the H sequences. In some embodiments, the antibodies provided herein have a V selected from SEQ ID NOs: 113, 151, 189, 836, 227, 265, 303, 763, 868, and 870 H sequences and have at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 amino acid substitutions. In some aspects, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, the antibodies described in this paragraph are referred to herein as "variants". In some embodiments, such variants are derived from the sequences provided herein, for example, by affinity maturation, site-directed mutagenesis, random mutagenesis, or any other method known in the art or described herein. In some embodiments, such variants are not derived from the sequences provided herein and can be newly isolated, for example, according to the methods for obtaining the antibodies provided herein.

[0219] 2.2.4. V L domain In some embodiments, the antibodies provided herein have a V selected from SEQ ID NOs: 114, 152, 190, 837, 228, 266, 304, 764, 869, and 871 L sequences. In some embodiments, the antibodies provided herein have the V of SEQ ID NO: 114 L sequences. In some embodiments, the antibodies provided herein have the V of SEQ ID NO: 152 L sequences. In some embodiments, the antibodies provided herein have the V of SEQ ID NO: 190 L sequences. In some embodiments, the antibodies provided herein have the V of SEQ ID NO: 837 LIt includes a sequence. In some embodiments, the antibodies provided herein have a V of SEQ ID NO: 228 L It includes a sequence. In some embodiments, the antibodies provided herein have a V of SEQ ID NO: 266 L It includes a sequence. In some embodiments, the antibodies provided herein have a V of SEQ ID NO: 304 L It includes a sequence. In some embodiments, the antibodies provided herein have a V of SEQ ID NO: 764 L It includes a sequence. In some embodiments, the antibodies provided herein have a V of SEQ ID NO: 869 L It includes a sequence. In some embodiments, the antibodies provided herein have a V of SEQ ID NO: 871 L It includes a sequence.

[0220] In some embodiments, the antibodies provided herein have a V that has at least about 50%, 60%, 70%, 80%, 90%, 95%, or 99% identity to an exemplary VL sequence selected from SEQ ID NOs: 114, 152, 190, 837, 228, 266, 304, 764, 869, and 871 L It includes a sequence. In some embodiments, the antibodies provided herein have a V selected from SEQ ID NOs: 114, 152, 190, 837, 228, 266, 304, 764, 869, and 871 L It includes a sequence and has at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 amino acid substitutions. In some aspects, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, the antibodies described in this paragraph are referred to herein as "variants". In some embodiments, such variants are derived from the sequences provided herein by, for example, affinity maturation, site-directed mutagenesis, random mutagenesis, or any other method known in the art or described herein. In some embodiments, such variants are not derived from the sequences provided herein and can be newly isolated, for example, according to the methods for obtaining the antibodies provided herein.

[0221] 2.2.5.V H-V L combination In some embodiments, the antibodies provided herein have a V selected from SEQ ID NOs: 113, 151, 189, 836, 227, 265, 303, 763, 868, and 870 H sequence and a V selected from SEQ ID NOs: 114, 152, 190, 837, 228, 266, 304, 764, 869, and 871 L sequence.

[0222] In some embodiments, the antibodies provided herein comprise the VH sequence of SEQ ID NO: 113 and the VL sequence of SEQ ID NO: 114. In some embodiments, the antibodies provided herein comprise the VH sequence of SEQ ID NO: 151 and the VL sequence of SEQ ID NO: 152. In some embodiments, the antibodies provided herein comprise the VH sequence of SEQ ID NO: 189 and the VL sequence of SEQ ID NO: 190. In some embodiments, the antibodies provided herein comprise the VH sequence of SEQ ID NO: 836 and the VL sequence of SEQ ID NO: 837. In some embodiments, the antibodies provided herein comprise the VH sequence of SEQ ID NO: 227 and the VL sequence of SEQ ID NO: 228. In some embodiments, the antibodies provided herein comprise the VH sequence of SEQ ID NO: 265 and the VL sequence of SEQ ID NO: 266. In some embodiments, the antibodies provided herein comprise the VH sequence of SEQ ID NO: 303 and the VL sequence of SEQ ID NO: 304. In some embodiments, the antibodies provided herein comprise the VH sequence of SEQ ID NO: 763 and the VL sequence of SEQ ID NO: 764. In some embodiments, the antibodies provided herein comprise the VH sequence of SEQ ID NO: 868 and the VL sequence of SEQ ID NO: 869. In some embodiments, the antibodies provided herein comprise the VH sequence of SEQ ID NO: 870 and the VL sequence of SEQ ID NO: 871.

[0223] In some embodiments, the antibodies provided herein have an exemplary V selected from SEQ ID NOs: 113, 151, 189, 836, 227, 265, 303, 763, 868, and 870 H sequence that has at least about 50%, 60%, 70%, 80%, 90%, 95%, or 99% identity to the V HAn array and an exemplary VL array selected from array numbers 114, 152, 190, 837, 228, 266, 304, 764, 869, and 871, having at least about 50%, 60%, 70%, 80%, 90%, 95%, or 99% identity to the V L including. In some embodiments, the antibodies provided herein are selected from array numbers 113, 151, 189, 836, 227, 265, 303, 763, 868, and 870, and have at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 amino acid substitutions in the V H array and an exemplary VL array selected from array numbers 114, 152, 190, 837, 228, 266, 304, 764, 869, and 871, having at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 amino acid substitutions in the V L array. In some aspects, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, the antibodies described in this paragraph are referred to herein as "variants." In some embodiments, such variants are derived from the sequences provided herein, for example, by affinity maturation, site-directed mutagenesis, random mutagenesis, or any other method known in the art or described herein. In some embodiments, such variants are not derived from the sequences provided herein and can be newly isolated, for example, according to the methods for obtaining the antibodies provided herein.

[0224] 2.2.6.CDR In some embodiments, the antibodies provided herein include 1 to 3 CDRs of the V H domain selected from array numbers 113, 151, 189, 836, 227, 265, 303, 763, 868, and 870. In some embodiments, the antibodies provided herein include 1 to 3 CDRs of the V HIt includes two to three CDRs of the domain. In some embodiments, the antibodies provided herein are V selected from SEQ ID NOs: 113, 151, 189, 836, 227, 265, 303, 763, 868, and 870 H It includes three CDRs of the domain. In some aspects, the CDRs are exemplary CDRs. In some aspects, the CDRs are Kabat CDRs. In some aspects, the CDRs are Chothia CDRs. In some aspects, the CDRs are AbM CDRs. In some aspects, the CDRs are Contact CDRs. In some aspects, the CDRs are IMGT CDRs.

[0225] In some embodiments, the CDRs have at least about 50%, 75%, 80%, 85%, 90%, or 95% identity to the CDR-H1, CDR-H2, or CDR-H3 of SEQ ID NOs: 113, 151, 189, 836, 227, 265, 303, 763, 868, and 870. In some embodiments, CDR-H1 is the CDR-H1 of the V selected from SEQ ID NOs: 113, 151, 189, 836, 227, 265, 303, 763, 868, and 870 and has at most 1, 2, 3, 4, or 5 amino acid substitutions. In some embodiments, CDR-H2 is the CDR-H2 of the V selected from SEQ ID NOs: 113, 151, 189, 836, 227, 265, 303, 763, 868, and 870 and has at most 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some embodiments, CDR-H3 is the CDR-H3 of the V selected from SEQ ID NOs: 113, 151, 189, 836, 227, 265, 303, 763, 868, and 870 H It is the CDR-H1 of the domain and has at most 1, 2, 3, 4, or 5 amino acid substitutions. In some embodiments, CDR-H2 is the CDR-H2 of the V selected from SEQ ID NOs: 113, 151, 189, 836, 227, 265, 303, 763, 868, and 870 H It is the CDR-H2 of the domain and has at most 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some embodiments, CDR-H3 is the CDR-H3 of the V selected from SEQ ID NOs: 113, 151, 189, 836, 227, 265, 303, 763, 868, and 870 HIt is the CDR-H3 of the domain and has at most 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, the antibodies described in this paragraph are referred to herein as "variants". In some embodiments, such variants are derived from the sequences provided herein by, for example, affinity maturation, site-directed mutagenesis, random mutagenesis, or any other method known in the art or described herein. In some embodiments, such variants are not derived from the sequences provided herein and can be newly isolated, for example, according to the methods for obtaining the antibodies provided herein.

[0226] In some embodiments, the antibodies provided herein comprise 1 to 3 CDRs of the V domain selected from SEQ ID NOs: 114, 152, 190, 837, 228, 266, 304, 764, 869, and 871. L In some embodiments, the antibodies provided herein comprise 2 to 3 CDRs of the V domain selected from SEQ ID NOs: 114, 152, 190, 837, 228, 266, 304, 764, 869, and 871. L In some embodiments, the antibodies provided herein comprise 3 CDRs of the V domain selected from SEQ ID NOs: 114, 152, 190, 837, 228, 266, 304, 764, 869, and 871. L In some embodiments, the antibodies provided herein comprise 3 CDRs of the V domain selected from SEQ ID NOs: 114, 152, 190, 837, 228, 266, 304, 764, 869, and 871. In some aspects, the CDRs are exemplary CDRs. In some aspects, the CDRs are Kabat CDRs. In some aspects, the CDRs are Chothia CDRs. In some aspects, the CDRs are AbM CDRs. In some aspects, the CDRs are Contact CDRs. In some aspects, the CDRs are IMGT CDRs.

[0227] In some embodiments, the CDR has at least about 50%, 75%, 80%, 85%, 90%, or 95% identity to the CDR-L1, CDR-L2, or CDR-L3 of SEQ ID NOs: 114, 152, 190, 837, 228, 266, 304, 764, 869, and 871. In some embodiments, CDR-L1 is the CDR-L1 of the V L domain selected from SEQ ID NOs: 114, 152, 190, 837, 228, 266, 304, 764, 869, and 871 and has at most 1, 2, 3, 4, or 5 amino acid substitutions. In some embodiments, CDR-L2 is the CDR-L2 of the V L domain selected from SEQ ID NOs: 114, 152, 190, 837, 228, 266, 304, 764, 869, and 871 and has at most 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some embodiments, CDR-L3 is the CDR-L3 of the V L domain selected from SEQ ID NOs: 114, 152, 190, 837, 228, 266, 304, 764, 869, and 871 and has at most 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions. In some aspects, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, the antibodies described in this paragraph are referred to herein as "variants". In some embodiments, such variants are derived from the sequences provided herein, for example, by affinity maturation, site-directed mutagenesis, random mutagenesis, or any other method known in the art or described herein. In some embodiments, such variants are not derived from the sequences provided herein and can be newly isolated, for example, according to the methods for obtaining the antibodies provided herein.

[0228] In some embodiments, the antibodies provided herein have 1 to 3 CDRs of the V H domain selected from SEQ ID NOs: 113, 151, 189, 836, 227, 265, 303, 763, 868, and 870, and the V LIt includes one to three CDRs of the domain. In some embodiments, the antibodies provided herein are V selected from SEQ ID NOs: 113, 151, 189, 836, 227, 265, 303, 763, 868, and 870 H It includes two to three CDRs of the domain and V selected from SEQ ID NOs: 114, 152, 190, 837, 228, 266, 304, 764, 869, and 871 L It includes two to three CDRs of the domain. In some embodiments, the antibodies provided herein are V selected from SEQ ID NOs: 113, 151, 189, 836, 227, 265, 303, 763, 868, and 870 H It includes three CDRs of the domain and V selected from SEQ ID NOs: 114, 152, 190, 837, 228, 266, 304, 764, 869, and 871 L It includes three CDRs of the domain. In some aspects, the CDRs are exemplary CDRs. In some aspects, the CDRs are Kabat CDRs. In some aspects, the CDRs are Chothia CDRs. In some aspects, the CDRs are AbM CDRs. In some aspects, the CDRs are Contact CDRs. In some aspects, the CDRs are IMGT CDRs.

[0229] In some embodiments, the CDRs have at least about 50%, 75%, 80%, 85%, 90%, or 95% identity to CDR-H1, CDR-H2, or CDR-H3 of SEQ ID NOs: 113, 151, 189, 836, 227, 265, 303, 763, 868, and 870, and at least about 50%, 75%, 80%, 85%, 90%, or 95% identity to CDR-L1, CDR-L2, or CDR-L3 of SEQ ID NOs: 114, 152, 190, 837, 228, 266, 304, 764, 869, and 871. In some embodiments, CDR-H1 is V selected from SEQ ID NOs: 113, 151, 189, 836, 227, 265, 303, 763, 868, and 870 HIt is CDR-H1 of the domain and has at most 1, 2, 3, 4, or 5 amino acid substitutions; CDR-H2 is a V selected from SEQ ID NOs: 113, 151, 189, 836, 227, 265, 303, 763, 868, and 870 H It is CDR-H2 of the domain and has at most 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions; CDR-H3 is a V selected from SEQ ID NOs: 113, 151, 189, 836, 227, 265, 303, 763, 868, and 870 H It is CDR-H3 of the domain and has at most 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions; CDR-L1 is a V selected from SEQ ID NOs: 114, 152, 190, 837, 228, 266, 304, 764, 869, and 871 L It is CDR-L1 of the domain and has at most 1, 2, 3, 4, 5, or 6 amino acid substitutions; CDR-L2 is a V selected from SEQ ID NOs: 114, 152, 190, 837, 228, 266, 304, 764, 869, and 871 L It is CDR-L2 of the domain and has at most 1, 2, 3, or 4 amino acid substitutions; and CDR-L3 is a V selected from SEQ ID NOs: 114, 152, 190, 837, 228, 266, 304, 764, 869, and 871 L It is CDR-L3 of the domain and has at most 1, 2, 3, 4, or 5 amino acid substitutions. In some embodiments, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, the antibodies described in this paragraph are referred to herein as "variants". In some embodiments, such variants are derived from the sequences provided herein by, for example, affinity maturation, site-directed mutagenesis, random mutagenesis, or any other method known in the art or described herein. In some embodiments, such variants are not derived from the sequences provided herein and can be newly isolated, for example, according to the methods for obtaining antibodies provided herein.

[0230] 25A CDR In some embodiments, the antibody comprises a heavy chain CDR sequence derived from antibody clone 25A. Exemplary antibody 25A CDR sequences determined by the Kabat, Chothia, AbM, Contact, and IMGT numbering systems are shown in Table 7. In some embodiments, the antibody comprises a CDR-H3 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-H3 sequence derived from antibody clone 25A. In some embodiments, the antibody comprises a CDR-H2 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-H2 sequence derived from antibody clone 25A. In some embodiments, the antibody comprises a CDR-H1 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-H1 sequence derived from antibody clone 25A. In some embodiments, the antibody comprises two heavy chain CDRs that are 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the corresponding two heavy chain CDRs derived from antibody clone 25A. In some embodiments, the antibody comprises three heavy chain CDRs that are 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the three heavy chain CDRs derived from antibody clone 25A.

[0231] In some embodiments, the antibody comprises a light chain CDR sequence derived from antibody clone 25A. In some embodiments, the antibody comprises a CDR-L3 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-L3 sequence derived from antibody clone 25A. In some embodiments, the antibody comprises a CDR-L2 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-L2 sequence derived from antibody clone 25A. In some embodiments, the antibody comprises a CDR-L1 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-L1 sequence derived from antibody clone 25A. In some embodiments, the antibody comprises two light chain CDRs that are 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the corresponding two light chain CDRs derived from antibody clone 25A. In some embodiments, the antibody comprises three light chain CDRs that are 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the three light chain CDRs derived from antibody clone 25A.

[0232] In some embodiments, the antibody comprises a CDR-H3 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-H3 sequence derived from antibody clone 25A and a CDR-L3 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-L3 sequence derived from antibody clone 25A. In some embodiments, the antibody comprises six CDR sequences that are 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the corresponding six CDRs derived from antibody clone 25A.

[0233] 25A3 CDR In some embodiments, the antibody comprises a heavy chain CDR sequence derived from antibody clone 25A3. Exemplary antibody 25A3 CDR sequences determined by the Kabat, Chothia, AbM, Contact, and IMGT numbering systems are shown in Table 8. In some embodiments, the antibody comprises a CDR-H3 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-H3 sequence derived from antibody clone 25A3. In some embodiments, the antibody comprises a CDR-H2 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-H2 sequence derived from antibody clone 25A3. In some embodiments, the antibody comprises a CDR-H1 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-H1 sequence derived from antibody clone 25A3. In some embodiments, the antibody comprises two heavy chain CDRs that are 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the corresponding two heavy chain CDRs derived from antibody clone 25A3. In some embodiments, the antibody comprises three heavy chain CDRs that are 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the three heavy chain CDRs derived from antibody clone 25A3.

