Factor XI anticoagulant antibodies

Abstract

Antibodies that bind to coagulation factor XI in the human body's apple3 domain and inhibit the activity of FXI by coagulation factor XIIa and also the activity of FIX by FXIa, as described above.

Description

Anticoagulant Factor XI antibodies Cross-referencing with related documents This document claims the benefit of U.S. Patent No. 888,349 / 62, filed June 14, 2016, which is hereby incorporated by reference in its entirety. Background of the invention 1) Field of invention The present invention relates to antibodies that bind to the 3-domain of human coagulation factor XI (FXI) and inhibit the activation of FXI by coagulation factor XIIa and the activity of FXIa on factor IX (FIX). 2) Description of related innovations Blood clotting disorders, including venous and arterial thrombosis, remain a major cause of morbidity and mortality in the Western world, despite the availability of a wide range of anticoagulant drugs, such as vitamin K antagonists (VKAs), heparins, and direct thrombin inhibitors (a type of enzyme that acts on the protein fibrinogen in the blood and causes blood to clot—translator's note) (Weitz et al., Chest 2008, S256-133:234; Hawkins, Drug-Therapy 2004 S 65 S-24:62). These drugs are effective in reducing the risk of blood clot formation in the vessels, but they have several limitations. For example, VKAs, or vitamin K antagonists (e.g., warfarin), have been the mainstay of oral anticoagulants, but VKA therapy management is complicated by significant risks associated with bleeding, slow onset and duration of action, and multiple dietary regimens and interactions with other medications (Hawkins, op. cit.; Ansel J, et al., Chest 2008, S 198 S-133:160).Drugs other than oral vitamin K antagonists (NOACs, including rivaroxaban, apizaban, edoxaban, and dabigatran), with fewer food and drug interactions and no need for monitoring, have shown at least non-inferior efficacy compared to warfarin. However, NOACs still increase the risk of bleeding, as evidenced by the 15% annual incidence of clinically relevant major or minor bleeding in the registered trials for stroke prevention by arterial smooth muscle dysregulation (Conley et al., New England Journal of Medicine 2009, 1151; Patel et al., New England Journal of Medicine 2011, 883-891: 365; Granger et al., New England Journal of Medicine 2011, 981-992: 365; Giugliano et al., New England Journal of Medicine 2013, 369: 2093-2014). This is largely because NOACs target proteins (factor Xa (FXa) and thrombin) that are essential for normal blood clotting (stopping bleeding or clotting).Therefore, there is an unmet need for new therapeutic approaches with better safety profiles in the prevention and treatment of vascular thromboembolic disorders and diseases. In the classical cascade model of blood coagulation (Figure 1A), blood coagulation is initiated either by the extrinsic (tissue factor (TF)-activated) or intrinsic (contact-activated) pathway, both of which enter a common pathway that culminates in the production of thrombin and the formation of fibrin (a type of insoluble filamentous protein formed by the action of thrombin on fibrinogen during blood coagulation; this protein forms a network that traps red blood cells and platelets and causes blood clotting—translator's note) (Fury and Fury, Cell 1988, 5018–505: 53; Jilani and Ren, J Trump Hemost 2007, 1112–1106: 5). External perfusion begins when TF, which is present in subdermal lesions and atherosclerotic ulcers, is exposed to flowing blood and forms a mixture with coagulation factor VIIa (FVIIIa).The TF-FVlla mixture (external thrombin mixture) then initiates blood coagulation in the common pathway, i.e., activating FX to form FXa, which in turn converts prothrombin to thrombin. The TF-FVlla mixture can also activate coagulation factor IX (FIX) to form FIXa. FIXa, in combination with coagulation factor VIII (FVIIIa) (internal thrombin mixture), can also cleave the FX substrate. The internal cascade is initiated when FXIIa is activated by contact or collision with negatively charged surfaces (e.g., collagen and glycosaminoglycans), and promotes thrombin production through the sequential activation of FIX, FIX, FX, and prothrombin.Thrombin, as the final protease in the coagulation cascade, can then contribute to the production of FXIa by directly activating FXI. Platelets, another important component of hemostasis in whole blood or anticoagulant-containing blood, can be activated by thrombin and subsequently support the formation of FXIa. FXI-dependent increased thrombin production can indirectly modulate fibrin degradation via thrombin-activatable fibrinolytic inhibitor (TAFI). Therefore, FXI interacts with several components in the coagulation system and plays a key role in blood coagulation and thrombus formation (Jilani and Ren, cited above; Imsley et al., Blood 2010, 2577-2569: 115). Blood coagulation factor XI (FXI) is a bipartite composed of 80 kDa identical subunits, each subunit starting at the N-terminus and consisting of four apple domains (A1, A2, A3, and A4) and a stimulatory domain (see Figure 1B). FIX is a zymogen that circulates in combination with high molecular weight kininogen (HK). HK binds to domain 2A of FXI and is a physiological cofactor for the activation of FXIIa from FXI to FXIa. The remaining apple domains of FXI also mediate important physiological functions. For example, the outer surface that can bind to FIX is located at 3A, while the surface that can bind to FXIIa is located at 4A. Residues that are critical for FXI cleavage or bisection are also located at 4A (Emsley et al., cited above). In recent years, numerous studies and efforts have demonstrated that FXI, with a relatively minor contribution to hemostasis, plays a fundamental role in the pathological process of blood clot formation, and is therefore a promising target for thrombosis or blood clot formation. Key data supporting this hypothesis are summarized below: (1) In a phase 2 trial of the antisense oligonucleotide FXI (ASO) from Ionise Pharmaceuticals (Buller et al., New England Journal of Medicine 2015; 232–240: 372), FXI ASO significantly reduced venous thromboembolism (VTE) in patients undergoing total knee replacement surgery, with a tendency toward less bleeding compared with enoxaparin; Human Genetics and Infectious Disease Research (Daga et al., Blood Clot Stopping Seminar; Chen et al., Today's Discovered Drugs)2014; Key, Society of Hematology Educational Program 2014, 70-66: 2014|) showed that severe FXI deficiency (hemophilia C) (a congenital bleeding disorder that usually affects males and is transmitted from mother to son—translator's note) reduces the risk of stroke due to focal anemia and blood clot formation in internal vessels; conversely, increased FXI levels lead to an increased risk of VTE and stroke due to focal anemia; and (3) a large number of preclinical studies have demonstrated that inhibition of FXI(a) or elimination of its function, without compromising hemostasis, provides profound protection against blood clot formation (Chen et al., cited document). It should be noted that monoclonal antibodies (monoclonal antibodies) are identical and similar antibodies because all clones or masses are produced by a single type and parent cell of the body's immune system. Given any desired substance, it is possible to make monoclonal antibodies that bind specifically to that substance, then they can be used to identify it.(11E14 and 6A1) have been shown to significantly reduce blood clot formation in the baboon AV shunt model of blood clot formation (US Patent No. 8,388,595; US Patent No. 316,236 US8, 2009; Tucker et al., Blood 2009, 936-944: 113; Cheng et al., Blood 2010, 3989-3981: 116). In addition, 11E14 (as it cross-reacts with mouse FXI) has been shown to be protective in experimental models of ischemic stroke in mice (Long et al., Stroke Research Transl. 2012, 389-381: 3). Additional mAbs targeting the FXI receptor have also been reported in preclinical models as an antithrombotic target to support FXI with minimal bleeding risk (van Montford et al., Thrombosis and Hemostasis 2013, 110; Takahashi et al., Coagulation Research 2010, 470-464: 125; van Montford et al., PhD, thesis, University of Amsterdam, Amsterdam, The Netherlands, 14 November 2014).Therefore, FXI inhibition with an improved benefit-risk profile compared to current standard anticoagulants is a promising strategy for novel antithrombotic therapy. There is currently a significant unmet medical need for antithrombotic therapies for patients with severe or end-stage renal disease (ESRD). Approximately 650,000 patients in the United States have severe or end-stage renal disease (ESRD), and these patients suffer from an extremely high prevalence of thromboembolic complications and thromboembolic events (MI, stroke / TIA, peripheral arterial disease (PAD), vascular access defects). ESRD patients are also more likely to have bleeding events than the general population. Because anticoagulants of any type are not routinely prescribed for ESRD patients (due to bleeding risks and lack of data for non-vitamin K antagonist oral anticoagulants (NOACs) in ESRD), there is little evidence to support an antithrombotic therapy that has an acceptable benefit-risk profile in these patients. Summary of this invention The present invention provides human antibodies that are capable of selectively binding to factor XI (anti-FXI antibodies) and preferably inhibit blood clotting and associated blood clot formation, thereby preventing bleeding complications. The anti-factor XI antibodies are compounds that are capable of binding to a defined epitope (epitope is a part of a foreign organism or its proteins that is recognized by the immune system and is targeted by antibodies or toxic T cells, or both—translator's note) of the 3A domain of factor XI. These antibodies exhibit neutralizing activity by preventing the conversion of the zymogen of FXI to its active form, FXIa, by FXIIa, and by inhibiting the activation of FIX by FXIa.These antibodies may be useful for inhibiting FXI, which could therefore provide a clinical antithrombotic effect with a lower risk of bleeding complications and therefore a greater therapeutic index compared to inhibition of the related coagulation factors FXa and thrombin. Therefore, these antibodies offer a therapeutic approach to prevent complications of blood clot formation in the vessels, for example, preventing stroke in spasticity of arterial muscle fibers (SPAF) disease. One eligible group at risk for thrombosis or blood clot formation in the future who could benefit from FXI inhibition is the group of patients with severe or end-stage renal disease (ESRD), in whom non-vitamin K oral anticoagulants (NOACs) are not typically used due to concerns about bleeding, resulting in a lack of clinical trial experience. The antibodies herein provide a novel anticoagulant therapy for the prevention of intravascular thromboembolism in ESRD patients. The antibodies herein may provide clinically relevant anticoagulant efficacy and benefit with an acceptable level of bleeding risk for ESRD patients. Apart from ESRD and SPAF, FXI inhibition may also be indicated in other patient populations at high risk of developing intravascular thromboembolism. These include: 1) prevention of venous thromboembolism (VTE) in orthopedic surgery or secondary prevention of VTE; reduction of revascularization surgery or reduction of major organ adverse events (MALE) in PAD; 3) treatment with a prophylactic drug in ACS. The present invention provides an antibody or an antigen-binding fragment thereof comprising at least six complementarity determining regions (CDRs) of an anti-FXI antibody of the αFXI-family. P18623, P18611 