[0234] In some embodiments, the antibody comprises a light chain CDR sequence derived from antibody clone 25A3. In some embodiments, the antibody comprises a CDR-L3 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-L3 sequence derived from antibody clone 25A3. In some embodiments, the antibody comprises a CDR-L2 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-L2 sequence derived from antibody clone 25A3. In some embodiments, the antibody comprises a CDR-L1 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-L1 sequence derived from antibody clone 25A3. In some embodiments, the antibody comprises two light chain CDRs that are 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the corresponding two light chain CDRs derived from antibody clone 25A3. In some embodiments, the antibody comprises three light chain CDRs that are 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the three light chain CDRs derived from antibody clone 25A3.

[0235] In some embodiments, the antibody comprises a CDR-H3 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-H3 sequence derived from antibody clone 25A3 and a CDR-L3 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-L3 sequence derived from antibody clone 25A3. In some embodiments, the antibody comprises six CDR sequences that are 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the corresponding six CDRs derived from antibody clone 25A3.

[0236] 25A5 CDR In some embodiments, the antibody comprises a heavy chain CDR sequence derived from antibody clone 25A5. Exemplary antibody 25A5 CDR sequences determined by the Kabat, Chothia, AbM, Contact, and IMGT numbering systems are shown in Table 9. In some embodiments, the antibody comprises a CDR-H3 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-H3 sequence derived from antibody clone 25A5. In some embodiments, the antibody comprises a CDR-H2 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-H2 sequence derived from antibody clone 25A5. In some embodiments, the antibody comprises a CDR-H1 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-H1 sequence derived from antibody clone 25A5. In some embodiments, the antibody comprises two heavy chain CDRs that are 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the corresponding two heavy chain CDRs derived from antibody clone 25A5. In some embodiments, the antibody comprises three heavy chain CDRs that are 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the three heavy chain CDRs derived from antibody clone 25A5.

[0237] In some embodiments, the antibody comprises a light chain CDR sequence derived from antibody clone 25A5. In some embodiments, the antibody comprises a CDR-L3 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-L3 sequence derived from antibody clone 25A5. In some embodiments, the antibody comprises a CDR-L2 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-L2 sequence derived from antibody clone 25A5. In some embodiments, the antibody comprises a CDR-L1 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-L1 sequence derived from antibody clone 25A5. In some embodiments, the antibody comprises two light chain CDRs that are 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the corresponding two light chain CDRs derived from antibody clone 25A5. In some embodiments, the antibody comprises three light chain CDRs that are 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the three light chain CDRs derived from antibody clone 25A5.

[0238] In some embodiments, the antibody comprises a CDR-H3 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-H3 sequence derived from antibody clone 25A5 and a CDR-L3 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-L3 sequence derived from antibody clone 25A5. In some embodiments, the antibody comprises six CDR sequences that are 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the corresponding six CDRs derived from antibody clone 25A5.

[0239] 25A5-T CDR In some embodiments, the antibody comprises a heavy chain CDR sequence derived from antibody clone 25A5-T. Exemplary antibody 25A5-T CDR sequences determined by the Kabat, Chothia, AbM, Contact, and IMGT numbering systems are shown in Table 10. In some embodiments, the antibody comprises a CDR-H3 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-H3 sequence derived from antibody clone 25A5-T. In some embodiments, the antibody comprises a CDR-H2 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-H2 sequence derived from antibody clone 25A5-T. In some embodiments, the antibody comprises a CDR-H1 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-H1 sequence derived from antibody clone 25A5-T. In some embodiments, the antibody comprises two heavy chain CDRs that are 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the corresponding two heavy chain CDRs derived from antibody clone 25A5-T. In some embodiments, the antibody comprises three heavy chain CDRs that are 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the three heavy chain CDRs derived from antibody clone 25A5-T.

[0240] In some embodiments, the antibody comprises a light chain CDR sequence derived from antibody clone 25A5-T. In some embodiments, the antibody comprises a CDR-L3 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-L3 sequence derived from antibody clone 25A5-T. In some embodiments, the antibody comprises a CDR-L2 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-L2 sequence derived from antibody clone 25A5-T. In some embodiments, the antibody comprises a CDR-L1 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-L1 sequence derived from antibody clone 25A5-T. In some embodiments, the antibody comprises two light chain CDRs that are 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the corresponding two light chain CDRs derived from antibody clone 25A5-T. In some embodiments, the antibody comprises three light chain CDRs that are 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the three light chain CDRs derived from antibody clone 25A5-T.

[0241] In some embodiments, the antibody comprises a CDR-H3 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-H3 sequence derived from antibody clone 25A5-T and a CDR-L3 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-L3 sequence derived from antibody clone 25A5-T. In some embodiments, the antibody comprises six CDR sequences that are 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the corresponding six CDRs derived from antibody clone 25A5-T.

[0242] 25G CDR In some embodiments, the antibody comprises a heavy chain CDR sequence derived from antibody clone 25G. Exemplary antibody 25G CDR sequences determined by the Kabat, Chothia, AbM, Contact, and IMGT numbering systems are shown in Table 11. In some embodiments, the antibody comprises a CDR-H3 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-H3 sequence derived from antibody clone 25G. In some embodiments, the antibody comprises a CDR-H2 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-H2 sequence derived from antibody clone 25G. In some embodiments, the antibody comprises a CDR-H1 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-H1 sequence derived from antibody clone 25G. In some embodiments, the antibody comprises two heavy chain CDRs that are 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the corresponding two heavy chain CDRs derived from antibody clone 25G. In some embodiments, the antibody comprises three heavy chain CDRs that are 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the three heavy chain CDRs derived from antibody clone 25G.

[0243] In some embodiments, the antibody comprises a light chain CDR sequence derived from antibody clone 25G. In some embodiments, the antibody comprises a CDR-L3 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-L3 sequence derived from antibody clone 25G. In some embodiments, the antibody comprises a CDR-L2 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-L2 sequence derived from antibody clone 25G. In some embodiments, the antibody comprises a CDR-L1 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-L1 sequence derived from antibody clone 25G. In some embodiments, the antibody comprises two light chain CDRs that are 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the corresponding two light chain CDRs derived from antibody clone 25G. In some embodiments, the antibody comprises three light chain CDRs that are 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the three light chain CDRs derived from antibody clone 25G.

[0244] In some embodiments, the antibody comprises a CDR-H3 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-H3 sequence derived from antibody clone 25G and a CDR-L3 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-L3 sequence derived from antibody clone 25G. In some embodiments, the antibody comprises six CDR sequences that are 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the corresponding six CDRs derived from antibody clone 25G.

[0245] 25G1 CDR In some embodiments, the antibody comprises a heavy chain CDR sequence derived from antibody clone 25G1. Exemplary antibody 25G1 CDR sequences determined by the Kabat, Chothia, AbM, Contact, and IMGT numbering systems are shown in Table 12. In some embodiments, the antibody comprises a CDR-H3 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-H3 sequence derived from antibody clone 25G1. In some embodiments, the antibody comprises a CDR-H2 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-H2 sequence derived from antibody clone 25G1. In some embodiments, the antibody comprises a CDR-H1 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-H1 sequence derived from antibody clone 25G1. In some embodiments, the antibody comprises two heavy chain CDRs that are 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the corresponding two heavy chain CDRs derived from antibody clone 25G1. In some embodiments, the antibody comprises three heavy chain CDRs that are 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the three heavy chain CDRs derived from antibody clone 25G1.

[0246] In some embodiments, the antibody comprises a light chain CDR sequence derived from antibody clone 25G1. In some embodiments, the antibody comprises a CDR-L3 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-L3 sequence derived from antibody clone 25G1. In some embodiments, the antibody comprises a CDR-L2 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-L2 sequence derived from antibody clone 25G1. In some embodiments, the antibody comprises a CDR-L1 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-L1 sequence derived from antibody clone 25G1. In some embodiments, the antibody comprises two light chain CDRs that are 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the corresponding two light chain CDRs derived from antibody clone 25G1. In some embodiments, the antibody comprises three light chain CDRs that are 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the three light chain CDRs derived from antibody clone 25G1.

[0247] In some embodiments, the antibody comprises a CDR-H3 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-H3 sequence derived from antibody clone 25G1 and a CDR-L3 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-L3 sequence derived from antibody clone 25G1. In some embodiments, the antibody comprises six CDR sequences that are 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the corresponding six CDRs derived from antibody clone 25G1.

[0248] 25G9 CDR In some embodiments, the antibody comprises a heavy chain CDR sequence derived from antibody clone 25G9. Exemplary antibody 25G9 CDR sequences determined by the Kabat, Chothia, AbM, Contact, and IMGT numbering systems are shown in Table 13. In some embodiments, the antibody comprises a CDR-H3 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-H3 sequence derived from antibody clone 25G9. In some embodiments, the antibody comprises a CDR-H2 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-H2 sequence derived from antibody clone 25G9. In some embodiments, the antibody comprises a CDR-H1 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-H1 sequence derived from antibody clone 25G9. In some embodiments, the antibody comprises two heavy chain CDRs that are 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the corresponding two heavy chain CDRs derived from antibody clone 25G9. In some embodiments, the antibody comprises three heavy chain CDRs that are 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the three heavy chain CDRs derived from antibody clone 25G9.

[0249] In some embodiments, the antibody comprises a light chain CDR sequence derived from antibody clone 25G9. In some embodiments, the antibody comprises a CDR-L3 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-L3 sequence derived from antibody clone 25G9. In some embodiments, the antibody comprises a CDR-L2 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-L2 sequence derived from antibody clone 25G9. In some embodiments, the antibody comprises a CDR-L1 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-L1 sequence derived from antibody clone 25G9. In some embodiments, the antibody comprises two light chain CDRs that are 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the corresponding two light chain CDRs derived from antibody clone 25G9. In some embodiments, the antibody comprises three light chain CDRs that are 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the three light chain CDRs derived from antibody clone 25G9.

[0250] In some embodiments, the antibody comprises a CDR-H3 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-H3 sequence derived from antibody clone 25G9 and a CDR-L3 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-L3 sequence derived from antibody clone 25G9. In some embodiments, the antibody comprises six CDR sequences that are 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the corresponding six CDRs derived from antibody clone 25G9.

[0251] 25 consensus CDR In some embodiments, the antibody comprises a heavy chain CDR sequence derived from the antibody group identified as group 25. Exemplary antibody group 25 consensus CDR sequences determined by the Kabat and Chothia numbering systems are shown in Table 14. In some embodiments, the antibody comprises a CDR-H3 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-H3 sequence derived from the antibody group identified as group 25. In some embodiments, the antibody comprises a CDR-H2 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-H2 sequence derived from the antibody group identified as group 25. In some embodiments, the antibody comprises a CDR-H1 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-H1 sequence derived from the antibody group identified as group 25. In some embodiments, the antibody comprises two heavy chain CDRs that are 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the corresponding two heavy chain CDRs derived from the antibody group identified as group 25. In some embodiments, the antibody comprises three heavy chain CDRs that are 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the three heavy chain CDRs derived from the antibody group identified as group 25.

[0252] In some embodiments, the antibody comprises a light chain CDR sequence derived from the antibody group identified as Group 25. In some embodiments, the antibody comprises a CDR-L3 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-L3 sequence derived from the antibody group identified as Group 25. In some embodiments, the antibody comprises a CDR-L2 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-L2 sequence derived from the antibody group identified as Group 25. In some embodiments, the antibody comprises a CDR-L1 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-L1 sequence derived from the antibody group identified as Group 25. In some embodiments, the antibody comprises two light chain CDRs that are 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the corresponding two light chain CDRs derived from the antibody group identified as Group 25. In some embodiments, the antibody comprises three light chain CDRs that are 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the three light chain CDRs derived from the antibody group identified as Group 25.

[0253] In some embodiments, the antibody comprises a CDR-H3 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-H3 sequence derived from the antibody group identified as Group 25 and a CDR-L3 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-L3 sequence derived from the antibody group identified as Group 25. In some embodiments, the antibody comprises six CDR sequences that are 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the corresponding six CDRs derived from the antibody group identified as Group 25.

[0254] 25A consensus CDR In some embodiments, the antibody comprises a heavy chain CDR sequence derived from antibody group lineage 25A. Exemplary consensus CDR sequences for antibody group lineage 25A as determined by the Kabat and Chothia numbering systems are shown in Table 21. In some embodiments, the antibody comprises a CDR-H3 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-H3 sequence derived from antibody group lineage 25A. In some embodiments, the antibody comprises a CDR-H2 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-H2 sequence derived from antibody group lineage 25A. In some embodiments, the antibody comprises a CDR-H1 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-H1 sequence derived from antibody group lineage 25A. In some embodiments, the antibody comprises two heavy chain CDRs that are 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the corresponding two heavy chain CDRs derived from antibody group lineage 25A. In some embodiments, the antibody comprises three heavy chain CDRs that are 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the three heavy chain CDRs derived from antibody group lineage 25A.

[0255] In some embodiments, the antibody comprises a light chain CDR sequence derived from antibody group lineage 25A. In some embodiments, the antibody comprises a CDR-L3 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-L3 sequence derived from antibody group lineage 25A. In some embodiments, the antibody comprises a CDR-L2 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-L2 sequence derived from antibody group lineage 25A. In some embodiments, the antibody comprises a CDR-L1 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-L1 sequence derived from antibody group lineage 25A. In some embodiments, the antibody comprises two light chain CDRs that are 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the corresponding two light chain CDRs derived from antibody group lineage 25A. In some embodiments, the antibody comprises three light chain CDRs that are 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the three light chain CDRs derived from antibody group lineage 25A.

[0256] In some embodiments, the antibody comprises a CDR-H3 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-H3 sequence derived from antibody group lineage 25A and a CDR-L3 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-L3 sequence derived from antibody group lineage 25A. In some embodiments, the antibody comprises six CDR sequences that are 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the corresponding six CDRs derived from antibody group lineage 25A.

[0257] 25G consensus CDR In some embodiments, the antibody comprises a heavy chain CDR sequence derived from antibody group lineage 25G. Exemplary consensus CDR sequences for antibody group lineage 25G as determined by the Kabat and Chothia numbering systems are shown in Table 21. In some embodiments, the antibody comprises a CDR-H3 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-H3 sequence derived from antibody group lineage 25G. In some embodiments, the antibody comprises a CDR-H2 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-H2 sequence derived from antibody group lineage 25G. In some embodiments, the antibody comprises a CDR-H1 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-H1 sequence derived from antibody group lineage 25G. In some embodiments, the antibody comprises two heavy chain CDRs that are 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the corresponding two heavy chain CDRs derived from antibody group lineage 25G. In some embodiments, the antibody comprises three heavy chain CDRs that are 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the three heavy chain CDRs derived from antibody group lineage 25G.

[0258] In some embodiments, the antibody comprises a light chain CDR sequence derived from antibody group lineage 25G. In some embodiments, the antibody comprises a CDR-L3 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-L3 sequence derived from antibody group lineage 25G. In some embodiments, the antibody comprises a CDR-L2 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-L2 sequence derived from antibody group lineage 25G. In some embodiments, the antibody comprises a CDR-L1 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-L1 sequence derived from antibody group lineage 25G. In some embodiments, the antibody comprises two light chain CDRs that are 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the corresponding two light chain CDRs derived from antibody group lineage 25G. In some embodiments, the antibody comprises three light chain CDRs that are 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the three light chain CDRs derived from antibody group lineage 25G.

[0259] In some embodiments, the antibody comprises a CDR-H3 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-H3 sequence derived from antibody group lineage 25G and a CDR-L3 sequence that is 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the CDR-L3 sequence derived from antibody group lineage 25G. In some embodiments, the antibody comprises six CDR sequences that are 50%, 75%, 80%, 85%, 90%, 95%, or 100% identical to the corresponding six CDRs derived from antibody group lineage 25G.

[0260] Variant CDR In some embodiments of any of the antibodies provided herein, an antibody CDR can include up to 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions relative to any of the CDR sequences described herein. In some aspects, the amino acid substitutions are conservative amino acid substitutions. In some embodiments, the antibodies described in this paragraph are referred to herein as "variants." In some embodiments, such variants are derived from the sequences provided herein by, for example, affinity maturation, site-directed mutagenesis, random mutagenesis, or any other method known in the art or described herein. In some embodiments, such variants are not derived from the sequences provided herein and can be newly isolated, for example, according to the methods for obtaining the antibodies provided herein.

[0261] 2.2.7. Functional Characteristics of Antibody Variants As noted above and as described elsewhere in this disclosure, antibody variants are provided herein, which are defined based on the percent identity to the exemplary antibody sequences provided herein or amino acid residue substitutions upon comparison to the exemplary antibody sequences provided herein.

[0262] In some embodiments, variants of the antibodies provided herein are specific for hTF. In some embodiments, variants of the antibodies provided herein are specific for cTF. In some embodiments, variants of the antibodies provided herein are specific for mTF. In some embodiments, variants of the antibodies provided herein are specific for hTF and cTF. In some embodiments, variants of the antibodies provided herein are specific for hTF and mTF. In some embodiments, variants of the antibodies provided herein are specific for cTF and mTF. In some embodiments, variants of the antibodies provided herein are specific for hTF, cTF, and mTF.

[0263] In some embodiments, variants of the antibodies derived from the exemplary antibody sequences provided herein retain affinity for hTF, and the strength measured by K D is within about 1.5-fold, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, or about 10-fold of the affinity of such exemplary antibodies. In some embodiments, variants of the antibodies derived from the exemplary antibody sequences provided herein retain affinity for cTF, and the strength measured by K D is within about 1.5-fold, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, or about 10-fold of the affinity of such exemplary antibodies. In some embodiments, variants of the antibodies derived from the exemplary antibody sequences provided herein retain affinity for mTF, and the strength measured by K D is within about 1.5-fold, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, or about 10-fold of the affinity of such exemplary antibodies. In some embodiments, variants of the antibodies derived from the exemplary antibody sequences provided herein retain affinity for both hTF and cTF, and the strength measured by K D is within about 1.5-fold, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, or about 10-fold of the affinity of such exemplary antibodies. In some embodiments, variants of the antibodies derived from the exemplary antibody sequences provided herein retain affinity for both hTF and mTF, and the strength measured by K D is within about 1.5-fold, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, or about 10-fold of the affinity of such exemplary antibodies. In some embodiments, variants of the antibodies derived from the exemplary antibody sequences provided herein retain affinity for both cTF and mTF, and the strength measured by K D is within about 1.5-fold, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, or about 10-fold of the affinity of such exemplary antibodies. In some embodiments, variants of the antibodies derived from the exemplary antibody sequences provided herein retain affinity for all three of hTF, cTF, and mTF, and the strength measured by K DThe strength measured is within about 1.5-fold, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, or about 10-fold of the affinity of such exemplary antibodies.

[0264] In some embodiments, variants of the antibodies provided herein retain the ability to inhibit TF signaling as measured by one or more of the assays or biological effects described herein. In some embodiments, variants of the antibodies provided herein retain the normal function of TF in the blood coagulation process.

[0265] In some embodiments, variants of the antibodies provided herein compete for binding to TF with antibodies selected from 25A, 25A3, 25A5, 25A5-T, 25G, 25G1, and 25G9, which are shown respectively in Table 5 of the present disclosure.

[0266] In some embodiments, variants of the antibodies provided herein permit the generation of human thrombin according to the thrombin generation assay (TGA). In some embodiments, variants of the antibodies provided herein do not inhibit the generation of human thrombin according to the thrombin generation assay (TGA).

[0267] In some embodiments, variants of the antibodies provided herein bind to human TF at a human TF binding site distinct from the human TF binding site to which human FX binds. In some embodiments, variants of the antibodies provided herein do not interfere with the ability of TF:FVIIa to convert FX to FXa.

[0268] In some embodiments, variants of the antibodies provided herein bind to human TF at a human TF binding site distinct from the human TF binding site to which human FVIIa binds. In some embodiments, variants of the antibodies provided herein do not compete with human FVIIa for binding to human TF.

[0269] In some embodiments, the variants of the antibodies provided herein inhibit FVIIa-dependent TF signaling.

[0270] In some embodiments, the variants of the antibodies provided herein bind to mouse TF (SEQ ID NO: 817). In some embodiments, the variants of the antibodies provided herein bind to mouse TF with an affinity (higher K value) weaker than the affinity of the antibody for hTF. D In some embodiments, the variants of the antibodies provided herein do not bind to mTF.

[0271] In some embodiments, the variants of the antibodies provided herein bind to porcine TF (SEQ ID NO: 824). In some embodiments, the variants of the antibodies provided herein bind to porcine TF with an affinity (higher K value) weaker than the affinity of the antibody for hTF. D In some embodiments, the variants of the antibodies provided herein do not bind to pTF.

[0272] In some embodiments, the variants of the antibodies provided herein bind to the same TF epitope as such antibodies.

[0273] 2.2.8. Other Functional Characteristics of Antibodies In some embodiments, the antibodies provided herein have one or more of the features set forth in (a)-(dd) below: (a) binds to human TF at a human TF binding site distinct from the human TF binding site to which human FVIIa binds; (b) does not inhibit the generation of human thrombin as determined by the thrombin generation assay (TGA); (c) does not suppress the thrombin peak (peak IIa) in the thrombin generation curve as compared to an isotype control; (d) does not extend the time (t t peak) from assay start to the thrombin peak in the thrombin generation curve as compared to an isotype control; (e) does not decrease the endogenous thrombin potential (ETP) as compared to an isotype control, as determined by the area under the thrombin generation curve; (f) allows the generation of human thrombin as determined by the thrombin generation assay (TGA); (g) maintains the thrombin peak (peak IIa) in the thrombin generation curve as compared to an isotype control; (h) maintains the time (t t peak) from assay start to the thrombin peak in the thrombin generation curve as compared to an isotype control; (i) protects the endogenous thrombin potential (ETP) as compared to an isotype control, as determined by the area under the thrombin generation curve; (j) binds to human TF at a human TF binding site distinct from the human TF binding site to which human FX binds; (k) TF:FVIIa does not interfere with the ability to convert FX to FXa; (l) does not compete with human FVIIa for binding to human TF; (m) inhibits FVIIa-dependent TF signaling; (n) binds to cynomolgus TF; (o) binds to mouse TF; (p) binds to rabbit TF; (q) binds to porcine TF; (s) the binding between the antibody and the extracellular domain of a variant TF comprising a mutation at amino acid residue 149 of the sequence shown in SEQ ID NO: 810 is less than 50% of the binding between the antibody and the extracellular domain of the TF of the sequence shown in SEQ ID NO: 810, as determined by the median fluorescence intensity of the antibody compared to an isotype control in a live cell staining assay; (t) the binding between the antibody and the extracellular domain of a variant TF comprising a mutation at amino acid residue 68 of the sequence shown in SEQ ID NO: 810 is, as determined by the median fluorescence intensity of the antibody compared to an isotype control in a live cell staining assay, between the antibody and,more than 50% of the binding between the extracellular domain of TF of the sequence shown in SEQ ID NO: 810; (u) the binding between the antibody and the extracellular domain of the variant TF containing mutations at amino acid residues 171 and 197 of the sequence shown in SEQ ID NO: 810 is less than 50% of the binding between the antibody and the extracellular domain of TF of the sequence shown in SEQ ID NO: 810 according to the median fluorescence intensity of the antibody compared to the isotype control in the live cell staining assay; (v) the binding between the antibody and the extracellular domain of human TF, when amino acid residues 1 to 77 of the sequence shown in SEQ ID NO: 810 are replaced with amino acid residues 1 to 76 of the extracellular domain of rat TF of the sequence shown in SEQ ID NO: 838, is more than 50% of the binding between the antibody and the extracellular domain of TF of the sequence shown in SEQ ID NO: 810 according to the median fluorescence intensity of the antibody compared to the isotype control in the live cell staining assay; (w) the binding between the antibody and the extracellular domain of human TF, when amino acid residues 39 to 77 of the sequence shown in SEQ ID NO: 810 are replaced with amino acid residues 38 to 76 of the extracellular domain of rat TF of the sequence shown in SEQ ID NO: 838, is more than 50% of the binding between the antibody and the extracellular domain of TF of the sequence shown in SEQ ID NO: 810 according to the median fluorescence intensity of the antibody compared to the isotype control in the live cell staining assay; (x) the binding between the antibody and the extracellular domain of human TF, when amino acid residues 94 to 107 of the sequence shown in SEQ ID NO: 810 are replaced with amino acid residues 99 to 112 of the extracellular domain of rat TF of the sequence shown in SEQ ID NO: 838, is more than 50% of the binding between the antibody and the extracellular domain of TF of the sequence shown in SEQ ID NO: 810 according to the median fluorescence intensity of the antibody compared to the isotype control in the live cell staining assay; (y) the binding between the antibody and the extracellular domain of human TF, when amino acid residues 146 to 158 of the sequence shown in SEQ ID NO: 810 are replaced with amino acid residues 151 to 163 of the extracellular domain of rat TF of the sequence shown in SEQ ID NO: 838, is less than 50% of the binding between the antibody and the extracellular domain of TF of the sequence shown in SEQ ID NO: 810 according to the median fluorescence intensity of the antibody compared to the isotype control in the live cell staining assay; (z) the binding between the antibody and the extracellular domain of human TF, when amino acid residues 159 to 219 of the sequence shown in SEQ ID NO: 810 are,When substituting with amino acid residues 164 - 224 of the extracellular domain of rat TF of the sequence shown in SEQ ID NO: 838, according to the median fluorescence intensity of the antibody compared to the isotype control in the live cell staining assay, it is less than 50% of the binding between the antibody and the extracellular domain of TF of the sequence shown in SEQ ID NO: 810; (aa) When substituting amino acid residues 159 - 189 of the sequence shown in SEQ ID NO: 810 with amino acid residues 164 - 194 of the extracellular domain of rat TF of the sequence shown in SEQ ID NO: 838 for the binding between the antibody and the extracellular domain of human TF, according to the median fluorescence intensity of the antibody compared to the isotype control in the live cell staining assay, it is less than 50% of the binding between the antibody and the extracellular domain of TF of the sequence shown in SEQ ID NO: 810; (bb) When substituting amino acid residues 159 - 174 of the sequence shown in SEQ ID NO: 810 with amino acid residues 164 - 179 of the extracellular domain of rat TF of the sequence shown in SEQ ID NO: 838 for the binding between the antibody and the extracellular domain of human TF, according to the median fluorescence intensity of the antibody compared to the isotype control in the live cell staining assay, it is less than 50% of the binding between the antibody and the extracellular domain of TF of the sequence shown in SEQ ID NO: 810; (cc) When substituting amino acid residues 167 - 174 of the sequence shown in SEQ ID NO: 810 with amino acid residues 172 - 179 of the extracellular domain of rat TF of the sequence shown in SEQ ID NO: 838 for the binding between the antibody and the extracellular domain of human TF, according to the median fluorescence intensity of the antibody compared to the isotype control in the live cell staining assay, it is less than 50% of the binding between the antibody and the extracellular domain of TF of the sequence shown in SEQ ID NO: 810; and (dd) When substituting amino acid residues 141 - 194 of the sequence shown in SEQ ID NO: 838 with amino acid residues 136 - 189 in the extracellular domain of human TF of the sequence shown in SEQ ID NO: 810 for the binding between the antibody and the extracellular domain of rat TF, according to the median fluorescence intensity of the antibody compared to the isotype control in the live cell staining assay, it is more than 50% of the binding between the antibody and the extracellular domain of TF of the sequence shown in SEQ ID NO: 810. In some embodiments, the antibodies provided herein have two or more of the characteristics shown in (a) - (dd) above. In some embodiments, the antibodies provided herein areIt has three or more of the features shown in (a) to (dd) above. In some embodiments, the antibodies provided herein have four or more of the features shown in (a) to (dd) above. In some embodiments, the antibodies provided herein have five or more of the features shown in (a) to (dd) above. In some embodiments, the antibodies provided herein have six or more of the features shown in (a) to (dd) above. In some embodiments, the antibodies provided herein have seven or more of the features shown in (a) to (dd) above. In some embodiments, the antibodies provided herein have eight or more of the features shown in (a) to (dd) above. In some embodiments, the antibodies provided herein have nine or more of the features shown in (a) to (dd) above. In some embodiments, the antibodies provided herein have ten or more of the features shown in (a) to (dd) above. In some embodiments, the antibodies provided herein have eleven or more of the features shown in (a) to (dd) above. In some embodiments, the antibodies provided herein have twelve or more of the features shown in (a) to (dd) above. In some embodiments, the antibodies provided herein have thirteen or more of the features shown in (a) to (dd) above. In some embodiments, the antibodies provided herein have fourteen or more of the features shown in (a) to (dd) above. In some embodiments, the antibodies provided herein have fifteen or more of the features shown in (a) to (dd) above. In some embodiments, the antibodies provided herein have sixteen or more of the features shown in (a) to (dd) above. In some embodiments, the antibodies provided herein have seventeen or more of the features shown in (a) to (dd) above. In some embodiments, the antibodies provided herein have eighteen or more of the features shown in (a) to (dd) above. In some embodiments, the antibodies provided herein have nineteen or more of the features shown in (a) to (dd) above. In some embodiments, the antibodies provided herein have twenty or more of the features shown in (a) to (dd) above. In some embodiments, the antibodies provided herein have twenty-one or more of the features shown in (a) to (dd) above. In some embodiments, the antibodies provided herein haveHas 22 or more of the features shown in (a) to (dd) above. In some embodiments, the antibodies provided herein have 23 of the features shown in (a) to (dd) above. In some embodiments, the antibodies provided herein have 24 of the features shown in (a) to (dd) above. In some embodiments, the antibodies provided herein have 25 of the features shown in (a) to (dd) above. In some embodiments, the antibodies provided herein have 26 of the features shown in (a) to (dd) above. In some embodiments, the antibodies provided herein have 27 of the features shown in (a) to (dd) above. In some embodiments, the antibodies provided herein have 28 of the features shown in (a) to (dd) above. In some embodiments, the antibodies provided herein have all 29 of the features shown in (a) to (dd) above. In some embodiments, the antibodies provided herein have all 30 of the features shown in (a) to (dd) above.,