family, or 18611-αFXI family or at least six complementarity determining regions (CDRs) of an anti-FXI antibody of the P18623-αFXI family, P 18611-αFXI family, or 18611-αFXI family, wherein one or more of the six CDRs have one, two, or three amino acid substitutions, additions, or deletions, or a combination thereof, such that an antibody of the 18623-αFXI family comprises a heavy chain variable region (HC) having the amino acid sequence shown in SEQ ID NO: 28 or 29, and a light chain variable region (LC) having the amino acid sequence shown in SEQ ID NO: 30; An antibody of the P18611 αFXI-family comprising a heavy chain variable region having the amino acid sequence shown in SEQ ID NO: 21 or 22 and a light chain (LC) variable region having the amino acid sequence shown in SEQ ID NO: 25; and an antibody of the 18611 αFXI-family comprising a heavy chain variable region having the amino acid sequence shown inin SEQ ID NO: 23 or 24 and a light chain variable region (LC) having the amino acid sequence shown in SEQ ID NO: 25. In other embodiments, the antibody or antigen-binding fragment thereof binds to the 3-domain of blood coagulation factor XI (FXI) and prevents the activation of FXI or the activation of factor IX by factor XI. In other aspects or embodiments of this invention, the six CDRs include or consist of 1 CDR.2CDR and 3CDR of the heavy chain (HC) of an anti-FXI antibody of the P18623-αFXI family, the P18623 family, the P 18611-αFXI family, or the 18611-αFXI family, such that an antibody of the P18623-αFXI family comprises a heavy chain variable region having the amino acid sequence shown in SEQ ID NO: 28 or 29 and a light chain variable region (LC) having the amino acid sequence shown in SEQ ID NO: 30; An antibody of the P 18611-αFXI family comprises a heavy chain variable region having the amino acid sequence shown in SEQ ID NO: 21 or 22 and a light chain variable region (LC) having the amino acid sequence shown in SEQ ID NO: 25; and, an antibody of the 18611-αFXI family comprises a heavy chain variable region having the amino acid sequence shown in SEQ ID NO: 23 or 24 and a light chain variable region (LC) having the amino acid sequence shown in SEQ ID NO: 25.In other embodiments, the antibody or antigen-binding fragment binds to the 3-domain of the blood anticoagulant factor XI (FXI) and prevents the activation of FXI or the activation of factor IX by Xia. In other aspects or embodiments of the invention, the antibody or antigen-binding component comprises a heavy chain variable region having an amino acid sequence selected from the group of amino acids comprising SEQ ID NO: 21, 22, 23 and 24; and comprises a light chain variable region having the amino acid sequence shown in SEQ ID NO: 25; Wherein the heavy chain variable framework region can include 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, or deletions, or a combination thereof, and the light chain variable framework region can include 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, or deletions, or a combination thereof. In other aspects or embodiments of the invention, the antibody or antigen-binding component comprises a heavy chain variable region having an amino acid sequence selected from the group of amino acid sequences comprising SEQ ID NO: 21, 22, 23, and 24; and a light chain variable region having the amino acid sequence shown in SEQ ID NO: 25. In other aspects or embodiments of the invention, the antibody or antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence selected from the group of amino acid sequences comprising SEQ ID NO: 28 and 29; and comprises a light chain variable region having the amino acid sequence shown in SEQ ID NO: 30; In such a way that the variable framework region of the heavy chain can include 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, or deletions, or a combination thereof, and the variable framework region of the light chain can include 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, or deletions, or a combination thereof. In other aspects or embodiments of the invention, the antibody or antigen-binding component comprises a heavy chain variable region having an amino acid sequence selected from the group of amino acid sequences comprising SEQ ID NO: 28 and 29; and comprises a light chain variable region having the amino acid sequence shown in SEQ ID NO: 30. In other aspects or embodiments of the invention, the antibody comprises a heavy chain constant domain of the isotype 3lgG, 2lgG, 1lgG or 4lgG. In other aspects, the constant domain can comprise 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, additions or deletions, or combinations thereof. In particular aspects, the constant domain may include a C-terminal lysine or may lack a C-terminal lysine. In other aspects or embodiments of the invention, the antibody comprises a heavy chain constant domain of the human IgG or IgG isotype 1. In another aspect, the heavy chain constant domain is of the IgG isotype 4 and further comprises a substitution of the N residue at position 228 (EU numbering) with proline, which corresponds to position 108 of SEQ ID NO: 16 or 17 (serine at position 108). In other aspects or embodiments of the invention, the antibody comprises a heavy chain constant domain comprising the amino acid sequence shown in SEQ ID NO: 16, 17, 18 or 19. In other aspects or embodiments of this invention, the antibody comprises a human kappa or lambda light chain constant domain. In other aspects or embodiments of the invention, the antibody comprises a light chain constant domain comprising the amino acid sequence shown in SEQ ID NO: 20. In other aspects or embodiments of the invention, the antibody or antigen-binding fragment thereof comprises a heavy chain constant domain having an amino acid sequence selected from the group of amino acids comprising SEQ ID NO: 33, 35, 37, 39, 45, 47, 49, 51, 57, 59, 61, 63, 69, 71, 73; and a light chain having the amino acid sequence shown in SEQ ID NO: 26. In other aspects or embodiments of the invention, the antibody or antigen-binding fragment thereof comprises a heavy chain constant domain having an amino acid sequence selected from the group of amino acids comprising SEQ ID NO: 41, 43, 53, 55, 65, 67, 77, and 79; and a light chain having the amino acid sequence shown in SEQ ID NO: 31. The present invention further provides an antibody or antigen-binding fragment comprising (a) a heavy chain variable domain (HC) having the amino acid sequence shown in SEQ ID NO: 28, and a light chain variable domain (LC) having the amino acid sequence shown in SEQ ID NO: 30; (b) a heavy chain variable domain (HC) having the amino acid sequence shown in SEQ ID NO: 29, and a light chain variable domain (LC) having the amino acid sequence shown in SEQ ID NO: 30; (b) a heavy chain variable domain (HC) having the amino acid sequence shown in SEQ ID NO: 21, and a light chain variable domain (LC) having the amino acid sequence shown in SEQ ID NO: 25; (c) a heavy chain variable domain (HC) having the amino acid sequence shown in SEQ ID NO: 22, and a light chain variable domain (LC) having the amino acid sequence shown in SEQ ID NO: 25; (d) aa heavy chain variable (HC) domain having the amino acid sequence shown in SEQ ID NO: 23, and a light chain variable (LC) domain having the amino acid sequence shown in SEQ ID NO: 25, or (e) a heavy chain variable (HC) domain having the amino acid sequence shown in SEQ ID NO: 24, and a light chain variable (LC) domain having the amino acid sequence shown in SEQ ID NO: 25. In other embodiments, the antibody or antigen-binding fragment thereof binds to the 3 domain of coagulation factor XI (FXI) and prevents the activation of FXI or the activation of factor IX by factor XI. In particular embodiments, the heavy chain and light chain variable regions may include 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, or deletions, or combinations thereof. In particular embodiments, the heavy chain and light chain constant regions may include 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, or deletions, or combinations thereof. In particular embodiments, the constant region may include a C-terminal lysine or lack a C-terminal lysine. In particular embodiments, the variable regions of the heavy chain and the light chain may comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, or deletions, or a combination thereof, and the constant regions of the heavy chain and the light chain may comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, or deletions, or a combination thereof. In particular embodiments, the constant region may comprise a C-terminal lysine or lack a C-terminal lysine. In other aspects or embodiments of the invention, the antibody can further comprise a heavy chain constant domain having the amino acid sequence shown in SEQ ID NO: 16, 17, 18 or 19 or a variant thereof and comprising 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, additions or deletions or combinations thereof. In other aspects or embodiments of the invention, the antibody can further comprise a light chain constant domain comprising the amino acid sequence shown in SEQ ID NO: 20 or a variant thereof comprising 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, additions or deletions, or combinations thereof. In another aspect or embodiment of the invention, the antibody or antigen-binding fragment thereof comprises (a) a heavy chain variable domain (HC) having the amino acid sequence shown in SEQ ID NO: 28, and a light chain variable domain (LC) having the amino acid sequence shown in SEQ ID NO: 30; (b) a heavy chain variable domain (HC) having the amino acid sequence shown in SEQ ID NO: 29, and a light chain variable domain (LC) having the amino acid sequence shown in SEQ ID NO: 30; (c) a heavy chain variable domain (HC) having the amino acid sequence shown in SEQ ID NO: 21, and a light chain variable domain (LC) having the amino acid sequence shown in SEQ ID NO: 25; (d) a heavy chain variable domain (HC) having the amino acid sequence shown in SEQ ID NO: 22, and a light chain variable domain (LC) having the amino acid sequence shown in SEQ ID NO: 25; (e) aa heavy chain (HC) variable domain having the amino acid sequence shown in SEQ ID NO: 23, and a light chain (LC) variable domain having the amino acid sequence shown in SEQ ID NO: 25; (f) a heavy chain (HC) variable domain having the amino acid sequence shown in SEQ ID NO: 24, and a light chain (LC) variable domain having the amino acid sequence shown in SEQ ID NO: 25; (g) a variant of (a), (b), (c), (d), (e) or (f), wherein the heavy chain (HC) variable framework region comprises 1, 2, 3, 4, 6, 6, 7, 8, 9 or 10 substitutions, additions, deletions, or combinations thereof; or, (h) a variant of (a), (b), (c), (d), (e), (f) or (g) wherein the light chain (HC) variable framework region contains 1, 2, 3, 4, 6, 6, 7, 8, 9 or 10 substitutions, additions, deletions, or combinations thereof. In addition, the present invention provides an antibody comprising (a) a heavy chain (HC) having a constant domain and a variable domain, wherein the variable domain comprises a heavy chain complementarity determining region 1 (HC-CDR) having the amino acid sequence shown in SEQ ID NO: 1; comprises a heavy chain complementarity determining region 2 (HC-CDR) having the amino acid sequence shown in SEQ ID NO: 2; and comprises a heavy chain complementarity determining region 3 (HC-CDR) having the amino acid sequence shown in SEQ ID NO: 3; (b) comprises a heavy chain (HC) having a constant domain and a variable domain, wherein the variable domain comprises a heavy chain complementarity determining region (HC-CDR) having the amino acid sequence shown in SEQ ID NO: 1; comprises a heavy chain complementarity determining