[0274] In some embodiments, the antibodies provided herein have one or more of the characteristics shown in (a)-(dd) below: (a) binds to human TF at a human TF binding site distinct from the human TF binding site to which human FVIIa binds; (b) does not inhibit the generation of human thrombin according to a thrombin generation assay (TGA); (c) does not suppress the thrombin peak (peak IIa) in the thrombin generation curve as compared to an isotype control; (d) does not extend the time (t t peak) from the start of the assay to the thrombin peak in the thrombin generation curve as compared to an isotype control; (e) does not reduce the endogenous thrombin potential (ETP) as compared to an isotype control according to the area under the thrombin generation curve; (f) allows the generation of human thrombin according to a thrombin generation assay (TGA); (g) maintains the thrombin peak (peak IIa) in the thrombin generation curve as compared to an isotype control; (h) maintains the time (t t peak) from the start of the assay to the thrombin peak in the thrombin generation curve as compared to an isotype control; (i) protects the endogenous thrombin potential (ETP) as compared to an isotype control according to the area under the thrombin generation curve; (j) binds to human TF at a human TF binding site distinct from the human TF binding site to which human FX binds; (k) TF:FVIIa does not interfere with the ability to convert FX to FXa; (l) does not compete with human FVIIa for binding to human TF; (m) inhibits FVIIa-dependent TF signaling; (n) binds to cynomolgus monkey TF; (o) binds to mouse TF; (p) binds to rabbit TF; (q) binds to porcine TF; (s) the binding between the antibody and the extracellular domain of a variant TF containing a mutation at amino acid residue 149 of the sequence shown in SEQ ID NO: 810 is less than 50% of the binding between the antibody and the extracellular domain of the TF of the sequence shown in SEQ ID NO: 810 according to the median fluorescence intensity of the antibody compared to an isotype control in a live cell staining assay; (t) the binding between the antibody and the extracellular domain of a variant TF containing a mutation at amino acid residue 68 of the sequence shown in SEQ ID NO: 810 is, according to the median fluorescence intensity of the antibody compared to an isotype control in a live cell staining assay, between the antibody and,more than 50% of the binding between the antibody and the extracellular domain of the TF of the sequence shown in SEQ ID NO: 810; (u) the binding between the antibody and the extracellular domain of the variant TF containing mutations at amino acid residues 171 and 197 of the sequence shown in SEQ ID NO: 810 is less than 50% of the binding between the antibody and the extracellular domain of the TF of the sequence shown in SEQ ID NO: 810 according to the median fluorescence intensity of the antibody compared to the isotype control in the live cell staining assay; (v) the binding between the antibody and the extracellular domain of human TF, when amino acid residues 1-77 of the sequence shown in SEQ ID NO: 810 are replaced with amino acid residues 1-76 of the extracellular domain of the rat TF of the sequence shown in SEQ ID NO: 838, is more than 50% of the binding between the antibody and the extracellular domain of the TF of the sequence shown in SEQ ID NO: 810 according to the median fluorescence intensity of the antibody compared to the isotype control in the live cell staining assay; (w) the binding between the antibody and the extracellular domain of human TF, when amino acid residues 39-77 of the sequence shown in SEQ ID NO: 810 are replaced with amino acid residues 38-76 of the extracellular domain of the rat TF of the sequence shown in SEQ ID NO: 838, is more than 50% of the binding between the antibody and the extracellular domain of the TF of the sequence shown in SEQ ID NO: 810 according to the median fluorescence intensity of the antibody compared to the isotype control in the live cell staining assay; (x) the binding between the antibody and the extracellular domain of human TF, when amino acid residues 94-107 of the sequence shown in SEQ ID NO: 810 are replaced with amino acid residues 99-112 of the extracellular domain of the rat TF of the sequence shown in SEQ ID NO: 838, is more than 50% of the binding between the antibody and the extracellular domain of the TF of the sequence shown in SEQ ID NO: 810 according to the median fluorescence intensity of the antibody compared to the isotype control in the live cell staining assay; (y) the binding between the antibody and the extracellular domain of human TF, when amino acid residues 146-158 of the sequence shown in SEQ ID NO: 810 are replaced with amino acid residues 151-163 of the extracellular domain of the rat TF of the sequence shown in SEQ ID NO: 838, is less than 50% of the binding between the antibody and the extracellular domain of the TF of the sequence shown in SEQ ID NO: 810 according to the median fluorescence intensity of the antibody compared to the isotype control in the live cell staining assay; (z) the binding between the antibody and the extracellular domain of human TF, when amino acid residues 159-219 of the sequence shown in SEQ ID NO: 810 are,When substituting with amino acid residues 164 - 224 of the extracellular domain of rat TF of the sequence shown in SEQ ID NO: 838, according to the median fluorescence intensity of the antibody compared to the isotype control in the live cell staining assay, it is less than 50% of the binding between the antibody and the extracellular domain of TF of the sequence shown in SEQ ID NO: 810; (aa) When substituting amino acid residues 159 - 189 of the sequence shown in SEQ ID NO: 810 with amino acid residues 164 - 194 of the extracellular domain of rat TF of the sequence shown in SEQ ID NO: 838 for the binding between the antibody and the extracellular domain of human TF, according to the median fluorescence intensity of the antibody compared to the isotype control in the live cell staining assay, it is less than 50% of the binding between the antibody and the extracellular domain of TF of the sequence shown in SEQ ID NO: 810; (bb) When substituting amino acid residues 159 - 174 of the sequence shown in SEQ ID NO: 810 with amino acid residues 164 - 179 of the extracellular domain of rat TF of the sequence shown in SEQ ID NO: 838 for the binding between the antibody and the extracellular domain of human TF, according to the median fluorescence intensity of the antibody compared to the isotype control in the live cell staining assay, it is less than 50% of the binding between the antibody and the extracellular domain of TF of the sequence shown in SEQ ID NO: 810; (cc) When substituting amino acid residues 167 - 174 of the sequence shown in SEQ ID NO: 810 with amino acid residues 172 - 179 of the extracellular domain of rat TF of the sequence shown in SEQ ID NO: 838 for the binding between the antibody and the extracellular domain of human TF, according to the median fluorescence intensity of the antibody compared to the isotype control in the live cell staining assay, it is less than 50% of the binding between the antibody and the extracellular domain of TF of the sequence shown in SEQ ID NO: 810; and (dd) When substituting amino acid residues 141 - 194 of the sequence shown in SEQ ID NO: 838 with amino acid residues 136 - 189 in the extracellular domain of human TF of the sequence shown in SEQ ID NO: 810 for the binding between the antibody and the extracellular domain of rat TF, according to the median fluorescence intensity of the antibody compared to the isotype control in the live cell staining assay, it is more than 50% of the binding between the antibody and the extracellular domain of TF of the sequence shown in SEQ ID NO: 810. In some embodiments, the antibodies provided herein have two or more of the characteristics shown in (a) - (dd) above. In some embodiments, the antibodies provided herein areIt has three or more of the features shown in (a) to (dd) above. In some embodiments, the antibodies provided herein have four or more of the features shown in (a) to (dd) above. In some embodiments, the antibodies provided herein have five or more of the features shown in (a) to (dd) above. In some embodiments, the antibodies provided herein have six or more of the features shown in (a) to (dd) above. In some embodiments, the antibodies provided herein have seven or more of the features shown in (a) to (dd) above. In some embodiments, the antibodies provided herein have eight or more of the features shown in (a) to (dd) above. In some embodiments, the antibodies provided herein have nine or more of the features shown in (a) to (dd) above. In some embodiments, the antibodies provided herein have ten or more of the features shown in (a) to (dd) above. In some embodiments, the antibodies provided herein have eleven or more of the features shown in (a) to (dd) above. In some embodiments, the antibodies provided herein have twelve or more of the features shown in (a) to (dd) above. In some embodiments, the antibodies provided herein have thirteen or more of the features shown in (a) to (dd) above. In some embodiments, the antibodies provided herein have fourteen or more of the features shown in (a) to (dd) above. In some embodiments, the antibodies provided herein have fifteen or more of the features shown in (a) to (dd) above. In some embodiments, the antibodies provided herein have sixteen or more of the features shown in (a) to (dd) above. In some embodiments, the antibodies provided herein have seventeen or more of the features shown in (a) to (dd) above. In some embodiments, the antibodies provided herein have eighteen or more of the features shown in (a) to (dd) above. In some embodiments, the antibodies provided herein have nineteen or more of the features shown in (a) to (dd) above. In some embodiments, the antibodies provided herein have twenty or more of the features shown in (a) to (dd) above. In some embodiments, the antibodies provided herein have twenty-one or more of the features shown in (a) to (dd) above. In some embodiments, the antibodies provided herein haveIt has 22 or more of the features shown in (a) to (dd) above. In some embodiments, the antibodies provided herein have 23 of the features shown in (a) to (dd) above. In some embodiments, the antibodies provided herein have 24 of the features shown in (a) to (dd) above. In some embodiments, the antibodies provided herein have 25 of the features shown in (a) to (dd) above. In some embodiments, the antibodies provided herein have 26 of the features shown in (a) to (dd) above. In some embodiments, the antibodies provided herein have 27 of the features shown in (a) to (dd) above. In some embodiments, the antibodies provided herein have 28 of the features shown in (a) to (dd) above. In some embodiments, the antibodies provided herein have all 29 of the features shown in (a) to (dd) above. In some embodiments, the antibodies provided herein have all 30 of the features shown in (a) to (dd) above.,

[0275] In some embodiments, the antibodies provided herein have two or more of the features shown in (a)-(dd) below: (a) binds to human TF at a human TF binding site distinct from the human TF binding site to which human FVIIa binds; (b) does not inhibit the generation of human thrombin as determined by the thrombin generation assay (TGA); (c) does not suppress the thrombin peak (peak IIa) in the thrombin generation curve as compared to an isotype control; (d) does not extend the time (t t peak) from the start of the assay to the thrombin peak in the thrombin generation curve as compared to an isotype control; (e) does not decrease the endogenous thrombin potential (ETP) as determined by the area under the thrombin generation curve as compared to an isotype control; (f) permits the generation of human thrombin as determined by the thrombin generation assay (TGA); (g) maintains the thrombin peak (peak IIa) in the thrombin generation curve as compared to an isotype control; (h) maintains the time (t t peak) from the start of the assay to the thrombin peak in the thrombin generation curve as compared to an isotype control; (i) protects the endogenous thrombin potential (ETP) as determined by the area under the thrombin generation curve as compared to an isotype control; (j) binds to human TF at a human TF binding site distinct from the human TF binding site to which human FX binds; (k) does not interfere with the ability of TF:FVIIa to convert FX to FXa; (l) does not compete with human FVIIa for binding to human TF; (m) inhibits FVIIa-dependent TF signaling; (n) binds to cynomolgus TF; (o) binds to mouse TF; (p) binds to rabbit TF; (q) binds to porcine TF; (s) the binding between the antibody and the extracellular domain of a variant TF comprising the mutation K149N in the sequence shown in SEQ ID NO: 810 is less than 50% of the binding between the antibody and the extracellular domain of the TF of the sequence shown in SEQ ID NO: 810 as determined by the median fluorescence intensity of the antibody compared to an isotype control in a live cell staining assay;(t) The binding between the antibody and the extracellular domain of the variant TF containing the mutation K68N in the sequence shown in SEQ ID NO: 810 is more than 50% of the binding between the antibody and the extracellular domain of the TF of the sequence shown in SEQ ID NO: 810 according to the median fluorescence intensity of the antibody compared to the isotype control in the live cell staining assay; (u) The binding between the antibody and the extracellular domain of the variant TF containing the mutations N171H and T197K in the sequence shown in SEQ ID NO: 810 is less than 50% of the binding between the antibody and the extracellular domain of the TF of the sequence shown in SEQ ID NO: 810 according to the median fluorescence intensity of the antibody compared to the isotype control in the live cell staining assay; (v) The binding between the antibody and the extracellular domain of human TF, when amino acid residues 1-77 of the sequence shown in SEQ ID NO: 810 are replaced with amino acid residues 1-76 of the extracellular domain of rat TF of the sequence shown in SEQ ID NO: 838, is more than 50% of the binding between the antibody and the extracellular domain of the TF of the sequence shown in SEQ ID NO: 810 according to the median fluorescence intensity of the antibody compared to the isotype control in the live cell staining assay; (w) The binding between the antibody and the extracellular domain of human TF, when amino acid residues 39-77 of the sequence shown in SEQ ID NO: 810 are replaced with amino acid residues 38-76 of the extracellular domain of rat TF of the sequence shown in SEQ ID NO: 838, is more than 50% of the binding between the antibody and the extracellular domain of the TF of the sequence shown in SEQ ID NO: 810 according to the median fluorescence intensity of the antibody compared to the isotype control in the live cell staining assay; (x) The binding between the antibody and the extracellular domain of human TF, when amino acid residues 94-107 of the sequence shown in SEQ ID NO: 810 are replaced with amino acid residues 99-112 of the extracellular domain of rat TF of the sequence shown in SEQ ID NO: 838, is more than 50% of the binding between the antibody and the extracellular domain of the TF of the sequence shown in SEQ ID NO: 810 according to the median fluorescence intensity of the antibody compared to the isotype control in the live cell staining assay;(y) The binding between the antibody and the extracellular domain of human TF becomes less than 50% of the binding between the antibody and the extracellular domain of TF of the sequence shown in SEQ ID NO: 810 as determined by the median fluorescence intensity of the antibody compared to the isotype control in a live cell staining assay when amino acid residues 146 - 158 of the sequence shown in SEQ ID NO: 810 are replaced with amino acid residues 151 - 163 of the extracellular domain of rat TF of the sequence shown in SEQ ID NO: 838; (z) The binding between the antibody and the extracellular domain of human TF becomes less than 50% of the binding between the antibody and the extracellular domain of TF of the sequence shown in SEQ ID NO: 810 as determined by the median fluorescence intensity of the antibody compared to the isotype control in a live cell staining assay when amino acid residues 159 - 219 of the sequence shown in SEQ ID NO: 810 are replaced with amino acid residues 164 - 224 in the extracellular domain of rat TF of the sequence shown in SEQ ID NO: 838; (aa) The binding between the antibody and the extracellular domain of human TF becomes less than 50% of the binding between the antibody and the extracellular domain of TF of the sequence shown in SEQ ID NO: 810 as determined by the median fluorescence intensity of the antibody compared to the isotype control in a live cell staining assay when amino acid residues 159 - 189 of the sequence shown in SEQ ID NO: 810 are replaced with amino acid residues 164 - 194 of the extracellular domain of rat TF of the sequence shown in SEQ ID NO: 838; (bb) The binding between the antibody and the extracellular domain of human TF becomes less than 50% of the binding between the antibody and the extracellular domain of TF of the sequence shown in SEQ ID NO: 810 as determined by the median fluorescence intensity of the antibody compared to the isotype control in a live cell staining assay when amino acid residues 159 - 174 of the sequence shown in SEQ ID NO: 810 are replaced with amino acid residues 164 - 179 of the extracellular domain of rat TF of the sequence shown in SEQ ID NO: 838; (cc) The binding between the antibody and the extracellular domain of human TF becomes less than 50% of the binding between the antibody and the extracellular domain of TF of the sequence shown in SEQ ID NO: 810 as determined by the median fluorescence intensity of the antibody compared to the isotype control in a live cell staining assay when amino acid residues 167 - 174 of the sequence shown in SEQ ID NO: 810 are replaced with amino acid residues 172 - 179 of the extracellular domain of rat TF of the sequence shown in SEQ ID NO: 838;And the binding between the antibody and the extracellular domain of rat TF is more than 50% of the binding between the antibody and the extracellular domain of human TF of the sequence shown in SEQ ID NO: 810, when amino acid residues 141 to 194 of the sequence shown in SEQ ID NO: 838 are substituted with amino acid residues 136 to 189 in the extracellular domain of human TF of the sequence shown in SEQ ID NO: 810, as determined by the median fluorescence intensity of the antibody compared to the isotype control in a live cell staining assay.;

[0276] In some embodiments, the antibodies provided herein have two or more of the characteristics shown in (a)-(dd) below: (a) binds to human TF at a human TF binding site distinct from the human TF binding site to which human FVIIa binds; (b) does not inhibit the generation of human thrombin according to the thrombin generation assay (TGA); (c) does not suppress the thrombin peak (peak IIa) in the thrombin generation curve as compared to the isotype control; (d) does not extend the time (t t peak) from the start of the assay to the thrombin peak in the thrombin generation curve as compared to the isotype control; (e) does not reduce the endogenous thrombin potential (ETP) as compared to the isotype control according to the area under the thrombin generation curve; (f) allows the generation of human thrombin according to the thrombin generation assay (TGA); (g) maintains the thrombin peak (peak IIa) in the thrombin generation curve as compared to the isotype control; (h) maintains the time (t t peak) from the start of the assay to the thrombin peak in the thrombin generation curve as compared to the isotype control; (i) protects the endogenous thrombin potential (ETP) as compared to the isotype control according to the area under the thrombin generation curve; (j) binds to human TF at a human TF binding site distinct from the human TF binding site to which human FX binds; (k) does not interfere with the ability of TF:FVIIa to convert FX to FXa; (l) does not compete with human FVIIa for binding to human TF; (m) inhibits FVIIa-dependent TF signaling; (n) binds to cynomolgus TF; (o) binds to mouse TF; (p) binds to rabbit TF; (q) binds to porcine TF; (s) the binding between the antibody and the extracellular domain of a variant TF comprising the mutation K149N in the sequence shown in SEQ ID NO: 810 is less than 50% of the binding between the antibody and the extracellular domain of the TF of the sequence shown in SEQ ID NO: 810 according to the median fluorescence intensity of the antibody as compared to the isotype control in a live cell staining assay;(t) The binding between the antibody and the extracellular domain of the variant TF containing the mutation K68N in the sequence shown in SEQ ID NO: 810 is more than 50% of the binding between the antibody and the extracellular domain of the TF of the sequence shown in SEQ ID NO: 810, as determined by the median fluorescence intensity of the antibody compared to the isotype control in the live cell staining assay; (u) The binding between the antibody and the extracellular domain of the variant TF containing the mutations N171H and T197K in the sequence shown in SEQ ID NO: 810 is less than 50% of the binding between the antibody and the extracellular domain of the TF of the sequence shown in SEQ ID NO: 810, as determined by the median fluorescence intensity of the antibody compared to the isotype control in the live cell staining assay; (v) The binding between the antibody and the extracellular domain of human TF, when amino acid residues 1 - 77 of the sequence shown in SEQ ID NO: 810 are replaced with amino acid residues 1 - 76 of the extracellular domain of rat TF of the sequence shown in SEQ ID NO: 838, is more than 50% of the binding between the antibody and the extracellular domain of the TF of the sequence shown in SEQ ID NO: 810, as determined by the median fluorescence intensity of the antibody compared to the isotype control in the live cell staining assay; (w) The binding between the antibody and the extracellular domain of human TF, when amino acid residues 39 - 77 of the sequence shown in SEQ ID NO: 810 are replaced with amino acid residues 38 - 76 of the extracellular domain of rat TF of the sequence shown in SEQ ID NO: 838, is more than 50% of the binding between the antibody and the extracellular domain of the TF of the sequence shown in SEQ ID NO: 810, as determined by the median fluorescence intensity of the antibody compared to the isotype control in the live cell staining assay; (x) The binding between the antibody and the extracellular domain of human TF, when amino acid residues 94 - 107 of the sequence shown in SEQ ID NO: 810 are replaced with amino acid residues 99 - 112 of the extracellular domain of rat TF of the sequence shown in SEQ ID NO: 838, is more than 50% of the binding between the antibody and the extracellular domain of the TF of the sequence shown in SEQ ID NO: 810, as determined by the median fluorescence intensity of the antibody compared to the isotype control in the live cell staining assay;(y) The binding between the (y) antibody and the extracellular domain of human TF becomes less than 50% of the binding between the antibody and the extracellular domain of TF of the sequence shown in SEQ ID NO: 810, as determined by the median fluorescence intensity of the antibody compared to the isotype control in a live cell staining assay, when amino acid residues 146 to 158 of the sequence shown in SEQ ID NO: 810 are replaced with amino acid residues 151 to 163 of the extracellular domain of rat TF of the sequence shown in SEQ ID NO: 838; (z) The binding between the (z) antibody and the extracellular domain of human TF becomes less than 50% of the binding between the antibody and the extracellular domain of TF of the sequence shown in SEQ ID NO: 810, as determined by the median fluorescence intensity of the antibody compared to the isotype control in a live cell staining assay, when amino acid residues 159 to 219 of the sequence shown in SEQ ID NO: 810 are replaced with amino acid residues 164 to 224 in the extracellular domain of rat TF of the sequence shown in SEQ ID NO: 838; (aa) The binding between the (aa) antibody and the extracellular domain of human TF becomes less than 50% of the binding between the antibody and the extracellular domain of TF of the sequence shown in SEQ ID NO: 810, as determined by the median fluorescence intensity of the antibody compared to the isotype control in a live cell staining assay, when amino acid residues 159 to 189 of the sequence shown in SEQ ID NO: 810 are replaced with amino acid residues 164 to 194 of the extracellular domain of rat TF of the sequence shown in SEQ ID NO: 838; (bb) The binding between the (bb) antibody and the extracellular domain of human TF becomes less than 50% of the binding between the antibody and the extracellular domain of TF of the sequence shown in SEQ ID NO: 810, as determined by the median fluorescence intensity of the antibody compared to the isotype control in a live cell staining assay, when amino acid residues 159 to 174 of the sequence shown in SEQ ID NO: 810 are replaced with amino acid residues 164 to 179 of the extracellular domain of rat TF of the sequence shown in SEQ ID NO: 838; (cc) The binding between the (cc) antibody and the extracellular domain of human TF becomes less than 50% of the binding between the antibody and the extracellular domain of TF of the sequence shown in SEQ ID NO: 810, as determined by the median fluorescence intensity of the antibody compared to the isotype control in a live cell staining assay, when amino acid residues 167 to 174 of the sequence shown in SEQ ID NO: 810 are replaced with amino acid residues 172 to 179 of the extracellular domain of rat TF of the sequence shown in SEQ ID NO: 838;And the binding between the (dd) antibody and the extracellular domain of rat TF is more than 50% of the binding between the antibody and the extracellular domain of human TF of the sequence shown in SEQ ID NO: 810 when the amino acid residues 141-194 of the sequence shown in SEQ ID NO: 838 are substituted with the amino acid residues 136-189 in the extracellular domain of human TF of the sequence shown in SEQ ID NO: 810, as determined by the median fluorescence intensity of the antibody compared to the isotype control in a live cell staining assay.;

[0277] In some embodiments, the antibodies provided herein exhibit a combination of the following characteristics: bind to human TF at a human TF binding site distinct from the human TF binding site to which human FVIIa binds; do not inhibit the generation of human thrombin as determined by a thrombin generation assay (TGA); and the binding between the antibody and the extracellular domain of a variant TF comprising mutations at amino acid residues 171 and 197 of the sequence shown in SEQ ID NO: 810 is less than 50% of the binding between the antibody and the extracellular domain of TF of the sequence shown in SEQ ID NO: 810, as determined by the median fluorescence intensity of the antibody compared to the isotype control in a live cell staining assay.

[0278] In some embodiments, the antibodies provided herein exhibit a combination of the following characteristics: bind to human TF at a human TF binding site distinct from the human TF binding site to which human FVIIa binds; do not inhibit the generation of human thrombin as determined by a thrombin generation assay (TGA); and the binding between the antibody and the extracellular domain of a variant TF comprising the mutations N171H and T197K of the sequence shown in SEQ ID NO: 810 is less than 50% of the binding between the antibody and the extracellular domain of TF of the sequence shown in SEQ ID NO: 810, as determined by the median fluorescence intensity of the antibody compared to the isotype control in a live cell staining assay.

[0279] In some embodiments, the antibodies provided herein exhibit a combination of the following characteristics: bind to human TF at a human TF binding site distinct from the human TF binding site to which human FVIIa binds; permit the generation of human thrombin as determined by a thrombin generation assay (TGA); and the binding between the antibody and the extracellular domain of a variant TF comprising mutations at amino acid residues 171 and 197 of the sequence shown in SEQ ID NO: 810 is less than 50% of the binding between the antibody and the extracellular domain of TF of the sequence shown in SEQ ID NO: 810 as determined by the median fluorescence intensity of the antibody compared to an isotype control in a live cell staining assay.

[0280] In some embodiments, the antibodies provided herein exhibit a combination of the following characteristics: bind to human TF at a human TF binding site distinct from the human TF binding site to which human FVIIa binds; permit the generation of human thrombin as determined by a thrombin generation assay (TGA); and the binding between the antibody and the extracellular domain of a variant TF comprising the mutations N171H and T197K of the sequence shown in SEQ ID NO: 810 is less than 50% of the binding between the antibody and the extracellular domain of TF of the sequence shown in SEQ ID NO: 810 as determined by the median fluorescence intensity of the antibody compared to an isotype control in a live cell staining assay.

[0281] In some embodiments, the antibodies provided herein exhibit a combination of the following characteristics: bind to human TF at a human TF binding site distinct from the human TF binding site to which human FVIIa binds; do not inhibit the generation of human thrombin as determined by a thrombin generation assay (TGA); the binding between the antibody and the extracellular domain of variant TF containing a mutation at amino acid residue 149 of the sequence shown in SEQ ID NO: 810 is less than 50% of the binding between the antibody and the extracellular domain of TF of the sequence shown in SEQ ID NO: 810, as determined by the median fluorescence intensity of the antibody compared to an isotype control in a live cell staining assay; and the binding between the antibody and the extracellular domain of variant TF containing mutations at amino acid residues 171 and 197 of the sequence shown in SEQ ID NO: 810 is less than 50% of the binding between the antibody and the extracellular domain of TF of the sequence shown in SEQ ID NO: 810, as determined by the median fluorescence intensity of the antibody compared to an isotype control in a live cell staining assay.

[0282] In some embodiments, the antibodies provided herein exhibit a combination of the following characteristics: bind to human TF at a human TF binding site distinct from the human TF binding site to which human FVIIa binds; do not inhibit the generation of human thrombin as determined by a thrombin generation assay (TGA); the binding between the antibody and the extracellular domain of variant TF containing the mutation K149N of the sequence shown in SEQ ID NO: 810 is less than 50% of the binding between the antibody and the extracellular domain of TF of the sequence shown in SEQ ID NO: 810, as determined by the median fluorescence intensity of the antibody compared to an isotype control in a live cell staining assay; and the binding between the antibody and the extracellular domain of variant TF containing the mutations N171H and T197K of the sequence shown in SEQ ID NO: 810 is less than 50% of the binding between the antibody and the extracellular domain of TF of the sequence shown in SEQ ID NO: 810, as determined by the median fluorescence intensity of the antibody compared to an isotype control in a live cell staining assay.

[0283] In some embodiments, the antibodies provided herein exhibit a combination of the following characteristics: bind to human TF at a human TF binding site distinct from the human TF binding site to which human FVIIa binds; permit the generation of human thrombin as determined by a thrombin generation assay (TGA); the binding between the antibody and the extracellular domain of a variant TF comprising a mutation at amino acid residue 149 of the sequence shown in SEQ ID NO: 810 is less than 50% of the binding between the antibody and the extracellular domain of TF of the sequence shown in SEQ ID NO: 810, as determined by the median fluorescence intensity of the antibody compared to an isotype control in a live cell staining assay; and the binding between the antibody and the extracellular domain of a variant TF comprising mutations at amino acid residues 171 and 197 of the sequence shown in SEQ ID NO: 810 is less than 50% of the binding between the antibody and the extracellular domain of TF of the sequence shown in SEQ ID NO: 810, as determined by the median fluorescence intensity of the antibody compared to an isotype control in a live cell staining assay.

[0284] In some embodiments, the antibodies provided herein exhibit a combination of the following characteristics: bind to human TF at a human TF binding site distinct from the human TF binding site to which human FVIIa binds; permit the generation of human thrombin as determined by a thrombin generation assay (TGA); the binding between the antibody and the extracellular domain of a variant TF comprising the mutation K149N of the sequence shown in SEQ ID NO: 810 is less than 50% of the binding between the antibody and the extracellular domain of TF of the sequence shown in SEQ ID NO: 810, as determined by the median fluorescence intensity of the antibody compared to an isotype control in a live cell staining assay; and the binding between the antibody and the extracellular domain of a variant TF comprising the mutations N171H and T197K of the sequence shown in SEQ ID NO: 810 is less than 50% of the binding between the antibody and the extracellular domain of TF of the sequence shown in SEQ ID NO: 810, as determined by the median fluorescence intensity of the antibody compared to an isotype control in a live cell staining assay.

[0285] In some embodiments, the antibodies provided herein exhibit a combination of the following characteristics: bind to human TF at a human TF binding site distinct from the human TF binding site to which human FVIIa binds; do not inhibit the generation of human thrombin as determined by a thrombin generation assay (TGA); bind to cynomolgus TF; the binding between the antibody and the extracellular domain of a variant TF comprising a mutation at amino acid residue 149 of the sequence set forth in SEQ ID NO: 810 is less than 50% of the binding between the antibody and the extracellular domain of TF of the sequence set forth in SEQ ID NO: 810, as determined by the median fluorescence intensity of the antibody compared to an isotype control in a live cell staining assay; and the binding between the antibody and the extracellular domain of a variant TF comprising mutations at amino acid residues 171 and 197 of the sequence set forth in SEQ ID NO: 810 is less than 50% of the binding between the antibody and the extracellular domain of TF of the sequence set forth in SEQ ID NO: 810, as determined by the median fluorescence intensity of the antibody compared to an isotype control in a live cell staining assay.

[0286] In some embodiments, the antibodies provided herein exhibit a combination of the following characteristics: bind to human TF at a human TF binding site distinct from the human TF binding site to which human FVIIa binds; do not inhibit the generation of human thrombin as determined by a thrombin generation assay (TGA); bind to cynomolgus TF; the binding between the antibody and the extracellular domain of a variant TF comprising the mutation K149N of the sequence set forth in SEQ ID NO: 810 is less than 50% of the binding between the antibody and the extracellular domain of TF of the sequence set forth in SEQ ID NO: 810, as determined by the median fluorescence intensity of the antibody compared to an isotype control in a live cell staining assay; and the binding between the antibody and the extracellular domain of a variant TF comprising the mutations N171H and T197K of the sequence set forth in SEQ ID NO: 810 is less than 50% of the binding between the antibody and the extracellular domain of TF of the sequence set forth in SEQ ID NO: 810, as determined by the median fluorescence intensity of the antibody compared to an isotype control in a live cell staining assay.

[0287] In some embodiments, the antibodies provided herein exhibit a combination of the following characteristics: bind to human TF at a human TF binding site distinct from the human TF binding site to which human FVIIa binds; permit the generation of human thrombin as determined by a thrombin generation assay (TGA); bind to cynomolgus TF; the binding between the antibody and the extracellular domain of a variant TF comprising a mutation at amino acid residue 149 of the sequence shown in SEQ ID NO: 810 is less than 50% of the binding between the antibody and the extracellular domain of TF of the sequence shown in SEQ ID NO: 810 as determined by the median fluorescence intensity of the antibody compared to an isotype control in a live cell staining assay; and the binding between the antibody and the extracellular domain of a variant TF comprising mutations at amino acid residues 171 and 197 of the sequence shown in SEQ ID NO: 810 is less than 50% of the binding between the antibody and the extracellular domain of TF of the sequence shown in SEQ ID NO: 810 as determined by the median fluorescence intensity of the antibody compared to an isotype control in a live cell staining assay.

[0288] In some embodiments, the antibodies provided herein exhibit a combination of the following characteristics: bind to human TF at a human TF binding site distinct from the human TF binding site to which human FVIIa binds; permit the generation of human thrombin as determined by a thrombin generation assay (TGA); bind to cynomolgus TF; the binding between the antibody and the extracellular domain of a variant TF comprising the mutation K149N of the sequence shown in SEQ ID NO: 810 is less than 50% of the binding between the antibody and the extracellular domain of TF of the sequence shown in SEQ ID NO: 810 as determined by the median fluorescence intensity of the antibody compared to an isotype control in a live cell staining assay; and the binding between the antibody and the extracellular domain of a variant TF comprising the mutations N171H and T197K of the sequence shown in SEQ ID NO: 810 is less than 50% of the binding between the antibody and the extracellular domain of TF of the sequence shown in SEQ ID NO: 810 as determined by the median fluorescence intensity of the antibody compared to an isotype control in a live cell staining assay.

[0289] 2.3. Affinity and Other Characteristics of TF Antibodies 2.3.1. Affinity of TF Antibodies In some embodiments, the affinity of the antibodies provided herein for TF is K D as shown, less than about 10 -5 M, less than about 10 -6 M, less than about 10 -7 M, less than about 10 -8 M, less than about 10 -9 M, less than about 10 -10 M, less than about 10 -11 M, or less than about 10 -12 M. In some embodiments, the affinity of the antibody is 10 -7 M to 10 -12 M. In some embodiments, the affinity of the antibody is 10 -7 M to 10 -11 M. In some embodiments, the affinity of the antibody is 10 -7 M to 10 -10 M. In some embodiments, the affinity of the antibody is 10 -7 M to 10 -9 M. In some embodiments, the affinity of the antibody is 10 -7 M to 10 -8 M. In some embodiments, the affinity of the antibody is 10 -8 M to 10 -12 M. In some embodiments, the affinity of the antibody is 10 -8 M to 10 -11 M. In some embodiments, the affinity of the antibody is 10 -9 M to 10 -11 M. In some embodiments, the affinity of the antibody is 10 -10 M to 10 -11 M.

[0290] In some embodiments, the K D value of the antibodies provided herein for cTF is 15-fold or less of the K D value of the antibody for hTF. In some embodiments, the K D value of the antibodies provided herein for cTF is 10-fold or less of the K D value of the antibody for hTF. In some embodiments, the K D value of the antibodies provided herein for cTF is the K DIt is 8 times or less the value. In some embodiments, the K for cTF of the antibody provided herein D value is 5 times or less the K of the antibody for hTF D value. In some embodiments, the K for cTF of the antibody provided herein D value is 3 times or less the K of the antibody for hTF D value. In some embodiments, the K for cTF of the antibody provided herein D value is 2 times or less the K of the antibody for hTF D value.

[0291] In some embodiments, the K for mTF of the antibody provided herein D value is 20 times or less the K of the antibody for hTF D value. In some embodiments, the K for mTF of the antibody provided herein D value is 15 times or less the K of the antibody for hTF D value. In some embodiments, the K for mTF of the antibody provided herein D value is 10 times or less the K of the antibody for hTF D value. In some embodiments, the K for mTF of the antibody provided herein D value is 5 times or less the K of the antibody for hTF D value. In some embodiments, the K for mTF of the antibody provided herein D value is D 2 times or less the value of the antibody for hTF.

[0292] In some embodiments, as described in Table 5 of PCT / US2019 / 12427 filed on January 4, 2019, the affinity of the antibody provided herein for hTF is K measured by Biacore DSelected from about 0.31 nM, about 6.20 nM, about 0.36 nM, about 0.08 nM, about 23.0 nM, about 0.94 nM, about 13.3 nM, about 0.47 nM, about 0.09 nM, about 1.75 nM, about 0.07 nM, about 0.14 nM, about 2.09 nM, about 0.06 nM, about 0.15 nM, about 1.46 nM, about 1.60 nM, and about 0.42 nM as shown. In some embodiments, K D Such affinity as shown is in the range of about 23.0 nM to about 0.06 nM. In some embodiments, such is about 23.0 nM or less.

[0293] In some embodiments, as described in Table 5 of PCT / US2019 / 12427 filed on January 4, 2019, the affinity of the antibodies provided herein for hTF is K measured by ForteBio D Selected from about 1.28 nM, about 2.20 nM, about 8.45 nM, about 1.67 nM, about 0.64 nM, about 21.9 nM, about 3.97 nM, about 35.8 nM, about 3.30 nM, about 2.32 nM, about 0.83 nM, about 2.40 nM, about 0.96 nM, about 0.86 nM, about 3.84 nM, about 1.02 nM, about 1.61 nM, about 2.52 nM, about 2.28 nM, and about 1.59 nM as shown. In some embodiments, K D Such affinity as shown is in the range of about 35.8 nM to about 0.64 nM. In some embodiments, such K D is about 35.8 nM or less.

[0294] In some embodiments, as described in Table 5 of PCT / US2019 / 12427 filed on January 4, 2019, the affinity of the antibodies provided herein for cTF is K measured by Biacore D Selected from about 0.26 nM, about 5.42 nM, about 0.21 nM, about 0.04 nM, about 18.0 nM, about 0.78 nM, about 16.4 nM, about 5.06 nM, about 0.08 nM, about 5.64 nM, about 0.12 nM, about 0.24 nM, about 5.66 nM, about 0.39 nM, about 5.69 nM, about 6.42 nM, and about 1.83 nM as shown. In some embodiments, K DSuch an affinity shown by is in the range of about 18.0 nM to about 0.04 nM. In some embodiments, such K D is about 18.0 nM or less.