region (HC-CDR) having the amino acid sequence shown in SEQ ID NO: 2; and comprises aHeavy chain complement (3 HC-CDR) having the amino acid sequence shown in SEQ ID NO: 4; or (c) having a heavy chain (HC) comprising a constant domain and a variable domain, wherein the variable domain comprises a heavy chain complementarity determining region 1 (1 HC-CDR) having the amino acid sequence shown in SEQ ID NO: 8; a heavy chain complementarity determining region 2 (2HC-CDR) having the amino acid sequence shown in SEQ ID NO: 9; and a heavy chain complementarity determining region 3 (3HC-CDR) having the amino acid sequence shown in SEQ ID NO: 10. In other embodiments, the antibody or antigen-binding fragment binds to the 3-domain of blood coagulation factor XI (FXI) and prevents the activation of FXI or the activation of factor IX by factor XIa. In other aspects or embodiments of the invention, the antibody comprises a heavy chain constant domain of the 3IgG, 2IgG, 1IgG or 4IgG isotype. In other aspects, the constant domain can comprise 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, additions or deletions, or a combination thereof, compared to the amino acid sequence of the native or native heavy chain constant domain for the 3IgG, 2IgG, 1IgG or 4IgG isotype. In particular aspects, the constant domain may comprise a C-terminal lysine or lack a C-terminal lysine. In other aspects or embodiments of the invention, the antibody comprises a heavy chain constant domain of human IgG isotype 1 or IgG 4. In another aspect, the heavy chain constant domain is of IgG isotype 4 and further comprises a substitution of the N residue at position 228 (EU numbering) with proline, which corresponds to position 108 of SEQ ID NO: 16 or 17 (serine at position 108). In other aspects or embodiments of the invention, the antibody has an IgG heavy chain constant domain comprising the amino acid sequence shown in SEQ ID NO: 16 or 17. In other aspects, the constant domain can comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, or deletions, or combinations thereof. In other aspects or embodiments of the invention, the antibody has an IgG heavy chain constant domain comprising the amino acid sequence shown in SEQ ID NO: 18 or 19. In other aspects, the constant domain can comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, or deletions, or combinations thereof. Furthermore, the present invention provides an antibody or antigen-binding component comprising: (a) a light chain (LC) having a constant domain and a variable domain, wherein the variable domain comprises a light chain complementarity determining region 1 (LC-CDR 1) having the amino acid sequence shown in SEQ ID NO: 5; comprises a light chain complementarity determining region 2 (LC-CDR 2) having the amino acid sequence shown in SEQ ID NO: 6; and comprises a light chain complementarity determining region 3 (LC-CDR 3) having the amino acid sequence shown in SEQ ID NO: 7, or (b) has a light chain (LC) that has a constant domain and a variable domain, such that the variable domain includes a light chain complementarity determining region 1 (1 LC-CDR) having the amino acid sequence shown in SEQ ID NO: 11; comprising a light chain complementarity determining region 2 (2 LC-CDR) having the amino acid sequence shown in SEQ ID NO: 12; and comprising a light chain complementarity determining region 3 (3LC-CDR) having the amino acid sequence shown in SEQ ID NO: 13. In other embodiments, the antibody or antigen-binding fragment thereof binds to the 3-chain domain of blood coagulation factor XI (FXI) and prevents the activation of FXI and / or the activation of factor IX by factor XIa. In other aspects or embodiments of the invention, the light chain (LC) comprises a human kappa light chain or a human lambda light chain or a variant thereof comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, or deletions, or combinations thereof, such that the antibody or antigen-binding component binds to the 3-domain of coagulation factor XI (FXI) and prevents the activation of FXI and / or the activation of factor IX by factor XIa. In other aspects or embodiments of the invention, the antibody comprises a light chain constant domain comprising the amino acid sequence set forth in SEQ ID NO: 20. In other aspects or embodiments of the invention, the antibody comprises a 4IgG heavy chain constant domain comprising the amino acid sequence set forth in SEQ ID NO: 16 or 17 or a variant thereof and comprising 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, additions, or deletions or combinations thereof, such that the antibody or antigen-binding fragment thereof binds to the 3-domain of blood coagulation factor XI (FXI) and prevents the activation of FXI and / or the activation of factor IX by factor XIa. In other aspects or embodiments of the invention, the antibody comprises an IgG heavy chain constant domain comprising the amino acid sequence set forth in SEQ ID NO: 18 or 19 or a variant thereof and comprising 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, additions, or deletions, or combinations thereof, such that the antibody or antigen-binding fragment thereof binds to the 3-domain of blood coagulation factor XI (FXI) and prevents the activation of FXI and / or the activation of factor IX by factor XIa. Furthermore, the present invention provides an antibody or antigen-binding component comprising: (a) A heavy chain (HC) having a constant domain and a variable domain, wherein the variable domain includes a heavy chain complementarity determining region. 1 (1HC-CDR) having the amino acid sequence shown in SEQ ID NO: 1; comprising a heavy chain complementarity determining region 2 (2HC-CDR) having the amino acid sequence shown in SEQ ID NO: 2; and comprising a heavy chain complementarity determining region 3 (3HC-CDR) having the amino acid sequence shown in SEQ ID NO: 3; and (b) has a light chain (LC) that has a constant domain and a variable domain, such that the variable domain includes a light chain complementarity determining region (1) 1LC-CDR) having the amino acid sequence shown in SEQ ID NO: 5; comprising a light chain complementarity determining region 2 (2LC-CDR) having the amino acid sequence shown in SEQ ID NO: 6; and comprising a light chain complementarity determining region 3 (3LC-CDR) having the amino acid sequence shown in SEQ ID NO: 7. In other embodiments, the antibody or antigen-binding fragment thereof binds to the 3-chain domain of blood coagulation factor XI (FXI) and prevents the activation of FXI and / or the activation of factor IX by factor XIa. In other aspects or embodiments of the invention, the light chain (LC) comprises a human kappa light chain or a human lambda light chain or a variant thereof comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, or deletions, or combinations thereof, such that the antibody or antigen-binding component binds to the 3-domain of coagulation factor XI (FXI) and prevents the activation of FXI and / or the activation of factor IX by factor XIa. In other aspects or embodiments of the invention, the antibody comprises a light chain constant domain comprising the amino acid sequence set forth in SEQ ID NO: 20. In other aspects or embodiments of the invention, the antibody comprises a heavy chain constant domain of the 3IgG, 2IgG, 1IgG or 4IgG isotype or a variant thereof, which, compared to the native amino acid sequence of the 3IgG, 2IgG, 1IgG or 4IgG isotype, comprises 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, additions or deletions, or a combination thereof, such that the antibody or antigen-binding fragment thereof binds to the 3Ig domain of coagulation factor XI (FXI) and prevents the activation of FXI or the activation of factor IX by XIa. In other aspects, the constant domain may comprise a C-terminal lysine or lack a C-terminal lysine. In other aspects or embodiments of the invention, the antibody comprises a heavy chain constant domain of human IgG or IgG isotype 1 or 4, or a variant thereof, comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 substitutions, additions, or deletions, or combinations thereof, such that the antibody or antigen-binding moiety binds to the 3-domain of coagulation factor XI (FXI) and prevents the activation of FXI or the activation of factor IX by XIa. In another aspect, the heavy chain constant domain is of IgG isotype 4 and further comprises a substitution of the N residue at position 228 (EU numbering) with proline, which corresponds to position 108 of SEQ ID NO: 16 or 17 (serine at position 108). In other aspects or embodiments of the invention, the antibody comprises a 4IgG heavy chain constant domain having the amino acid sequence set forth in SEQ ID NO: 16 or 17 or a variant thereof comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, or deletions, or combinations thereof, such that the antibody or antigen-binding moiety binds to the 3-domain of blood coagulation factor XI (FXI) and prevents the activation of FXI or the activation of factor IX by XIa. In other aspects or embodiments of the invention, the antibody comprises an IgG heavy chain constant domain comprising the amino acid sequence set forth in SEQ ID NO: 18 or 19 or a variant thereof, comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, or deletions, or combinations thereof, wherein the antibody or antigen-binding moiety binds to the 3 domain of coagulation factor XI (FXI) and prevents the activation of FXI or the activation of factor IX by XIa. Furthermore, the present invention provides an antibody or antigen-binding component comprising: (a) a heavy chain (HC) having a constant domain and a variable domain, wherein the variable domain comprises a heavy chain complementarity determining region 1 (HC-CDR) having the amino acid sequence shown in SEQ ID NO: 1; comprises a heavy chain complementarity determining region 2 (HC-CDR) having the amino acid sequence shown in SEQ ID NO: 2; and comprises a heavy chain complementarity determining region 3 (HC-CDR) having the amino acid sequence shown in SEQ ID NO: 4, and (b) has a light chain (LC) having a constant domain and a variable domain, wherein the variable domain comprises a light chain complementarity determining region 1 (LC-CDR) having the amino acid sequence shown in SEQ ID NO: 5; comprises a light chain complementarity determining region 2 (LC-CDR) having the amino acid sequence shown in SEQ ID NO: 6; and comprises a light chain complementarity determining region 3 (LC-CDR) having the amino acid sequence shown in SEQ ID NO: 7. In other embodiments, the antibody or antigen-binding fragment thereof binds to the 3-chain domain of coagulation factor XI (FXI) and prevents the activation of FXI and / or the activation of factor IX by factor XIa. In other aspects or embodiments of the invention, the light chain (LC) comprises a human kappa light chain or a human lambda light chain or a variant thereof comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, or deletions, or combinations thereof, such that the antibody or antigen-binding component binds to the 3-domain of blood coagulation factor XI (FXI) and prevents the activation of FXI and / or the activation of factor IX by factor XIa. In other aspects or embodiments of the invention, the antibody comprises a light chain constant domain comprising the amino acid sequence set forth in SEQ ID NO: 20. In other aspects or embodiments of the invention, the antibody comprises a heavy chain constant domain of the 3lgG, 2lgG, 1lgG or 4lgG isotype or a variant thereof, which, compared to the native amino acid sequence of the 3lgG, 2lgG, 1lgG or 4lgG isotype, comprises 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, additions or deletions, or a combination thereof, such that the antibody or antigen-binding moiety thereof binds to the 3-terminal domain of coagulation factor XI (FXI) and prevents the activation of FXI or the activation of factor IX by XIa. In other aspects, the constant domain may comprise a C-terminal lysine or lack a C-terminal lysine. In other aspects or embodiments of the invention, the antibody comprises a heavy chain constant domain of human IgG or IgG isotype 1 or 4, or a variant thereof, comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, or deletions, or a combination thereof, such that the antibody or antigen-binding moiety binds to the 3-domain of coagulation factor XI (FXI) and prevents the activation of FXI or the activation of factor IX by factor XIa. In another aspect, the heavy chain constant domain is of the 4IgG isotype and further comprises a substitution of a serine to proline residue at position 228 (EU numbering), which corresponds to position 108 of sequence ID number 16 or 17 (serine at position 108). In other aspects or embodiments of the invention, the antibody comprises a 4IgG heavy chain constant domain having the amino acid sequence set forth in SEQ ID NO: 16 or 17 or a variant thereof comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, or deletions, or combinations thereof, such that the antibody or antigen-binding moiety binds to the 3-domain of blood coagulation factor XI (FXI) and prevents the activation of FXI or the activation of factor IX by XIa. In other aspects or embodiments of the invention, the antibody comprises an IgG heavy chain constant domain comprising the amino acid sequence set forth in SEQ ID NO: 18 or 19 or a variant thereof, comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, or deletions, or combinations thereof, wherein the antibody or antigen-binding moiety binds to the 3 domain of coagulation factor XI (FXI) and prevents the activation of FXI or the activation of factor IX by XIa. Furthermore, the present invention provides an antibody or antigen-binding component comprising: (a) a heavy chain (HC) having a constant domain and a variable domain, wherein the variable domain comprises a heavy chain complementarity determining region 1 (LC-CDR) having the amino acid sequence shown in SEQ ID NO: 8; comprises a heavy chain complementarity determining region 2 (HC-CDR) having the amino acid sequence shown in SEQ ID NO: 9; and comprises a heavy chain complementarity determining region 3 (HC-CDR) having the amino acid sequence shown in SEQ ID NO: 10, and (b) has a light chain (LC) having a constant domain and a variable domain, wherein the variable domain comprises a light chain complementarity determining region 1 (LC-CDR 1) having the amino acid sequence shown in SEQ ID NO: 11; comprises a light chain complementarity determining region 2 (LC-CDR 2) having the amino acid sequence shown in SEQ ID NO: 12; and comprises a light chain complementarity determining region 3 (LC-CDR 3) having the amino acid sequence shown in SEQ ID NO: 13. In other embodiments, the antibody or antigen-binding fragment thereof binds to the 3-chain domain of coagulation factor XI (FXI) and prevents the activation of FXI and / or the activation of factor IX by factor XIa. In other aspects or embodiments of the invention, the light chain (LC) comprises a human kappa light chain or a human lambda light chain or a variant thereof comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, or deletions, or combinations thereof, such that the antibody or antigen-binding component binds to the 3-domain of blood coagulation factor XI (FXI) and prevents the activation of FXI and / or the activation of factor IX by factor XIa. In other aspects or embodiments of the invention, the antibody comprises a light chain constant domain comprising the amino acid sequence set forth in SEQ ID NO: 20. In other aspects or embodiments of the invention, the antibody comprises a heavy chain constant domain of the 3lgG, 2lgG, 1lgG or 4lgG isotype or a variant thereof, which, compared to the original or native amino acid sequence of the 3lgG, 2lgG, 1lgG or 4lgG isotype, comprises 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, additions or deletions, or a combination thereof, such that the antibody or antigen-binding moiety thereof binds to the 3-terminal domain of blood coagulation factor XI (FXI), and prevents the activation of FXI or the activation of factor IX by XIa. In other aspects, the constant domain may comprise a C-terminal lysine or lack a C-terminal lysine. In other aspects or embodiments of the invention, the antibody comprises a heavy chain constant domain of human IgG1 or IgG4 isotypes or a variant thereof comprising 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, additions, or deletions or combinations thereof, such that the antibody or antigen-binding moiety binds to the 3-chain domain of blood coagulation factor XI (FXI) and prevents the activation of FXI or the activation of factor IX by factor XIa. In another aspect, the heavy chain constant domain is of the 4IgG isotype and further comprises a substitution of the serine residue with proline at position 228 (EU numbering), which corresponds to position 108 of sequence ID number 16 or 17 (serine at position 108). In other aspects or embodiments of the invention, the antibody comprises a 4IgG heavy chain constant domain having the amino acid sequence set forth in SEQ ID NO: 16 or 17 or a variant thereof comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, or deletions, or combinations thereof, such that the antibody or antigen-binding moiety binds to the 3-domain of blood coagulation factor XI (FXI) and prevents the activation of FXI or the activation of factor IX by XIa. In other aspects or embodiments of the invention, the antibody comprises an IgG heavy chain constant domain comprising the amino acid sequence set forth in SEQ ID NO: 18 or 19 or a variant thereof, comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, or deletions, or combinations thereof, wherein the antibody or antigen-binding moiety binds to the 3 domain of coagulation factor XI (FXI) and prevents the activation of FXI or the activation of factor IX by XIa. In other aspects or embodiments of the invention, the present invention provides an antibody comprising: (a) a heavy chain (HC) comprising a constant domain and a variable domain, wherein the variable domain comprises (i) a heavy chain (HC) framework and a heavy chain complementarity determining region (HC-CDR) having the amino acid sequence shown in SEQ ID NO: 8, having a heavy chain complementarity determining region (HC-CDR) having the amino acid sequence shown in SEQ ID NO: 8, (2 HC-CDR) having the amino acid sequence shown in SEQ ID NO: 9, and having a 3 heavy chain complementarity determining region (3 HC-CDR) having the amino acid sequence shown in SEQ ID NO: 10; (ii) a heavy chain framework and a 1 heavy chain complementarity determining region (1 HC-CDR) having the amino acid sequence shown in SEQ ID NO: 1, a 2 heavy chain complementarity determining region (2 HC-CDR) having the amino acid sequence shown in SEQ ID NO: 2, and a 3 heavy chain complementarity determining region (3 HC-CDR) having the amino acid sequence shown in SEQ ID NO: 3; (iii) a heavy chain framework and a 1 heavy chain complementarity determining region (1 HC-CDR) having the amino acid sequence shown in SEQ ID NO: 1, a 2 heavy chain complementarity determining region (2 HC-CDR) having the amino acid sequence shown in SEQ ID NO: 2, and a 3 heavy chain complementarity determining region (3HC-CDR) having the amino acid sequence shown in SEQ ID NO: 4; (iv) a variant of (i), (ii) or (iii) such that at least one of 1 HC-CDR , 2 HC-CDR) or 3 CDRs comprising 1, 2, or 3 amino acid substitutions, additions, or deletions, or a combination thereof; or (v), comprising a variant of (i), (ii), (iii), or (iv), such that the heavy chain framework comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, or deletions, or a combination thereof; (b) a light chain (LC) having a constant domain and a variable domain, such that the variable domain comprises (i) a light chain framework (LC) and a light chain comprising a light chain complementarity determining region 1 (LC-CDR 1) having the amino acid sequence shown in SEQ ID NO: 11, having a light chain complementarity determining region 2 (LC-CDR 2) having the amino acid sequence shown in SEQ ID NO: 12, and having a light chain complementarity determining region 3 (LC-CDR 3) having the amino acid sequence shown in SEQ ID NO: 13; (ii) a light chain (LC) framework and a light chain complementarity determining region 1 (1 LC-CDR) having the amino acid sequence shown in SEQ ID NO: 5, a light chain complementarity determining region 2 (2 LC-CDR) having the amino acid sequence shown in SEQ ID NO: 6, and a light chain complementarity determining region 3 (3 LC-CDR) having the amino acid sequence shown in SEQ ID NO: 7; (iii) a variant of (i) or (ii) such that at least one of 1 HC-CDR,2LC-CDR or 3LC-CDR comprises 1, 2, or 3 amino acid substitutions, additions, or deletions, or a combination thereof; or (iv) a variant of (i), (ii), or (iii), such that the light chain framework comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, or deletions, or a combination thereof; or (c) comprises a heavy chain of (a) and a light chain of (b); such that the antibody binds to the apple 3 domain of blood coagulation factor XI (FXI) and prevents the activation of FXI or the activation of factor IX by factor XIa., In other aspects or embodiments of the invention, the antibody of claim 18, wherein the heavy chain constant domain comprises the amino acid sequence shown in SEQ ID NO: 16, 17, 18, or 19. In other aspects or embodiments of the invention, the antibody of claim 18 or 19, wherein the heavy chain constant domain comprises the amino acid sequence shown in SEQ ID NO: 20. In addition, the present invention provides an antibody comprising a heavy chain having the amino acid sequence shown in SEQ ID NO: 33 and a light chain having the amino acid sequence shown in SEQ ID NO: 26. Furthermore, the present invention provides an antibody comprising a heavy chain having the amino acid sequence shown in SEQ ID NO: 25 and a light chain having the amino acid sequence shown in SEQ ID NO: 26. The present invention further provides an antibody comprising a heavy chain having the amino acid sequence shown in SEQ ID NO: 45 and a light chain having the amino acid sequence shown in SEQ ID NO: 26. Furthermore, the present invention provides an antibody comprising a heavy chain having the amino acid sequence shown in SEQ ID NO: 47, and a light chain having the amino acid sequence shown in SEQ ID NO: 26. In addition, the present invention provides an antibody comprising a heavy chain having the amino acid sequence shown in SEQ ID NO: 49 and a light chain having the amino acid sequence shown in SEQ ID NO: 26. Furthermore, the present invention provides an antibody comprising a heavy chain having the amino acid sequence shown in SEQ ID NO: 51 and a light chain having the amino acid sequence shown in SEQ ID NO: 26. Furthermore, the present invention provides an antibody comprising a heavy chain having the amino acid sequence shown in SEQ ID NO: 59 and a light chain having the amino acid sequence shown in SEQ ID NO: 26. Furthermore, the present invention provides an antibody comprising a heavy chain having the amino acid sequence shown in SEQ ID NO: 61 and a light chain having the amino acid sequence shown in SEQ ID NO: 26. Furthermore, the present invention provides an antibody comprising a heavy chain having the amino acid sequence shown in SEQ ID NO: 63 and a light chain having the amino acid sequence shown in SEQ ID NO: 26. In addition, the present invention provides an antibody comprising a heavy chain