[0295] In some embodiments, as described in Table 5 of PCT / US2019 / 12427 filed on January 4, 2019, the affinity of the antibodies provided herein for cTF is K measured by ForteBio D shown by is selected from about 1.43 nM, about 2.70 nM, about 7.65 nM, about 1.36 nM, about 0.76 nM, about 17.5 nM, about 4.99 nM, about 42.9 nM, about 12.0 nM, about 15.0 nM, about 0.57 nM, about 3.40 nM, about 1.05 nM, about 0.94 nM, about 4.12 nM, about 1.11 nM, about 1.96 nM, about 4.07 nM, about 2.71 nM, and about 4.16 nM. In some embodiments, the affinity such as shown by K D is in the range of about 42.9 nM to about 0.57 nM. In some embodiments, such K D is about 42.9 nM or less.

[0296] In some embodiments, as described in Table 5 of PCT / US2019 / 12427 filed on January 4, 2019, the affinity of the antibodies provided herein for mTF is K measured by Biacore D shown by is selected from about 5.4 nM, about 2.9 nM, about 21 nM, and about 2.4 nM. In some embodiments, the affinity such as shown by K D is in the range of about 21 nM to about 2.4 nM. In some embodiments, such K D is about 21 nM or less.

[0297] In some embodiments, as described in Table 5 of PCT / US2019 / 12427 filed on January 4, 2019, the affinity of the antibodies provided herein for mTF is K measured by ForteBio DIt is selected from about 263 nM, about 131 nM, about 188 nM, about 114 nM, about 34.2 nM, about 9.16 nM, about 161 nM, about 72.1 nM, about 360 nM, about 281 nM, about 41.4 nM, about 6.12 nM, about 121 nM, and about 140 nM as shown by D Such an affinity as shown by D is in the range of about 360 nM to about 6.12 nM. In some embodiments, such a K

[0298] In some embodiments, as described in FIGS. 1A and 1B of PCT / US2019 / 12427 filed on January 4, 2019, the affinity of the antibody provided herein for hTF is the EC 50 shown by selected from about 50 pM, about 58 pM, about 169 pM, about 77 pM, about 88 pM, about 134 pM, about 85 pM, about 237 pM, about 152 pM, about 39 pM, about 559 pM, about 280 pM, about 255 pM, about 147 pM, about 94 pM, about 117 pM, about 687 pM, about 532 pM, and about 239 pM. In some embodiments, such an affinity is in the range of about 687 pM to about 39 pM. In some embodiments, such an EC 50 is about 687 pM or less.

[0299] In some embodiments, as described in FIGS. 2A and 2B of PCT / US2019 / 12427 filed on January 4, 2019, the affinity of the antibody provided herein for hTF is the EC 50 shown by selected from about 455 nM, about 87 nM, about 11 nM, about 3.9 nM, about 3.0 nM, about 3.4 nM, about 255 nM, about 2.9 nM, about 3.6 nM, and about 4.0 nM. In some embodiments, such an affinity is in the range of about 455 nM to about 2.9 nM. In some embodiments, such an EC 50 is about 455 pM or less.

[0300] In some embodiments, the K of the antibody provided herein for pTFD The value is 20 times or less that of the K of the antibody with respect to hTF. D The value is 15 times or less that of the K of the antibody provided herein with respect to pTF. In some embodiments, the K of the antibody provided herein with respect to pTF D The value is 15 times or less that of the K of the antibody with respect to hTF. D The value is 10 times or less that of the K of the antibody provided herein with respect to pTF. In some embodiments, the K of the antibody provided herein with respect to pTF D The value is 10 times or less that of the K of the antibody with respect to hTF. D The value is 5 times or less that of the K of the antibody provided herein with respect to pTF. In some embodiments, the K of the antibody provided herein with respect to pTF D The value is 5 times or less that of the K of the antibody with respect to hTF. D The value is 2 times or less that of the K of the antibody provided herein with respect to pTF. In some embodiments, the K of the antibody provided herein with respect to pTF D The value is 2 times or less that of the K of the antibody with respect to hTF. D The value is 2 times or less.

[0301] In some embodiments, as described in Table 40 of PCT / US2019 / 12427 filed on January 4, 2019, the affinity of the antibody provided herein with respect to pTF is the K measured by Biacore D shown as 3.31 nM or 12.9 nM.

[0302] 2.3.2. Thrombin generation in the presence of TF antibody In some embodiments, the TF antibody provided herein does not inhibit the generation of human thrombin according to the thrombin generation assay (TGA). In certain embodiments, the TF antibody provided herein permits the generation of human thrombin according to the thrombin generation assay (TGA).

[0303] In some embodiments, in a thrombin generation assay (TGA), in the presence of a TF antibody of 100 nM or more, the percentage of the thrombin generation peak (peak IIa%) obtained as compared to the antibody-free control condition is at least 40%. In some embodiments, in a thrombin generation assay (TGA), in the presence of a TF antibody of 100 nM or more, peak IIa% obtained as compared to the antibody-free control condition is at least 50%. In some embodiments, in a thrombin generation assay (TGA), in the presence of a TF antibody of 100 nM or more, peak IIa% obtained as compared to the antibody-free control condition is at least 60%. In some embodiments, in a thrombin generation assay (TGA), in the presence of a TF antibody of 100 nM or more, peak IIa% obtained as compared to the antibody-free control condition is at least 70%. In some embodiments, in a thrombin generation assay (TGA), in the presence of a TF antibody of 100 nM or more, peak IIa% obtained as compared to the antibody-free control condition is at least 80%. In some embodiments, in a thrombin generation assay (TGA), in the presence of a TF antibody of 100 nM or more, peak IIa% obtained as compared to the antibody-free control condition is at least 90%. In some embodiments, in a thrombin generation assay (TGA), in the presence of a TF antibody of 100 nM or more, peak IIa% obtained as compared to the antibody-free control condition is at least 95%. In some embodiments, in a thrombin generation assay (TGA), in the presence of a TF antibody of 100 nM or more, peak IIa% obtained as compared to the antibody-free control condition is at least 99%.

[0304] In some embodiments, in the thrombin generation assay (TGA), in the presence of 50 nM or more of the TF antibody, the peak IIa% obtained as compared to the antibody-free control condition is at least 40%. In some embodiments, in the thrombin generation assay (TGA), in the presence of 50 nM or more of the TF antibody, the peak IIa% obtained as compared to the antibody-free control condition is at least 50%. In some embodiments, in the thrombin generation assay (TGA), in the presence of 50 nM or more of the TF antibody, the peak IIa% obtained as compared to the antibody-free control condition is at least 60%. In some embodiments, in the thrombin generation assay (TGA), in the presence of 50 nM or more of the TF antibody, the peak IIa% obtained as compared to the antibody-free control condition is at least 70%. In some embodiments, in the thrombin generation assay (TGA), in the presence of 50 nM or more of the TF antibody, the peak IIa% obtained as compared to the antibody-free control condition is at least 80%. In some embodiments, in the thrombin generation assay (TGA), in the presence of 50 nM or more of the TF antibody, the peak IIa% obtained as compared to the antibody-free control condition is at least 90%. In some embodiments, in the thrombin generation assay (TGA), in the presence of 50 nM or more of the TF antibody, the peak IIa% obtained as compared to the antibody-free control condition is at least 95%. In some embodiments, in the thrombin generation assay (TGA), in the presence of 50 nM or more of the TF antibody, the peak IIa% obtained as compared to the antibody-free control condition is at least 99%.

[0305] In some embodiments, in a thrombin generation assay (TGA), in the presence of a TF antibody of 10 nM or more, the peak IIa% obtained as compared to the antibody-free control condition is at least 60%. In some embodiments, in a thrombin generation assay (TGA), in the presence of a TF antibody of 10 nM or more, the peak IIa% obtained as compared to the antibody-free control condition is at least 70%. In some embodiments, in a thrombin generation assay (TGA), in the presence of a TF antibody of 10 nM or more, the peak IIa% obtained as compared to the antibody-free control condition is at least 80%. In some embodiments, in a thrombin generation assay (TGA), in the presence of a TF antibody of 10 nM or more, the peak IIa% obtained as compared to the antibody-free control condition is at least 90%. In some embodiments, in a thrombin generation assay (TGA), in the presence of a TF antibody of 10 nM or more, the peak IIa% obtained as compared to the antibody-free control condition is at least 95%. In some embodiments, in a thrombin generation assay (TGA), in the presence of a TF antibody of 10 nM or more, the peak IIa% obtained as compared to the antibody-free control condition is at least 99%.

[0306] In some embodiments, as described in Tables 6 and 37 of PCT / US2019 / 12427 filed on January 4, 2019, in a thrombin generation assay (TGA) without antibody pre-incubation, in the presence of a 100 nM TF antibody, the peak IIa% obtained as compared to the antibody-free control condition is selected from about 99%, about 100%, about 103%, about 64%, about 52%, about 87%, about 96%, about 98%, and about 53%. In some embodiments, such peak IIa% is in the range of about 52% to about 103%. In some embodiments, such peak IIa% is at least about 52%.

[0307] In some embodiments, as described in Tables 6 and 37 of PCT / US2019 / 12427, filed on January 4, 2019, in a thrombin generation assay (TGA) without antibody pre-incubation, in the presence of 50 nM TF antibody, the peak IIa% obtained as compared to the antibody-free control condition is selected from about 99%, about 100%, about 103%, about 67%, about 58%, about 89%, about 96%, about 98%, about 68%, about 62%, and about 88%. In some embodiments, such peak IIa% ranges from about 58% to about 103%. In some embodiments, such peak IIa% is about 58% or more.

[0308] In some embodiments, as described in Tables 6 and 37 of PCT / US2019 / 12427, filed on January 4, 2019, in a thrombin generation assay (TGA) without antibody pre-incubation, in the presence of 100 nM TF antibody, the peak IIa% obtained as compared to the antibody-free control condition is selected from about 100%, about 99%, about 103%, about 87%, about 83%, about 95%, about 98%, about 86%, and about 96%. In some embodiments, such peak IIa% ranges from about 83% to about 103%. In some embodiments, such peak IIa% is about 83% or more.

[0309] In some embodiments, as described in Tables 7 and 38 of PCT / US2019 / 12427, filed on January 4, 2019, in a thrombin generation assay (TGA) without antibody pre-incubation, in the presence of 100 nM TF antibody, the peak IIa% obtained as compared to the antibody-free control condition is selected from about 108%, about 105%, about 111%, about 58%, about 47%, about 91%, about 103%, about 109%, about 107%, and about 45%. In some embodiments, such peak IIa% ranges from about 45% to about 111%. In some embodiments, such peak IIa% is about 45% or more.

[0310] In some embodiments, as described in Tables 7 and 38 of PCT / US2019 / 12427, filed on January 4, 2019, in a thrombin generation assay (TGA) without antibody pre-incubation, in the presence of 50 nM TF antibody, the peak IIa% obtained compared to the antibody-free control condition is selected from about 107%, about 104%, about 114%, about 62%, about 49%, about 87%, about 105%, about 109%, about 55%, and about 92%. In some embodiments, such peak IIa% ranges from about 49% to about 114%. In some embodiments, such peak IIa% is about 49% or more.

[0311] In some embodiments, as described in Tables 7 and 38 of PCT / US2019 / 12427, filed on January 4, 2019, in a thrombin generation assay (TGA) without antibody pre-incubation, in the presence of 10 nM TF antibody, the peak IIa% is selected from about 105%, about 114%, about 76%, about 68%, about 94%, about 108%, about 104%, about 74%, and about 93%. In some embodiments, such peak IIa% ranges from about 68% to about 114%. In some embodiments, such peak IIa% is about 68% or more.

[0312] In some embodiments, in a thrombin generation assay (TGA), in the presence of 100 nM or more TF antibody, the percent of endogenous thrombin potential (ETP%) obtained compared to the antibody-free control condition is at least 80%. In some embodiments, in a thrombin generation assay (TGA), in the presence of 100 nM or more TF antibody, the ETP% obtained compared to the antibody-free control condition is at least 90%. In some embodiments, in a thrombin generation assay (TGA), in the presence of 100 nM or more TF antibody, the ETP% obtained compared to the antibody-free control condition is at least 95%. In some embodiments, in a thrombin generation assay (TGA), in the presence of 100 nM or more TF antibody, the ETP% obtained compared to the antibody-free control condition is at least 99%.

[0313] In some embodiments, in the thrombin generation assay (TGA), in the presence of a TF antibody of 50 nM or more, the ETP% obtained as compared to the antibody-free control condition is at least 80%. In some embodiments, in the thrombin generation assay (TGA), in the presence of a TF antibody of 50 nM or more, the ETP% obtained as compared to the antibody-free control condition is at least 90%. In some embodiments, in the thrombin generation assay (TGA), in the presence of a TF antibody of 50 nM or more, the ETP% obtained as compared to the antibody-free control condition is at least 95%. In some embodiments, in the thrombin generation assay (TGA), in the presence of a TF antibody of 50 nM or more, the ETP% obtained as compared to the antibody-free control condition is at least 99%.

[0314] In some embodiments, in the thrombin generation assay (TGA), in the presence of a TF antibody of 10 nM or more, the ETP% obtained as compared to the antibody-free control condition is at least 80%. In some embodiments, in the thrombin generation assay (TGA), in the presence of a TF antibody of 10 nM or more, the ETP% obtained as compared to the antibody-free control condition is at least 90%. In some embodiments, in the thrombin generation assay (TGA), in the presence of a TF antibody of 10 nM or more, the ETP% obtained as compared to the antibody-free control condition is at least 95%. In some embodiments, in the thrombin generation assay (TGA), in the presence of a TF antibody of 10 nM or more, the ETP% obtained as compared to the antibody-free control condition is at least 99%.

[0315] In some embodiments, as described in Tables 6 and 37 of PCT / US2019 / 12427, filed on January 4, 2019, in a thrombin generation assay (TGA) without antibody pre-incubation, in the presence of 100 nM TF antibody, the ETP% obtained compared to the antibody-free control condition is selected from about 108%, about 103%, about 109%, about 100%, about 96%, about 102%, about 105%, and about 92%. In some embodiments, such ETP% ranges from about 92% to about 109%. In some embodiments, such ETP% is about 92% or more.

[0316] In some embodiments, as described in Tables 6 and 37 of PCT / US2019 / 12427, filed on January 4, 2019, in a thrombin generation assay (TGA) without antibody pre-incubation, in the presence of 50 nM TF antibody, the ETP% obtained compared to the antibody-free control condition is selected from about 108%, about 103%, about 111%, about 101%, about 97%, about 104%, about 106%, about 93%, about 96%, and about 105%. In some embodiments, such ETP% ranges from about 93% to about 111%. In some embodiments, such ETP% is about 93% or more.

[0317] In some embodiments, as described in Tables 6 and 37 of PCT / US2019 / 12427, filed on January 4, 2019, in a thrombin generation assay (TGA) without antibody pre-incubation, in the presence of 10 nM TF antibody, the ETP% obtained compared to the antibody-free control condition is selected from about 106%, about 109%, about 105%, about 104%, about 107%, about 99%, about 101%, and about 102%. In some embodiments, such ETP% ranges from about 99% to about 109%. In some embodiments, such ETP% is about 99% or more.

[0318] In some embodiments, as described in Tables 7 and 38 of PCT / US2019 / 12427, filed January 4, 2019, in a thrombin generation assay (TGA) without antibody pre-incubation, in the presence of 100 nM TF antibody, the ETP% obtained as compared to the antibody-free control condition is selected from about 110%, about 104%, about 106%, about 98%, about 95%, about 108%, about 107%, about 96%, about 92%, and about 103%. In some embodiments, such ETP% ranges from about 92% to about 110%. In some embodiments, such ETP% is about 92% or more.

[0319] In some embodiments, as described in Tables 7 and 38 of PCT / US2019 / 12427, filed January 4, 2019, in a thrombin generation assay (TGA) without antibody pre-incubation, in the presence of 50 nM TF antibody, the ETP% obtained as compared to the antibody-free control condition is selected from about 110%, about 106%, about 108%, about 103%, about 96%, about 109%, about 102%, about 104%, about 94%, and about 98%. In some embodiments, such ETP% ranges from about 94% to about 110%. In some embodiments, such ETP% is about 94% or more.

[0320] In some embodiments, as described in Tables 7 and 38 of PCT / US2019 / 12427, filed January 4, 2019, in a thrombin generation assay (TGA) without antibody pre-incubation, in the presence of 10 nM TF antibody, the ETP% obtained as compared to the antibody-free control condition is selected from about 107%, about 106%, about 110%, about 103%, about 100%, about 105%, about 102%, and about 101%. In some embodiments, such ETP% ranges from about 100% to about 110%. In some embodiments, such ETP% is about 100% or more.

[0321] 2.3.3. Conversion of FXa in the presence of TF antibody In some embodiments, the antibodies provided herein bind human TF at a human TF binding site that is different from the human TF binding site to which human FX binds. In certain embodiments, the antibodies provided herein do not interfere with the ability of TF:FVIIa to convert FX to FXa.