having the amino acid sequence shown in SEQ ID NO: 69 and a light chain having the amino acid sequence shown in SEQ ID NO: 26. The present invention further provides an antibody comprising a heavy chain having the amino acid sequence shown in SEQ ID NO: 33, and a light chain having the amino acid sequence shown in SEQ ID NO: 26. The present invention further provides an antibody comprising a heavy chain having the amino acid sequence shown in SEQ ID NO: 71, and comprising a light chain having the amino acid sequence shown in SEQ ID NO: 26. The present invention further provides an antibody comprising a heavy chain having the amino acid sequence shown in SEQ ID NO: 73, and a light chain having the amino acid sequence shown in SEQ ID NO: 26. The present invention further provides an antibody comprising a heavy chain having the amino acid sequence shown in SEQ ID NO: 75, and a light chain having the amino acid sequence shown in SEQ ID NO: 26. The present invention further provides an antibody comprising a heavy chain having the amino acid sequence shown in SEQ ID NO: 39, and a light chain having the amino acid sequence shown in SEQ ID NO: 31. The present invention further provides an antibody comprising a heavy chain having the amino acid sequence shown in SEQ ID NO: 41, and a light chain having the amino acid sequence shown in SEQ ID NO: 31. The present invention further provides an antibody comprising a heavy chain having the amino acid sequence shown in SEQ ID NO: 43, and a light chain having the amino acid sequence shown in SEQ ID NO: 31. The present invention further provides an antibody comprising a heavy chain having the amino acid sequence shown in SEQ ID NO: 53, and a light chain having the amino acid sequence shown in SEQ ID NO: 31. The present invention further provides an antibody comprising a heavy chain having the amino acid sequence shown in SEQ ID NO: 55, and a light chain having the amino acid sequence shown in SEQ ID NO: 31. The present invention further provides an antibody comprising a heavy chain having the amino acid sequence shown in SEQ ID NO: 57, and a light chain having the amino acid sequence shown in SEQ ID NO: 31. The present invention further provides an antibody comprising a heavy chain having the amino acid sequence shown in SEQ ID NO: 65, and a light chain having the amino acid sequence shown in SEQ ID NO: 31. Furthermore, the present invention provides an antibody comprising a heavy chain having the amino acid sequence shown in SEQ ID NO: 67, and a light chain having the amino acid sequence shown in SEQ ID NO: 31. The present invention further provides an antibody comprising a heavy chain having the amino acid sequence shown in SEQ ID NO: 69, and a light chain having the amino acid sequence shown in SEQ ID NO: 31. The present invention further provides an antibody comprising a heavy chain having the amino acid sequence shown in SEQ ID NO: 77, and a light chain having the amino acid sequence shown in SEQ ID NO: 31. The present invention further provides an antibody comprising a heavy chain having the amino acid sequence shown in SEQ ID NO: 79, and a light chain having the amino acid sequence shown in SEQ ID NO: 31. Furthermore, the present invention provides an antibody or antigen-binding fragment comprising an antibody comprising a heavy chain having the amino acid sequence shown in SEQ ID NO: 73, 71, 69, 63, 61, 59, 51, 49, 47, 45, 37, 35, 33 or 75 and comprising a light chain comprising the amino acid sequence shown in SEQ ID NO: 26; or an antibody comprising a heavy chain having the amino acid sequence shown in SEQ ID NO: 77,69,67,65,57,55,53,43,41,39 or 79 and having a light chain comprising the amino acid sequence shown in SEQ ID NO: 31 competes with or blocks the reaction or crosslinks it, provided that the antibody or antigen-binding component does not contain mouse or rat amino acid sequences. In another embodiment, the antibody or antigen-binding component does not comprise non-human amino acid sequences. In another embodiment, the antibody comprises (i) a human IgG1 constant domain or a variable or modified derivative thereof or (ii) a human IgG4 constant domain or a variable or modified derivative thereof. In another embodiment, the 1lgG or 4lgG constant domain is variable and includes at least 9, 8, 7, 6, 5, 4, 3, 2, 1 or 10 amino acid substitutions, additions, or deletions, or combinations thereof. In another embodiment, the 1lgG or 4lgG constant domain is variable and includes at least 9, 8, 7, 6, 5, 4, 3, 2, 1 or 10 amino acid substitutions, additions, or deletions, or combinations thereof. In another embodiment, the 4IgG constant domain is a variable that comprises at least one substitution of N at position 228 (EU numbering) or position 108 with a proline residue, as shown herein. In another embodiment, the constant domain of 1lgG or 4lgG is variable and lacks at least one lysine at the C-terminus. In another embodiment, the antibody or antigen-binding component comprises variable domain sequences, which comprise a framework, that are specific for human antibodies. In addition, the present invention provides a human antibody or antigen-binding fragment comprising an antibody comprising a heavy chain having the amino acid sequence shown in SEQ ID NO: 33, 35, 37, 39, 45, 47, 49, 51, 57, 59, 61, 63, 69, 71, 73 or 75 and a light chain comprising the amino acid sequence shown in SEQ ID NO: 26; or an antibody comprising a heavy chain having the amino acid sequence shown in SEQ ID NO: 39,41,43,53,55,65,67,77 or 79 and having a light chain comprising the amino acid sequence shown in SEQ ID NO: 31 competes with or blocks its crosslinking. In another embodiment, the antibody or antigen-binding component does not comprise non-human amino acid sequences. In another embodiment, the antibody comprises (i) a human IgG1 constant domain or a variable or modified derivative thereof or (ii) a human IgG4 constant domain or a variable or modified derivative thereof. In another embodiment, the 1lgG or 4lgG constant domain is variable and includes at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, or deletions, or a combination thereof. In another embodiment, the constant domain of 1lgG or 4lgG is variable and includes at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, additions, or deletions, or a combination thereof. In another embodiment, the 4IgG constant domain is a variant that includes at least one substitution of N at position 228 (EU numbering) or position 108 with a proline residue, as shown herein. In another embodiment, the constant domain of 1lgG or 4lgG is a variable that lacks at least one lysine at the C-terminus. In another embodiment, the antibody or antigen-binding component comprises variable domain sequences that comprise a framework that is specific to human antibodies. The present invention further provides a human antibody or antigen-binding fragment that binds to an epitope on coagulation factor XI (FXI) comprising the amino acid sequence YATRQFPSLEHRNICL (SEQ ID NO: 82) and the amino acid sequence HTQTGTPTRITKL (SEQ ID NO: 83), provided that the antibody comprises (i) a human IgG constant domain or a variant or modified derivative thereof. In certain embodiments, binding to the epitope is determined by hydrogen deuterium exchange mass spectrometry. In another embodiment, the 1lgG or 4lgG constant domain is a variable that includes at least 1,2,3,4,5,6,7,8,9 or 10 amino acid substitutions, additions, or deletions, or a combination thereof. In another embodiment, the 1lgG or 4lgG constant domain is variable and includes at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, or deletions, or a combination thereof. In another embodiment, the 4IgG constant domain is a variant that includes at least one substitution of N at position 228 (EU numbering) or position 108 with a proline residue, as shown herein. In another embodiment, the constant domain of 1lgG or 4lgG is a variable that lacks at least one lysine at the C-terminus. In another embodiment, the antibody or antigen-binding component comprises variable domain sequences that comprise a framework that is specific to human antibodies. Additionally, the present invention provides an isolated nucleic acid molecule encoding the light chain variable domain or the heavy chain variable domain of any of the above-mentioned antibodies or antigen-binding fragments thereof. Furthermore, the present invention provides a humanized antibody or antigen-binding fragment that binds to an epitope on coagulation factor XI (FXI) comprising the amino acid sequence YATRQFPSLEHRNICL (SEQ ID NO: 82) and the amino acid sequence HTQTGTPTRITKL (SEQ ID NO: 83), provided that the antibody comprises (i) a human IgG constant domain or a variant or modified derivative thereof. In some embodiments, binding to the epitope is determined by hydrogen deuterium exchange mass spectrometry. In another embodiment, the 1lgG or 4lgG constant domain is a variant or mutated variant comprising at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, additions, or deletions, or a combination thereof. In another embodiment, the 1lgG or 4lgG constant domain is a mutated or variable variant comprising at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, additions, or deletions, or a combination thereof. In another embodiment, the 4IgG constant domain is a variant that includes at least one substitution of N at position 228 (EU numbering) or position 108 with a proline residue, as shown herein. In another embodiment, the constant domain of 1lgG or 4lgG is a variable that lacks at least one lysine at the C-terminus. In another embodiment, the antibody or antigen-binding component comprises variable domain sequences that comprise a framework that is specific to human antibodies. Additionally, the present invention provides an isolated nucleic acid molecule encoding the light chain variable domain or the heavy chain variable domain of any of the above-mentioned antibodies or antigen-binding fragments thereof. In addition, the present invention provides a composition comprising an antibody or antigen-binding fragment of one of the antibodies or antigen-binding fragments mentioned above and a pharmaceutically acceptable carrier or diluent. Furthermore, the present invention provides a method for treating a thrombotic disorder or disease in a patient comprising administering to the patient an effective amount of an antibody or antigen-binding fragment of any of the antibodies or antigen-binding fragments mentioned above. Furthermore, the present invention provides a method for treating a thrombotic disorder or disease in a patient comprising administering to a patient in need thereof an effective amount of an antibody or antigen-binding fragment of any of the above-mentioned antibodies or antigen-binding fragments. Furthermore, the present invention provides the use of any of the antibodies or antigen-binding components mentioned above for the manufacture of a medicament for the treatment of a disorder or disease of vascular occlusion by a blood clot. The present invention further provides an antibody of any of the antibodies or antigen-binding fragments mentioned above for the treatment of a disorder or disease of vascular occlusion by a blood clot. In addition, the present invention provides a method for producing an antibody or antigen-binding component comprising (i) a heavy chain, which has a constant domain and a variable domain, wherein the variable domain comprises a heavy chain having a 1-HC-CDR having the amino acid sequence shown in SEQ ID NO: 1, a 2-HC-CDR having the amino acid sequence shown in SEQ ID NO: 2, and a 3-HC-CDR having the amino acid sequence shown in SEQ ID NO: 3 or 4; and (ii) a light chain having a constant domain and a variable