[0322] In some embodiments, in the presence of 100 nM or more of the TF antibody, the percentage of FXa conversion (FXa%) obtained as compared to the antibody-free control condition is at least 75%. In some embodiments, in the presence of 100 nM or more of the TF antibody, the FXa% obtained as compared to the antibody-free control condition is at least 80%. In some embodiments, in the presence of 100 nM or more of the TF antibody, the FXa% obtained as compared to the antibody-free control condition is at least 85%. In some embodiments, in the presence of 100 nM or more of the TF antibody, the FXa% obtained as compared to the antibody-free control condition is at least 90%. In some embodiments, in the presence of 100 nM or more of the TF antibody, the FXa% obtained as compared to the antibody-free control condition is at least 95%.

[0323] In some embodiments, in the presence of 50 nM or more of the TF antibody, the FXa% obtained as compared to the antibody-free control condition is at least 75%. In some embodiments, in the presence of 50 nM or more of the TF antibody, the FXa% obtained as compared to the antibody-free control condition is at least 80%. In some embodiments, in the presence of 50 nM or more of the TF antibody, the FXa% obtained as compared to the antibody-free control condition is at least 85%. In some embodiments, in the presence of 50 nM or more of the TF antibody, the FXa% obtained as compared to the antibody-free control condition is at least 90%. In some embodiments, in the presence of 50 nM or more of the TF antibody, the FXa% obtained as compared to the antibody-free control condition is at least 95%.

[0324] In some embodiments, in the presence of a TF antibody of 25 nM or more, the FXa% obtained as compared to the antibody-free control condition is at least 75%. In some embodiments, in the presence of a TF antibody of 25 nM or more, the FXa% obtained as compared to the antibody-free control condition is at least 80%. In some embodiments, in the presence of a TF antibody of 25 nM or more, the FXa% obtained as compared to the antibody-free control condition is at least 85%. In some embodiments, in the presence of a TF antibody of 25 nM or more, the FXa% obtained as compared to the antibody-free control condition is at least 90%. In some embodiments, in the presence of a TF antibody of 25 nM or more, the FXa% obtained as compared to the antibody-free control condition is at least 95%.

[0325] In some embodiments, in the presence of a TF antibody of 12.5 nM or more, the FXa% obtained as compared to the antibody-free control condition is at least 75%. In some embodiments, in the presence of a TF antibody of 12.5 nM or more, the FXa% obtained as compared to the antibody-free control condition is at least 80%. In some embodiments, in the presence of a TF antibody of 12.5 nM or more, the FXa% obtained as compared to the antibody-free control condition is at least 85%. In some embodiments, in the presence of a TF antibody of 12.5 nM or more, the FXa% obtained as compared to the antibody-free control condition is at least 90%. In some embodiments, in the presence of a TF antibody of 12.5 nM or more, the FXa% obtained as compared to the antibody-free control condition is at least 95%.

[0326] In some embodiments, as described in Table 8 of PCT / US2019 / 12427 filed on January 4, 2019, in the presence of 100 nM of a TF antibody, the FXa% obtained as compared to the antibody-free control condition is selected from about 89%, about 96%, about 116%, about 108%, about 117%, about 105%, about 112%, about 106%, about 103%, about 111%, about 98%, and about 101%. In some embodiments, such FXa% is in the range of about 89% to about 117%. In some embodiments, such FXa% is at least about 89%.

[0327] In some embodiments, as set forth in Table 8 of PCT / US2019 / 12427, filed January 4, 2019, the % FXa obtained in the presence of 50 nM TF antibody, compared to antibody-free control conditions, is selected from about 94%, about 93%, about 78%, about 102%, about 99%, about 104%, about 105%, about 108%, about 107%, about 97%, and about 106%. In some embodiments, such % FXa is in the range of about 78% to about 108%. In some embodiments, such % FXa is about 78% or greater.

[0328] In some embodiments, as set forth in Table 8 of PCT / US2019 / 12427, filed January 4, 2019, the % FXa obtained in the presence of 25 nM TF antibody, compared to antibody-free control conditions, is selected from about 81%, about 89%, about 85%, about 109%, about 96%, about 97%, about 108%, about 104%, about 103%, about 112%, and about 89%. In some embodiments, such % FXa is in the range of about 81% to about 112%. In some embodiments, such % FXa is about 81% or greater.

[0329] In some embodiments, as set forth in Table 8 of PCT / US2019 / 12427, filed January 4, 2019, the % FXa obtained in the presence of 12.5 nM TF antibody, compared to antibody-free control conditions, is selected from about 87%, about 89%, about 82%, about 99%, about 101%, about 98%, about 113%, about 106%, about 115%, about 110%, about 120%, about 85%, and about 108%. In some embodiments, such % FXa is in the range of about 82% to about 120%. In some embodiments, such % FXa is about 82% or greater.

[0330] 2.3.4. Binding of FVIIa in the presence of TF antibody In some embodiments, the antibodies provided herein bind human TF at a human TF binding site that is different from the human TF binding site to which human FVIIa binds. In certain embodiments, the antibodies provided herein do not compete with human FVIIa for binding to human TF.

[0331] In some embodiments, in the presence of TF antibody at 250 nM or more, the percentage of FVIIa binding (FVIIa%) obtained as compared to the antibody-free control condition is at least 75%. In some embodiments, in the presence of TF antibody at 250 nM or more, the FVIIa% obtained as compared to the antibody-free control condition is at least 80%. In some embodiments, in the presence of TF antibody at 250 nM or more, the FVIIa% obtained as compared to the antibody-free control condition is at least 85%. In some embodiments, in the presence of TF antibody at 250 nM or more, the FVIIa% obtained as compared to the antibody-free control condition is at least 90%. In some embodiments, in the presence of TF antibody at 250 nM or more, the FVIIa% obtained as compared to the antibody-free control condition is at least 95%.

[0332] In some embodiments, in the presence of TF antibody at 83 nM or more, the percentage of FVIIa binding (FVIIa%) obtained as compared to the antibody-free control condition is at least 75%. In some embodiments, in the presence of TF antibody at 83 nM or more, the FVIIa% obtained as compared to the antibody-free control condition is at least 80%. In some embodiments, in the presence of TF antibody at 83 nM or more, the FVIIa% obtained as compared to the antibody-free control condition is at least 85%. In some embodiments, in the presence of TF antibody at 83 nM or more, the FVIIa% obtained as compared to the antibody-free control condition is at least 90%. In some embodiments, in the presence of TF antibody at 83 nM or more, the FVIIa% obtained as compared to the antibody-free control condition is at least 95%.

[0333] In some embodiments, in the presence of a TF antibody of 28 nM or more, the FVIIa% obtained as compared to the antibody-free control condition is at least 75%. In some embodiments, in the presence of a TF antibody of 28 nM or more, the FVIIa% obtained as compared to the antibody-free control condition is at least 80%. In some embodiments, in the presence of a TF antibody of 28 nM or more, the FVIIa% obtained as compared to the antibody-free control condition is at least 85%. In some embodiments, in the presence of a TF antibody of 28 nM or more, the FVIIa% obtained as compared to the antibody-free control condition is at least 90%. In some embodiments, in the presence of a TF antibody of 28 nM or more, the FVIIa% obtained as compared to the antibody-free control condition is at least 95%.

[0334] In some embodiments, in the presence of a TF antibody of 9.25 nM or more, the FVIIa% obtained as compared to the antibody-free control condition is at least 75%. In some embodiments, in the presence of a TF antibody of 9.25 nM or more, the FVIIa% obtained as compared to the antibody-free control condition is at least 80%. In some embodiments, in the presence of a TF antibody of 9.25 nM or more, the FVIIa% obtained as compared to the antibody-free control condition is at least 85%. In some embodiments, in the presence of a TF antibody of 9.25 nM or more, the FVIIa% obtained as compared to the antibody-free control condition is at least 90%. In some embodiments, in the presence of a TF antibody of 9.25 nM or more, the FVIIa% obtained as compared to the antibody-free control condition is at least 95%.

[0335] In some embodiments, as described in Table 9 of PCT / US2019 / 12427 filed on January 4, 2019, in the presence of 250 nM of a TF antibody, the FVIIa% obtained as compared to the antibody-free control condition is selected from about 98%, about 87%, about 80%, about 92%, about 95%, about 89%, about 91%, about 97%, about 94%, about 101%, and about 96%. In some embodiments, such FVIIa% is in the range of about 80% to about 101%. In some embodiments, such FVIIa% is about 80% or more.

[0336] In some embodiments, as described in Table 9 of PCT / US2019 / 12427 filed on January 4, 2019, in the presence of 83 nM TF antibody, the FVIIa% obtained compared to the antibody-free control condition is selected from about 97%, about 88%, about 77%, about 93%, about 94%, about 91%, about 98%, about 100%, and about 92%. In some embodiments, such FVIIa% ranges from about 77% to about 100%. In some embodiments, such FVIIa% is about 77% or more.

[0337] In some embodiments, as described in Table 9 of PCT / US2019 / 12427 filed on January 4, 2019, in the presence of 28 nM TF antibody, the FVIIa% obtained compared to the antibody-free control condition is selected from about 101%, about 87%, about 79%, about 96%, about 93%, about 95%, about 98%, about 100%, about 102%, about 99%, about 92%, and about 91%. In some embodiments, such FVIIa% ranges from about 79% to about 102%. In some embodiments, such FVIIa% is about 79% or more.

[0338] In some embodiments, as described in Table 9 of PCT / US2019 / 12427 filed on January 4, 2019, in the presence of 9.25 nM TF antibody, the FVIIa% obtained compared to the antibody-free control condition is selected from about 100%, about 90%, about 76%, about 97%, about 93%, about 99%, about 98%, about 102%, about 101%, and about 95%. In some embodiments, such FVIIa% ranges from about 76% to about 102%. In some embodiments, such FVIIa% is about 76% or more.

[0339] 2.3.5. FVIIa-Dependent TF Signaling in the Presence of TF Antibody In some embodiments, the antibodies provided herein inhibit FVIIa-dependent TF signaling. In some embodiments, inhibition of FVIIa-dependent TF signaling measures a decrease in IL8. In some embodiments, inhibition of FVIIa-dependent TF signaling measures a decrease in GM-CSF.

[0340] In some embodiments, in the presence of 100 nM or more of the TF antibody, the interleukin 8 concentration (IL8 conc) obtained as compared to the antibody-free control condition is decreased by at least 70%. In some embodiments, in the presence of 100 nM or more of the TF antibody, the IL8 conc obtained as compared to the antibody-free control condition is decreased by at least 80%. In some embodiments, in the presence of 100 nM or more of the TF antibody, the IL8 conc obtained as compared to the antibody-free control condition is decreased by at least 90%.

[0341] In some embodiments, in the presence of 40 nM or more of the TF antibody, the IL8 conc obtained as compared to the antibody-free control condition is decreased by at least 70%. In some embodiments, in the presence of 40 nM or more of the TF antibody, the IL8 conc obtained as compared to the antibody-free control condition is decreased by at least 80%. In some embodiments, in the presence of 40 nM or more of the TF antibody, the IL8 conc obtained as compared to the antibody-free control condition is decreased by at least 90%.

[0342] In some embodiments, in the presence of 16 nM or more of the TF antibody, the IL8 conc obtained as compared to the antibody-free control condition is decreased by at least 60%. In some embodiments, in the presence of 16 nM or more of the TF antibody, the IL8 conc obtained as compared to the antibody-free control condition is decreased by at least 70%. In some embodiments, in the presence of 16 nM or more of the TF antibody, the IL8 conc obtained as compared to the antibody-free control condition is decreased by at least 80%. In some embodiments, in the presence of 16 nM or more of the TF antibody, the IL8 conc obtained as compared to the antibody-free control condition is decreased by at least 90%.

[0343] In some embodiments, in the presence of a TF antibody of 6.4 nM or more, the IL8 conc obtained as compared to the antibody-free control condition is reduced by at least 50%. In some embodiments, in the presence of a TF antibody of 6.4 nM or more, the IL8 conc obtained as compared to the antibody-free control condition is reduced by at least 60%. In some embodiments, in the presence of a TF antibody of 6.4 nM or more, the IL8 conc obtained as compared to the antibody-free control condition is reduced by at least 70%. In some embodiments, in the presence of a TF antibody of 6.4 nM or more, the IL8 conc obtained as compared to the antibody-free control condition is reduced by at least 80%. In some embodiments, in the presence of a TF antibody of 6.4 nM or more, the IL8 conc obtained as compared to the antibody-free control condition is reduced by at least 90%.

[0344] In some embodiments, in the presence of a TF antibody of 100 nM or more, the granulocyte macrophage colony-stimulating factor concentration (GM-CSF conc) obtained as compared to the antibody-free control condition is reduced by at least 70%. In some embodiments, in the presence of a TF antibody of 100 nM or more, the GM-CSF conc obtained as compared to the antibody-free control condition is reduced by at least 80%. In some embodiments, in the presence of a TF antibody of 100 nM or more, the GM-CSF conc obtained as compared to the antibody-free control condition is reduced by at least 90%.

[0345] In some embodiments, in the presence of a TF antibody of 40 nM or more, the GM-CSF conc obtained as compared to the antibody-free control condition is reduced by at least 70%. In some embodiments, in the presence of a TF antibody of 40 nM or more, the GM-CSF conc obtained as compared to the antibody-free control condition is reduced by at least 80%. In some embodiments, in the presence of a TF antibody of 40 nM or more, the GM-CSF conc obtained as compared to the antibody-free control condition is reduced by at least 90%.

[0346] In some embodiments, in the presence of 16 nM or more of the TF antibody, the GM-CSF conc obtained as compared to the antibody-free control condition is reduced by at least 60%. In some embodiments, in the presence of 16 nM or more of the TF antibody, the GM-CSF conc obtained as compared to the antibody-free control condition is reduced by at least 70%. In some embodiments, in the presence of 16 nM or more of the TF antibody, the GM-CSF conc obtained as compared to the antibody-free control condition is reduced by at least 80%. In some embodiments, in the presence of 16 nM or more of the TF antibody, the GM-CSF conc obtained as compared to the antibody-free control condition is reduced by at least 90%.

[0347] In some embodiments, in the presence of 6.4 nM or more of the TF antibody, the GM-CSF conc obtained as compared to the antibody-free control condition is reduced by at least 50%. In some embodiments, in the presence of 6.4 nM or more of the TF antibody, the GM-CSF conc obtained as compared to the antibody-free control condition is reduced by at least 60%. In some embodiments, in the presence of 6.4 nM or more of the TF antibody, the GM-CSF conc obtained as compared to the antibody-free control condition is reduced by at least 70%. In some embodiments, in the presence of 6.4 nM or more of the TF antibody, the GM-CSF conc obtained as compared to the antibody-free control condition is reduced by at least 80%. In some embodiments, in the presence of 6.4 nM or more of the TF antibody, the GM-CSF conc obtained as compared to the antibody-free control condition is reduced by at least 90%.

[0348] In some embodiments, as described in Table 10 of PCT / US2019 / 12427 filed on January 4, 2019, in the presence of 100 nM of the TF antibody, the percentage of interleukin 8 (IL8%) obtained as compared to the antibody-free control condition is selected from about 2%, about 9%, about 8%, about 6%, about 13%, about 1%, about 3%, about 4%, and about 5%. In some embodiments, such IL8% is in the range of about 1% to about 13%. In some embodiments, such IL8% is about 13% or less.

[0349] In some embodiments, as set forth in Table 10 of PCT / US2019 / 12427, filed on January 4, 2019, the IL8% obtained in the presence of 40 nM TF antibody, compared to the antibody-free control condition, is selected from about 2%, about 8%, about 7%, about 10%, about 14%, about 4%, about 5%, and about 6%. In some embodiments, such IL8% ranges from about 2% to about 14%. In some embodiments, such IL8% is about 14% or less.

[0350] In some embodiments, as set forth in Table 10 of PCT / US2019 / 12427, filed on January 4, 2019, the IL8% obtained in the presence of 16 nM TF antibody, compared to the antibody-free control condition, is selected from about 2%, about 3%, about 10%, about 8%, about 7%, about 16%, about 9%, about 15%, about 5%, and about 6%. In some embodiments, such IL8% ranges from about 2% to about 16%. In some embodiments, such IL8% is about 16% or less.

[0351] In some embodiments, as set forth in Table 10 of PCT / US2019 / 12427, filed on January 4, 2019, the IL8% obtained in the presence of 6.4 nM TF antibody, compared to the antibody-free control condition, is selected from about 3%, about 4%, about 11%, about 9%, about 14%, about 22%, about 12%, about 6%, about 5%, about 15%, about 21%, and about 8%. In some embodiments, such IL8% ranges from about 3% to about 22%. In some embodiments, such IL8% is about 22% or less.

[0352] In some embodiments, as described in Table 11 of PCT / US2019 / 12427, filed on January 4, 2019, the percentage of granulocyte macrophage colony-stimulating factor (GM-CSF%) obtained in the presence of 100 nM TF antibody compared to antibody-free control conditions is selected from about 6%, about 7%, about 22%, about 20%, about 12%, about 19%, about 17%, about 25%, about 5%, about 14%, about 11%, and about 10%. In some embodiments, such GM-CSF% ranges from about 5% to about 25%. In some embodiments, such GM-CSF% is about 25% or less.

[0353] In some embodiments, as described in Table 11 of PCT / US2019 / 12427, filed on January 4, 2019, the GM-CSF% obtained in the presence of 40 nM TF antibody compared to antibody-free control conditions is selected from about 6%, about 7%, about 19%, about 15%, about 18%, about 16%, about 26%, about 5%, about 13%, about 11%, and about 10%. In some embodiments, such GM-CSF% ranges from about 5% to about 26%. In some embodiments, such GM-CSF% is about 26% or less.

[0354] In some embodiments, as described in Table 11 of PCT / US2019 / 12427, filed on January 4, 2019, the GM-CSF% obtained in the presence of 16 nM TF antibody compared to antibody-free control conditions is selected from about 6%, about 7%, about 22%, about 19%, about 14%, abou...

Claims

1. An antibody-drug conjugate comprising: a. An antigen-binding protein (Ab) that binds to human tissue factor (TF) (SEQ ID NO: 810) and comprises VH-CDR1, VH-CDR2, and VH-CDR3, and VL-CDR1, VL-CDR2, and VL-CDR3, wherein the VH-CDR1, the VH-CDR2, and the VH-CDR3 each comprise the amino acid sequences of VH-CDR1, VH-CDR2, and VH-CDR3 shown in VH comprising the amino acid sequence of SEQ ID NO: 151, and the VL-CDR1, the VL-CDR2, and the VL-CDR3 each comprise the amino acid sequences of VL-CDR1, VL-CDR2, and VL-CDR3 shown in VL comprising the amino acid sequence of SEQ ID NO: 152, said antigen-binding protein (Ab); and b. One or more linker-toxin moieties of formula VIII: wherein # represents the point of attachment of the linker-toxin moiety to the Ab via a covalent bond, said linker-toxin moiety.

2. The antibody-drug conjugate according to claim 1, wherein the Ab comprises a VH comprising the amino acid sequence of SEQ ID NO: 151 and a VL comprising the amino acid sequence of SEQ ID NO:

152.

3. (i) the VH-CDR1 comprises the amino acid sequence of SEQ ID NO: 115, the VH-CDR2 comprises the amino acid sequence of SEQ ID NO: 116, the VH-CDR3 comprises the amino acid sequence of SEQ ID NO: 117, the VL-CDR1 comprises the amino acid sequence of SEQ ID NO: 118, the VL-CDR2 comprises the amino acid sequence of SEQ ID NO: 119, and the VL-CDR3 comprises the amino acid sequence of SEQ ID NO: 120; (ii) the VH-CDR1 comprises the amino acid sequence of SEQ ID NO: 121, the VH-CDR2 comprises the amino acid sequence of SEQ ID NO: 122, the VH-CDR3 comprises the amino acid sequence of SEQ ID NO: 123, the VL-CDR1 comprises the amino acid sequence of SEQ ID NO: 124, the VL-CDR2 comprises the amino acid sequence of SEQ ID NO: 125, and the VL-CDR3 comprises the amino acid sequence of SEQ ID NO: 126; (iii) the VH - CDR1 contains the amino acid sequence of SEQ ID NO: 127, the VH - CDR2 contains the amino acid sequence of SEQ ID NO: 128, the VH - CDR3 contains the amino acid sequence of SEQ ID NO: 129, the VL - CDR1 contains the amino acid sequence of SEQ ID NO: 130, the VL - CDR2 contains the amino acid sequence of SEQ ID NO: 131, and the VL - CDR3 contains the amino acid sequence of SEQ ID NO: 132; (iv) the VH - CDR1 contains the amino acid sequence of SEQ ID NO: 133, the VH - CDR2 contains the amino acid sequence of SEQ ID NO: 134, the VH - CDR3 contains the amino acid sequence of SEQ ID NO: 135, the VL - CDR1 contains the amino acid sequence of SEQ ID NO: 136, the VL - CDR2 contains the amino acid sequence of SEQ ID NO: 137, and the VL - CDR3 contains the amino acid sequence of SEQ ID NO: 138; (v) the VH - CDR1 contains the amino acid sequence of SEQ ID NO: 139, the VH - CDR2 contains the amino acid sequence of SEQ ID NO: 140, the VH - CDR3 contains the amino acid sequence of SEQ ID NO: 141, the VL - CDR1 contains the amino acid sequence of SEQ ID NO: 142, the VL - CDR2 contains the amino acid sequence of SEQ ID NO: 143, and the VL - CDR3 contains the amino acid sequence of SEQ ID NO: 144, or (vi) the VH - CDR1 contains the amino acid sequence of SEQ ID NO: 145, the VH - CDR2 contains the amino acid sequence of SEQ ID NO: 146, the VH - CDR3 contains the amino acid sequence of SEQ ID NO: 147, the VL - CDR1 contains the amino acid sequence of SEQ ID NO: 148, the VL - CDR2 contains the amino acid sequence of SEQ ID NO: 149, and the VL - CDR3 contains the amino acid sequence of SEQ ID NO: 150; The antibody - drug conjugate according to claim 1.

4. The Ab is QVQLVQSGAEVKKPGASVKVSACKASGYTFDVYGISWVRQAPGQGLEWMGWIA PYSGNTNYAQKLQG RVTMTTDTSTSTAYMELRSLRSDDTA VYYCARDA GTYSPFGYGM DVWGQGT TVTVSSASTKG P S V F P L A P S S K S T S G G T A A L G C L V K D Y F P E P V T V S W N S G A L T S G V H T F P A V L Q S S G L Y S L S S V V T V P S S S L G T Q T Y I C N V N H K P S N T K V D K R V E P K S C D K T H T C P P C P A P E L L G G P S V F L F P P K P K D T L M I S R T P E V T C V V V D V S H E D P E V K F N W Y V D G V E V H N A K T K P R E E Q Y N S T Y R V V S V L T V L H Q D W L N G K E Y K C K V S N K A L P A P I E K T I S K A K G Q P R E P Q V Y T L P P S R E E M T K N Q V S L T C L V K G F Y P S D I A V E W E S N G Q P E N N Y K T T P P V L D S D G S F F L Y S K L T V D K S R W Q Q G N V F S C S V M H E A L H N H Y T Q K S L S L S P G (SEQ ID NO: 926) a heavy chain sequence comprising, and DIQM TQSPSTLSASVGDRVTITCQASQ SINNWLAWYQQKPGKAPKLLIYKAYNLESGVP SRFSGSGSGTEFTLTISSLQPDD F A TYYCQLFQSLPPFTFGGG TKVEIKRTVAA PSVFIFPP SDEQLKSGTASVVCL LNNF YP REAKVQWKVDNA LQSGNSQESVT EQDSKDS TYS LSSTLTLSKADYEKHKVYACEVTHQGLSSPV TK SFNRGEC (SEQ ID NO: 927) a light chain sequence comprising The antibody-drug conjugate according to any one of claims 1 to 3, comprising **Claim 5** Formula IX: having, wherein: Ab includes VH - CDR1, VH - CDR2, and VH - CDR3, and VL - CDR1, VL - CDR2, and VL - CDR3, where the VH - CDR1, the VH - CDR2, and the VH - CDR3 respectively include the amino acid sequences of VH - CDR1, VH - CDR2, and VH - CDR3 shown in VH containing the amino acid sequence of SEQ ID NO: 151, and the VL - CDR1, the VL - CDR2, and the VL - CDR3 respectively include the amino acid sequences of VL - CDR1, VL - CDR2, and VL - CDR3 shown in VL containing the amino acid sequence of SEQ ID NO: 152; and n is an integer selected from the group consisting of 1, 2, 3, 4, and 5, The antibody - drug conjugate according to claim 1.

6. Formula IX: having, wherein: n is an integer selected from the group consisting of 1, 2, 3, 4, and 5, and Ab includes VH containing the amino acid sequence of SEQ ID NO: 151 and VL containing the amino acid sequence of SEQ ID NO: 152; and / or Ab is QVQLVQSGAEVKRPASVKVSCKASGYTFDVYGISWVRQAPGQGLEWMGWIA PYSGNTNYAQKLQGRVTMTTDTSSTSTAYMELRSLRSDDTA VYYCARDAGTYSPFGYGMDVWGQGTTVTVSSASTKGPSVFPLAPSSKS TSGGTAALGCLVKDFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS VVTVPSSSLGTQTYICNVNHKPSNTKVSDKRVEPKSCDKTHTCPPCPA PELLGGPVFLLPPKPKDTLMISRTPEVTCVVVDVSHEDPENVKFNWYVD GVEVHNAKTKPREEQYNSTYRVVSSVLTVLHQDWLNGKEYKCKVSNKALP APIEKTIASKAKGQPREPQVYTLPPSREEMTKNPVSLTCLVKGFYPSDIA VEWESNGQPENNYYKTPPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSSVMHEALHNHYTQKSLLSPG (SEQ ID NO: 926) a heavy chain sequence comprising, and DIQMTQSPSTLSASVGDRVTITCQASQSIINNWLAWYQQKPGKAPKLLIYKAYNLESGVPSRFSSGSGSGSTEFTLTISSLQPDDFFATYYCQLFQSLPPFTFGGG TKVEIKRTVAAPSVFIFPPSEDQLKSGTASVVCLNNFYPREAKVQWKVDNALQSGSQESVT EQDSKDSSTYSLSSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNREGEC (SEQ ID NO: 927) a light chain sequence comprising the antibody-drug conjugate according to claim 1.

7. Formula IX: an antibody-drug conjugate of formula: wherein: n is an integer selected from the group consisting of 2, 3, and 4, and Ab is QVQLVQSGAEVKKPGASVKVSCKASGYTFDVYGISWVRQAPGQGLEWMGWIA PYSGNTNYAQKLQGRVTMTTDTSSTSTAYMELRSLRSDDTA VYYCARDAGTYSPFGYGM DWGQGTTVTVSSASTKGPSVFPLAPSSKS TSGGT AALGCLVK DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK SCDKTHTCPPCPA PELLGGPSVF LFPPKPKDTLMISRTPEVT CVVVDSHEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRVV S VLT VLHQDWLNGKEYKCKVSNKALPA PIEKTISKAKGQPREPQVYTLPPSREEMTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYYKTTP PVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKS LSLSPG (SEQ ID NO: 926) a heavy chain sequence comprising, and DIQMTQSPSTLSASVGDRVTITCQASQSI NNWL AWYQQKPGKAPKLLIYKAYNL E SGVP S RFSGSGSGSTEFTL TISSLQPDD FATYYCQLFQSLPPFTFGGG TKVEIKRTVAAPS VFIFPP SDEQLKSGTASVVCL LNNF YPREAKVQWKVDNA LQSGSNSQESVT EQDSK DSTYSLSSTLTL SKADYEKH KVYACEVT HQGLSSPVTKSFNRGEC (SEQ ID NO: 927) comprising a light chain sequence comprising said antibody-drug conjugate. [

8. ] A formulation comprising the antibody-drug conjugate according to any one of claims 1 to 7 and a pharmaceutically acceptable carrier. [

9. ] The formulation according to claim 8, comprising various drug-antibody ratio (DAR) species, wherein the average DAR of the formulation is 2 to 4. [

10. ] A method for preparing an antibody-drug conjugate, comprising reacting a nucleophilic or electrophilic group in an antigen-binding protein (Ab) that binds to human tissue factor (TF) (SEQ ID NO: 810) with a linker-toxin moiety represented by Formula VIII: wherein ## represents the point of attachment of the linker-toxin moiety to the Ab via a covalent bond, to provide the antibody-drug conjugate. The Ab comprises VH-CDR1, VH-CDR2, and VH-CDR3, and VL-CDR1, VL-CDR2, and VL-CDR3, wherein the VH-CDR1, the VH-CDR2, and the VH-CDR3 each comprise the amino acid sequences of VH-CDR1, VH-CDR2, and VH-CDR3 shown in VH comprising the amino acid sequence of SEQ ID NO: 151, and the VL-CDR1, the VL-CDR2, and the VL-CDR3 each comprise the amino acid sequences of VL-CDR1, VL-CDR2, and VL-CDR3 shown in VL comprising the amino acid sequence of SEQ ID NO:

152. said method. [

11. ] The method according to claim 10, wherein the nucleophilic or electrophilic group in the Ab is a thiol or an amine. [

12. ] The method according to claim 10, wherein the Ab comprises the VH sequence of SEQ ID NO: 151 and the VL sequence of SEQ ID NO:

152. [

13. ] (i) the VH - CDR1 contains the amino acid sequence of SEQ ID NO: 115, the VH - CDR2 contains the amino acid sequence of SEQ ID NO: 116, the VH - CDR3 contains the amino acid sequence of SEQ ID NO: 117, the VL - CDR1 contains the amino acid sequence of SEQ ID NO: 118, the VL - CDR2 contains the amino acid sequence of SEQ ID NO: 119, and the VL - CDR3 contains the amino acid sequence of SEQ ID NO: 120; (ii) the VH - CDR1 contains the amino acid sequence of SEQ ID NO: 121, the VH - CDR2 contains the amino acid sequence of SEQ ID NO: 122, the VH - CDR3 contains the amino acid sequence of SEQ ID NO: 123, the VL - CDR1 contains the amino acid sequence of SEQ ID NO: 124, the VL - CDR2 contains the amino acid sequence of SEQ ID NO: 125, and the VL - CDR3 contains the amino acid sequence of SEQ ID NO: 126; (iii) the VH - CDR1 contains the amino acid sequence of SEQ ID NO: 127, the VH - CDR2 contains the amino acid sequence of SEQ ID NO: 128, the VH - CDR3 contains the amino acid sequence of SEQ ID NO: 129, the VL - CDR1 contains the amino acid sequence of SEQ ID NO: 130, the VL - CDR2 contains the amino acid sequence of SEQ ID NO: 131, and the VL - CDR3 contains the amino acid sequence of SEQ ID NO: 132; (iv) the VH - CDR1 contains the amino acid sequence of SEQ ID NO: 133, the VH - CDR2 contains the amino acid sequence of SEQ ID NO: 134, the VH - CDR3 contains the amino acid sequence of SEQ ID NO: 135, the VL - CDR1 contains the amino acid sequence of SEQ ID NO: 136, the VL - CDR2 contains the amino acid sequence of SEQ ID NO: 137, and the VL - CDR3 contains the amino acid sequence of SEQ ID NO: 138; (v) the VH - CDR1 contains the amino acid sequence of SEQ ID NO: 139, the VH - CDR2 contains the amino acid sequence of SEQ ID NO: 140, the VH - CDR3 contains the amino acid sequence of SEQ ID NO: 141, the VL - CDR1 contains the amino acid sequence of SEQ ID NO: 142, the VL - CDR2 contains the amino acid sequence of SEQ ID NO: 143, and the VL - CDR3 contains the amino acid sequence of SEQ ID NO: 144, or (vi) the VH - CDR1 contains the amino acid sequence of SEQ ID NO: 145, the VH - CDR2 contains the amino acid sequence of SEQ ID NO: 146, the VH - CDR3 contains the amino acid sequence of SEQ ID NO: 147, the VL - CDR1 contains the amino acid sequence of SEQ ID NO: 148, the VL - CDR2 contains the amino acid sequence of SEQ ID NO: 149, and the VL - CDR3 contains the amino acid sequence of SEQ ID NO: 150, The method according to claim 10.

14. The Ab is QVQLVQSGAEVKRPAGSVKVSCKASGYTFDVYGISWVRQAPGQGLEWMGWIA PYSGNTNYAQKLQGRVTMTTDTSSTSTAYMELRSLRSDDTA VYYCARDA GTYSPFGYGM DVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKV DKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVT CVVVDSHEDPEVKFNWYVDGV E VHNAKTKPRE EQYNSTYR VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPP SREEMTK NQVS LTCLVKGFYPSDIAVEWESNGQPENNYYKTPPPVLDSDG SFFLYSKLTVDKS RWQQGNVFSCSVMHEALHNHYTQKS LS LSPG (SEQ ID NO: 926) a heavy chain sequence containing DIQMTQSPSTLSASVGDRVTITCQASQINNWLAWYQQKPGKAPKLLIYKAYNLESGP SRFSGSGSGTEFTLTISSLQPDDFATYYCQLFQSLPPFTFGGG TKVEIKRTVAAPS VFIFPP SDEQLKSGTASVVCL LNNF YPREAKVQWKVDNALQSGSNQESVT EQDSKDS TYSLSS TLTLSKADYEKH KVYACEVTHQGLSSPVTKSFN RGE C (SEQ ID NO: 927) a light chain sequence containing The method according to claim 10.

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