domain, wherein the variable domain comprises a light chain complementarity determining region (LC-CDR) having the amino acid sequence shown in SEQ ID NO: 5, a LC-CDR having the amino acid sequence shown in SEQ ID NO: 6, and a LC-CDR having the amino acid sequence shown in SEQ ID NO: 7, and also inThe invention relates to a method comprising providing a host cell having a nucleic acid molecule encoding a heavy chain and a nucleic acid molecule encoding a light chain; and further comprising culturing the host cell under conditions and for a time sufficient to produce an antibody or antigen-binding moiety. In other aspects or embodiments of this invention, the antibody comprises a heavy chain constant domain of the 3IgG, 2IgG, 1IgG, or 4IgG isotype. In other aspects or embodiments of this invention, the antibody comprises a heavy chain constant domain of the 4IgG isotype. In other aspects or embodiments of this invention, the antibody comprises a heavy chain constant domain comprising the amino acid sequence shown in SEQ ID NO: 16, 17, 18, or 19. In other aspects or embodiments of the invention, the light chain comprises a human kappa light chain or a human lambda light chain. In other aspects or embodiments of the invention, the antibody comprises a light chain constant domain comprising the amino acid sequence shown in SEQ ID NO: 20. In other aspects or embodiments of the invention, the host cell is a Chinese hamster ovary cell or a human neonatal kidney 293 cell. In other aspects or embodiments of this invention, the host cell is a yeast or filamentous fungal cell. In addition, the present invention provides a method for making an antibody or antigen-binding component comprising (i) a heavy chain having a constant domain and a variable domain, wherein the variable domain comprises a heavy chain having a heavy chain complementarity determining region 1 (HC-CDR) having the amino acid sequence shown in SEQ ID NO: 1, a heavy chain complementarity determining region (HC-CDR) having the amino acid sequence shown in SEQ ID NO: 2, and a heavy chain complementarity determining region 3 (HC-CDR) having the amino acid sequence shown in SEQ ID NO: 3 or 4; and (ii) a light chain having a constant domain and a variable domain, wherein the variable domain comprises a light chain complementarity determining region 1 (LC-CDR 1) having the amino acid sequence shown in SEQ ID NO: 5, a light chain complementarity determining region 2 (LC-CDR 2) having the amino acid sequence shown in SEQ ID NO: 6, and a LC-CDR 3.which has the amino acid sequence shown in SEQ ID NO: 7, a method comprising providing a host cell having a nucleic acid molecule encoding the heavy chain and a nucleic acid molecule encoding the light chain; and further comprising culturing the host cell under conditions and for a time sufficient to produce the antibody or antigen-binding moiety. In other aspects or embodiments of this invention, the antibody comprises a heavy chain constant domain of the 3IgG, 2IgG, 1IgG, or 4IgG isotype. In other aspects or embodiments of this invention, the antibody comprises a heavy chain constant domain of the IgG4 isotype. In other aspects or embodiments of this invention, the antibody comprises a heavy chain constant domain comprising the amino acid sequence shown in SEQ ID NO: 16, 17, 18, or 19. In other aspects or embodiments of the invention, the light chain comprises a human kappa light chain or a human lambda light chain. In other aspects or embodiments of the invention, the antibody comprises a light chain constant domain comprising the amino acid sequence shown in SEQ ID NO: 20. In other aspects or embodiments of the invention, the host cell is a Chinese hamster ovary cell or a human neonatal kidney 293 cell. In other aspects or embodiments of this invention, the host cell is a yeast or filamentous fungal cell. A method for producing an antibody or antigen-binding fragment comprising a heavy chain variable domain comprising a heavy chain complementarity determining region 1 (HC-CDR) having the amino acid sequence shown in SEQ ID NO: 1, a 2 HC-CDR) having the amino acid sequence shown in SEQ ID NO: 2, and a 3 HC-CDR having the amino acid sequence shown in SEQ ID NO: 3 or 4, and a 1 HC-CDR having the amino acid sequence shown in SEQ ID NO: 8, a 2 HC-CDR) having the amino acid sequence shown in SEQ ID NO: 9, and a 3 HC-CDR having the amino acid sequence shown in SEQ ID NO: 10; and (ii) a light chain variable domain comprising a light chain 1 complementarity determining region (1 LC-CDR) having the amino acid sequence shown in SEQ ID NO: 5, a light chain 2 complementarity determining region (2 LC-CDR) having the amino acid sequence shown in SEQ ID NO: 6, andA 3 LC-CDR having the amino acid sequence shown in SEQ ID NO: 7, or a 1 LC-CDR or light chain determining region having the amino acid sequence shown in SEQ ID NO: 11; a 2 LC-CDR having the amino acid sequence shown in SEQ ID NO: 12, and a 3 LC-CDR having the amino acid sequence shown in SEQ ID NO: 13, a method comprising: providing a host cell with a nucleic acid molecule encoding the heavy chain and a nucleic acid molecule encoding the light chain; and culturing the host cell under conditions and for a time sufficient to produce the antibody or antigen-binding moiety. In other aspects or embodiments of this invention, the antibody comprises a heavy chain constant domain of the 3IgG, 2IgG, 1IgG, or 4IgG isotype. In other aspects or embodiments of this invention, the antibody comprises a heavy chain constant domain of the 4IgG isotype. In other aspects or embodiments of this invention, the antibody comprises a heavy chain constant domain comprising the amino acid sequence shown in SEQ ID NO: 16, 17, 18, or 19. In other aspects or embodiments of the invention, the light chain comprises a human kappa light chain or a human lambda light chain. In other aspects or embodiments of the invention, the antibody comprises a light chain constant domain comprising the amino acid sequence shown in SEQ ID NO: 20. In other aspects or embodiments of the invention, the host cell is a Chinese hamster ovary cell or a human neonatal kidney 293 cell. In other aspects or embodiments of this invention, the host cell is a yeast or filamentous fungal cell. In addition, the present invention provides a composition comprising any of the antibodies recited above and a pharmaceutically acceptable carrier. In particular embodiments, the composition comprises a heavy chain lacking a C-terminal lysine. In particular embodiments, the composition comprises an antibody recited herein, such that the predominant or prominent form of the antibody comprises a heavy chain having a C-terminal lysine. In particular embodiments, the composition comprises an antibody recited herein, such that the predominant or prominent form of the antibody comprises a heavy chain lacking a C-terminal lysine. In particular embodiments, the composition comprises an antibody recited herein, such that about 100% of the antibodies in the composition comprise a heavy chain lacking a C-terminal lysine. Description As used herein, the term "antibody" refers to both a complete immunoglobulin, including artificially produced forms, and to any antibody that exhibits a desired biological activity. Thus, the term is used in its broadest or most inclusive sense, and specifically includes monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies (polyclonal antibodies are antibodies derived from several different cell lines), multispecific antibodies (e.g., bispecific antibodies), humanized antibodies, fully human antibodies, biparatopic antibodies (capable of binding to two different antigens), and epitope), and polygenic antibodies, but is not limited to these."Parental or source antibodies" refer to antibodies obtained by exposing an immune system to an antigen, before the antibodies are modified for use for a specific purpose, such as humanizing an antibody for use as a human therapeutic antibody. In one embodiment, an "antibody" refers to a glycoprotein (a glycoprotein refers to a complex protein with carbohydrate components—translator's explanation) that comprises at least two heavy chains (HC) and two light chains (LC), which are linked together by disulfide bonds, or by a moiety that can bind to its antigen. Each heavy chain is composed of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. In some naturally occurring antibodies IgG, IgD and IgA, the heavy chain constant region is composed of three domains 2 CH, 1 CH and 3 CH. In some naturally occurring antibodies, each light chain is composed of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region is composed of one domain, CL. In addition, the VH and LV regions are divided into lower regions of hypervariable potential, called complementarity determining regions (CDRs), which are separated by more stable regions called framework regions (FRs).Each VH and VL consists of three CDRs and four FRs, arranged from the amino terminus to the carboxyl terminus as follows: FR3, CDR3, FR2, CDR2, FR1, CDR1FR The variable regions of the heavy and light chains contain a binding or binding domain that reacts with an antigen. The constant region of antibodies can mediate the binding of the immunoglobulin to host factors or tissues, including various cells of the immune system (for example, effector cells). An effector is usually a small molecule that selectively binds to a protein and modulates or regulates its biological activities.Thus, effector molecules act as ligands that can increase or decrease enzyme activity, gene expression, or cellular signaling—translator's explanation)) and the first component (q1c) of the classical complement system (the complement system is derived from many small plasma proteins that form the biochemical cascade of the immune system, leading to cell wall destruction, movement of cells and other multicellular organisms toward a chemical stimulus, and inflammation, and can be used to identify cytophagous pathogens—translator's explanation). In general, the basic structural unit of an antibody consists of a tetramer. Each tetramer consists of two identical pairs of polypeptide chains, each pair consisting of a "light" chain (about 25 kDa) and a "heavy" chain (about 50-70 kDa). The amino-terminal portion of each chain contains a variable region of about 100 to 110 or more amino acids that are primarily responsible for antigen recognition. The carboxyl-terminal portion of the heavy chain can specify a constant region that is primarily responsible for effector function. Generally, human light chains are classified as kappa and lambda light chains. In addition, human heavy chains are generally classified as mu, delta, gamma, alpha, or epsilon, determining the antibody isotype as IgM, IgD, IgG, IgA, and IgE, respectively.Within the light and heavy chains, the constant and variable regions are connected by a "J" region consisting of about 12 or more amino acids, and the heavy chain also contains a "D" region consisting of about 10 or more amino acids. For general information, see Basic Immunology, Chapter 7 (Powell, W., editor, 2nd ed., Raven Press, New York (1989)). The heavy chain of an antibody may or may not contain a terminal lysine (K), a terminal glycine, or a lysine (GK). Thus, specifically, embodiments of antibodies herein include a heavy chain constant region amino acid sequence shown herein that lacks a terminal lysine, but terminates with a glycine residue, which further include embodiments in which a terminal glycine residue is also absent. This is because the terminal lysine, and sometimes the glycine and lysine together, are cleaved during the process of antibody expression (the process of information transfer or gene expression is the process in which the information within a gene is used to produce a functional product. Various steps can be considered for the process of gene expression, which generally include transcription, RNA splicing, translation, and post-translational modifications of a protein—translator's note). As used herein, the term "antigen-binding fragment" refers to fragments of antibodies, i.e., fragments of antibodies that retain the ability to specifically bind to antibodies bound by the full-length antibody, for example, fragments that retain or retain one or more CDR regions. Examples of antigen-binding fragments include, but are not limited to: Fab, Fab', F(ab')2, and Fv fragments; diabodies; single-chain antibody molecules, e.g., sc-Fv; nanobodies and multispecific antibodies composed of antibody fragments. As used herein, a "Fab fragment" is composed of a light chain and CH1 and the variable regions of a heavy chain. The heavy chain of a Fab molecule cannot form a disulfide bond with another heavy chain molecule. A "Fab fragment" can be the product of papain digestion of an antibody. As used herein, a "Fab fragment" contains a light chain and a portion or component of a heavy chain that contains the VH domain and the CH1 domain, as well as the region between the CH1 and CH2 domains. Therefore, an interchain disulfide bond can be formed between the two heavy chains of two Fab' fragments to form an F(ab')2 molecule. As used herein, a "F(ab')2" is a component containing two light chains and two heavy chains, containing the VH domain and a portion of the constant region between the CH1 and CH2 domains, thus forming an interchain disulfide bond between the two heavy chains. Thus, a F(ab')2 is composed of two Fab' components held together by a disulfide bond between the two heavy chains. A "F(ab')2" can be the product of pepsin cleavage or breakdown of an antibody. As used herein, an "Fv region" includes the variable regions of both heavy and light chains, but lacks the constant regions. These and other potential structures are described in Chan and Carter (2010), National Immunology Review, 10:301. These antibody fragments are obtained using conventional techniques known to those skilled in the art, and the fragments are screened for convenience and applicability similar to that used for whole antibodies. Antigen-binding fragments can be produced by synthetic or polygenetically engineered DNA techniques, or by enzymatic or chemical cleavage of whole immunoglobulins. As used herein, the “Fc” region contains two heavy chain components, comprising the CH1 and CH2 domains of an antibody. The two heavy chain components are held together by two or more disulfide bonds and by hydrophobic interactions of the CH3 domains. As used herein, a "diabody" refers to a small fragment of an antibody that has two antigen-binding moieties, the moieties comprising a heavy chain variable domain (VH) linked to a light chain variable domain (VL) on the same polypeptide chain (VH-VL or VL-VH). Using a linker that is too short to allow pairing between the two domains on the same chain, the domains are forced to pair with complementary domains from other chains, producing two antigen-binding moieties. Diabodies are described more fully in, for example,; 11161 / 93: WO 097, 404 EP and Holiger et al. (1993), Proceedings of the American Academy of Sciences 6448-6444: 90. For a general review of engineered antibody variants, see Holiger and Hudson (2005) National Biotechnology 1136-11226: 23. As used herein, a "bispecific antibody" is a synthetic hybrid antibody that has two different light / heavy chain pairs and therefore has two different binding sites or regions. For example, a bispecific antibody can comprise a first light / heavy chain pair comprising a heavy chain and a light chain from a first antibody comprising at least six CDRs from the αFXI-13654p, αFXI-13716p or αFXI-13716 antibody, or embodiments in which one or more of the six CDRs have one, two, or three amino acid substitutions, additions, or deletions, or combinations thereof, along with a second light / heavy chain pair comprising a heavy chain and a light chain from a second antibody that is specific for an antigen of interest, other than FXI. Bispecific antibodies can be produced by a variety of methods, including fusion or ligation of hybridomas (a hybrid cell produced by the fusion or ligation of a lymphocyte or mononuclear white blood cell with a tumor cell—translator's explanation) or ligation of Fab' fragments.See, for example, Song Sivilai et al. (1990) Clinical Experimental Immunology 315-321: 79; Costenelli et al. (1992) Journal of Immunology 1547-1553: 148. In addition, bispecific antibodies can be formed as “diabodies” (Holliger et al. (1993) Proceedings of the American Academy of Sciences 6444-6448: 90) or as “janosciences” (Traneker et al. (1991) EMBO J, 3655-3659: 10; Traneker et al. (1992) International Journal of Cancer Supplement 51-52: 7). As used herein, "isolated" antibodies or antigen-binding portions thereof are at least partially free from other biological molecules of the cells or cell cultures in which they were produced. Such biological molecules include nucleic acids, proteins, lipids, carbohydrates, or other substances such as cellular debris and growth media. In addition, an isolated antibody or antigen-binding portion may be partially free from components of the expression system, such as biological molecules from a host cell or its growth media. In general, the term "isolated" is not intended to refer to the complete absence of such biological molecules or to the absence of water, diluents, or salts, or to pharmaceutical materials or formulations containing the antibodies or components thereof. As used herein, a "monoclonal antibody" refers to a population of antibodies that are essentially or highly homogeneous, i.e., the antibody molecules that make up the population are identical in amino acid sequence, except for possible natural mutations that may be present in small amounts. In contrast, conventional antibody preparations (polyclonal) typically contain a large number of different antibodies that have different amino acid sequences in their variable domains, which are usually specific for different epitopes. The modifier "monoclonal" denotes the specificity of the antibody as obtained from a highly homogeneous population of antibodies, and should not be construed as necessarily producing antibodies by any particular method. For example, monoclonal antibodies to be used in accordance with the present invention can be produced by the hybridoma method first described by Kohler et al. (1975) Nature 256:495, or can be produced by DNA engineering methods (e.g., U.S. Patent No. 4,816,111).567). Also, "monoclonal antibodies" can be isolated or separated from a library or bank of bacteriophage antibodies by techniques described in, for example, Klaxon et al. (1991), Nature 352:624-628 and Marx et al. (1991) Molecular Biology 222:581-597. See also Pirsta (2005) Clinical Immunology 116:731. As used herein, a "multi-gene antibody" is an antibody that has a variable domain from a first antibody and a constant domain from a second antibody, such that (i) the first and second antibodies are from different species (U.S. Patent No. 4,816,569; and Morrison et al., (1984), Proceedings of the National Academy of Sciences of the United States of America, 81: 6851-6855) or (ii) the first and second antibodies are from different isotypes, e.g., the variable domain from an IgG1 antibody and the constant domains from an IgG4 antibody, e.g., αFXI-13465p-IgG4 (S228P). In one embodiment or aspect, the variable domains are derived from a human antibody ("parent antibody"), and the constant domain sequences are derived from a non-human antibody (e.g., mouse, rat, dog, monkey, gorilla, horse). In another embodiment or aspect, the variable domains are derived from a non-human antibody (parent antibody) (e.g., mouse, rat, dog, monkey, gorilla, horse), and the constant domain sequences are derived from a human antibody.In another embodiment, the variable domains are derived from a human IgG1 antibody ("parent antibody"), and the constant domain sequences are derived from a human IgG4 antibody. As used herein, a "humanized antibody" refers to antibodies that contain sequences from both human and non-human (e.g., mouse, rat) antibodies. Generally, a humanized antibody comprises all of at least one, and preferably two, variable domains, in which the supervariable loops correspond to loops from non-human immunoglobulins, and all or a substantial portion of the framework regions (FRs) are from a human immunoglobulin sequence. The humanized antibody may optionally comprise at least a portion of a human immunoglobulin constant region (Fc). As used herein, a "fully human antibody" refers to an antibody that comprises human immunoglobulin amino acid sequences or variable sequences thereof, which include mutations that are artificially introduced or induced to produce a fully human antibody with modified function or effect compared to an antibody lacking said mutations. A fully human antibody does not comprise non-human immunoglobulin amino acid sequences, e.g., constant domains and variable domains, including CDRs that have human sequences distinct from those resulting from the mutations noted above. A fully human antibody can comprise amino acid sequences from antibodies or immunoglobulins obtained from a fully human antibody bank, the diversity of which is generated in computers (see, for example, U.S. Patent Nos. 688,877,8 or 730,691,8).A fully human antibody includes such antibodies that are produced in a non-human organism. For example, a fully human antibody may contain mouse carbohydrate chains if produced in a mouse, a mouse cell, or a hybridoma derived from a mouse cell. Similarly, a "mouse or rodent" antibody refers to an antibody that contains only mouse or rodent immunoglobulin sequences. Conversely, a fully human antibody may contain rat carbohydrate chains if produced in a rat, a rat cell, or a hybridoma derived from a rat cell. Similarly, "rat antibody" refers to an antibody that contains only rat immunoglobulin sequences. As used herein, "non-human amino acid sequences" in relation to antibodies or immunoglobulins refers to an amino acid sequence that is specific to an amino acid sequence from a non-human mammal. The term does not include amino acid sequences of antibodies or immunoglobulins obtained from a completely non-human antibody bank, where the diversity or variation is generated by computers (e.g., U.S. Patent Nos. 8,877,688 or 8,691,730). As used herein, "effector functions" refer to biological activities that are attributable to the Fc region of an antibody, which are distinct from the antibody isotype. Examples of effector functions or functions include: Clq binding and complement-dependent toxicity (CDC); Fc receptor binding; antibody-mediated cell-mediated cytotoxicity (ADCC); xenobiotics; downregulation (the term downregulation is a process by which a cell reduces the number of receptors for a hormone or neurotransmitter to reduce its sensitivity to that molecule. Increasing the number of receptors is also called upregulation—translator's note) of cell surface receptors (e.g., B cell receptors); and B cell activation. The variable regions of each light / heavy chain pair form the binding sites or regions of the antibody. Thus, in general, a complete antibody has two binding sites. With the exception of dual-functional or bispecific antibodies, the two binding sites are generally identical. In general, the variable domains of both heavy and light chains consist of three hypervariable regions, also known as complementarity determining regions (CDRs), and are located within relatively constant framework (FR) regions. The CDRs are usually regulated by framework regions, and allow binding to a specific epitope. In general, from the N-terminus to the C-terminus, both light and heavy chains have variable domains consisting of 4 FR3, CDR3, FR2, CDR2, FR1, CDR1FR. In general, the assignment of amino acids to each domain is in accordance with the definitions in Protein Sequences of Use in Immunology, Kabat et al., National Institutes of Health, Bethesda, MD, 5th ed.; National Institutes of Health Publications, No. 91-3242 (1991); Kabat (1978) Chem. Consult., 32:1-76; Kabat et al., (1977), J. Biol., 252:6609-6616; Shasaya, et al., (1987), J. Molecular Biology, 196:901-917; or Shasaya et al., (1989), Nature, 342:878-883. As used herein, "supervariable region" refers to the amino acid residues of an antibody that are responsible for binding to an antigen. The supervariable region includes the amino acid residues of a "complementarity determining region" or "CDR" (i.e., 1CDRL, 2CDRL, and 3CDRL in the light chain variable domain and 1CDRL, 2CDRL, and 3CDRL in the heavy chain variable domain). See Kabat et al., (1991) Protein Sequences Applied in Immunology, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD (definition of the CDR regions of an antibody by sequence); see also Shasaya and Lesk (1987), Journal of Molecular Biology, 196: 901–917 (definition of the CDR regions of an antibody by structure). As used herein, "framework" or "FR" residues refer to variable domain residues other than the hypervariable region residues, which are defined herein as CDR residues. As used herein, "conservatively modified variables" or "conservative substitutions" refer to substitutions of amino acids with other amino acids that have similar properties (e.g., in terms of charge, side chain size, degree of hydrophobicity / hydrophilicity, conformation and rigidity, etc.), so that the changes can often be made without altering the biological activity of the protein. Those skilled in the art will appreciate that, in general, amino acid substitutions only in nonessential regions of a polypeptide do not significantly alter biological activity (see, e.g., Watson et al., (1987) Molecular Biology of the Gene, Benjamin / Cummings Publishing Company, p. 224 (4th ed.)). In addition, amino acid substitutions that are structurally or functionally similar to the original are less likely to eliminate or abrogate biological activity. Conservative substitutions are listed in the table below. Conservative Substitution Core Residue Conservative Substitution Core Residue Ala (A) Gly; Ser Leu (L) Ile; Val Arg (R) Lys; His Lys (K) Arg; His Asn (N) Gln; His Met (M) Leu; Ile; Tyr Asp (D) Glu; Asn Phe (F) Tyr; Met; Leu Cys (C) Ser; Ala Pro (P) Ala Gln (Q) Asn Ser (S) Thr Glu (E) Asp; Gln Thr (T) Ser Gly (G) Ala Trp (W) Tyr; Phe His (H) Asn; Gln Tyr (Y) Trp; Phe Ile (I) Leu; Val Val (V) Ile; Leu As used herein, "epitope" or "antigenic determinant" refers to a site on an antigen (e.g., FXI) to which an immunoglobulin or antibody selectively binds. Epitopes within antigens can be generated from either adjacent amino acids (usually a linear epitope) or non-linear amino acids that are brought together by a third conformational change in the protein (usually a face-shaped or isomorphic epitope). Usually, but not always, epitopes formed from adjacent amino acids are not exposed to denaturing solvents, while epitopes formed from the third conformation of the protein are usually destroyed during treatment with denaturing solvents. Typically, an epitope containing 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2.1 or 15 amino acids in a unique spatial configuration. Methods for determining which epitopes are bound by a desired antibody (i.e., epitope mapping or topography) are well known in the art and include, for example, immunoblot assays or antibody labeling and antibody-antigen precipitation, such that overlapping or adjacent peptides (e.g., from FXI) are tested for reactivity with a desired antibody (e.g., an anti-FXI antibody). Methods for determining the spatial configuration of epitopes include techniques available in the art and those described herein, for example, X-ray crystallography, 2-dimensional nuclear magnetic resonance, and HDX-MS (see, for example, Epitope Topography Conventions in Methods in Molecular Biology, vol. 66, J. A. Morris, editor, (1996)). The term "epitope mapping" refers to the process of identifying molecular determinants on the antibody of interest in antibody-antigen recognition. The term "binds to the same epitope" with respect to two or more antibodies means that, as determined by an arbitrary method, the antibodies bind to the same portion of the amino acid residue. Techniques for determining whether antibodies bind to the "same epitope on FXI" as the antibodies described herein include, for example, epitope topography methods, such as, X-ray crystallography analyses of antigen:antibody mixtures, which provide atomic resolution of the epitope, and hydrogen deuterium / hydrogen exchange mass spectrometry (HDX-MS). Other methods that monitor antibody binding to antigen components (e.g., protein hydrolysates) or other antigen mutants have been to detect loss of binding due to modifications of an amino acid residue within an antigen sequence that is commonly considered to be indicative of a component of the epitope (e.g., alanine probe mutagenesis—Cunningham and Walls (1985) Science 244:1081). In addition, hybrid computational methods for epitope mapping can also be used.These methods rely on the ability of the antibody of interest to isolate the affinity or attraction of short peptides from banks or libraries of peptide displays of xenobiotic combination. Antibodies that "compete with other antibodies for binding to a target such as FXI" refer to antibodies that (partially or completely) prevent other antibodies from binding to the target. Whether antibodies compete with each other for binding to the target, that is, whether and to what extent an antibody prevents the binding of another antibody to a target, can be determined using well-known competition assays. In some assays, an antibody competes with another antibody and prevents its binding to the target by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% inhibition. The level of inhibition or competition can vary depending on which antibody is the "blocking antibody" (i.e., the cold antibody that is first primed or activated with the target). Competition tests or assays can be performed as described in, for example, Ed Harlow and David Lane, Cold Spring Harbor Laboratory, 2006; 4277prot.pdb / 1101.10:doi or in Chapter 11 of "Using Antibodies" by Ed Harlow and David Lane, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA, 1999. Competing antibodies bind to the same epitope, an overlapping epitope or to adjacent epitopes (e.g., as evidenced by steric hindrance). Other competitive binding assays include: direct or indirect solid-state radioimmunoassay (RIA), direct or indirect solid-state enzyme immunoassay (EIA), sandwich competition assay (Stalyet al., Methods in Enzymology 9: 242); Direct solid-state biotin-avidin EIA assay (see Kirkland et al., Journal of Immunology, 137: 3614 (1986); direct solid-state labeling assay, direct solid-state labeled sandwich assay (see Harlow and Lin, Antibodies: A Laboratory Manual, Cold Spring Harbor Press (1988)); RIA using direct solid-state labeling using a 1-125 label (see Marle and Sarin, Molecular Immunology, 25(1): 7 (1988)); direct solid-state biotin-avidin EIA assay (Chang and Sarin, Virology, 176: 546 (1990)); and direct labeled RIA assay (Moldenhar et al., Scandinavian Journal of Immunology, 32: 77 (1990)). As used herein, "binds specifically or selectively", in relation to an antigen or molecule such as FXI, refers to the preferential association of an antibody or other ligand, either in whole or in part, with FXI and not with other molecules, particularly molecules found in human serum or blood. Antibodies typically bind selectively and with high affinity to cognate antigens, as evidenced by a dissociation constant (KD) of 10-7 to 10-11M or less. Any KD greater than about 10-6M is generally considered to be indicative of non-selective binding. As used herein, an antibody that "selectively" binds to an antigen refers to an antibody that binds with high affinity to the antigen and antigens of significant similarity, which means that it has a KD of less than 10-7M or less, in some embodiments, a KD of 10-8M or less, or 5x10-9M or less, or between 10-8M and 10-11M or less, but does not bind with high affinity to unrelated antigens.The kinetics of binding can be determined by surface plasmon resonance (surface plasmon resonance is a biophysical technique used by biochemists to measure the binding interactions of very small amounts of target proteins. A ligand is immobilized or fixed on a special chip and a solution of the target molecule flows over the chip. The flow and progression of binding are then measured by optical devices—translator's note), as described here in Example 1. An antigen is "highly identical or similar" to a desired antigen if it exhibits a high degree of amino acid sequence identity with a desired antigen, for example, if it exhibits at least 80%, at least 90%, at least 95%, at least 97%, or at least 99% or more of the amino acid sequence identity of that desired antigen. For example, an antibody that selectively binds to human FXI may also cross-react with FXI from some non-human primate species (e.g., cynomolgus monkey), but may not cross-react with FXI from other species, or with an antigen other than FXI. As used herein, "isolated nucleic acid molecule" means a DNA or RNA of mRNA, genomic cDNA, or synthetic origin, or a combination thereof, that is not linked to all or part of the polynucleotide in which the isolated polynucleotide is naturally found, or is associated with a polynucleotide with which it is not associated in nature. For the purposes of this article, it is to be understood that a "nucleic acid molecule" that includes a nucleotide sequence does not include complete chromosomes. Isolated nucleic acid molecules "comprising" the specified nucleic acid sequences may, in addition to the specified sequences, contain coding sequences for up to ten or even up to twenty or more proteins or portions thereof, or may contain regulatory sequences operably linked to control the expression of the coding or encoding region of said nucleic acid sequences, or may contain carrier sequences. As used herein, "treatment" or "treating" means administering a therapeutic agent, such as a composition containing any of the antibodies or antigen-binding fragments thereof of the present invention, internally or externally to a person or patient having one or more symptoms of a disease, or suspected of having a disease, for which the agent has a therapeutic or prophylactic function. Typically, the agent is administered in an amount effective to alleviate or reduce one or more symptoms of the disease in the person or population being treated, whether by inducing regression or inhibiting the progression of such symptoms by any clinically measurable amount. The amount of therapeutic agent effective to alleviate any particular symptom of the disease may vary depending on such factors as the condition of the disease, the age, and weight of the patient, and the ability of the drug to elicit a desired response in the individual. Whether a symptom of a disease has been alleviated can be assessed by any clinical measurement used by physicians or healthcare providers to assess the severity or progression of that symptom.It also includes a postponement or delay in the development of symptoms associated with a disorder or a reduction in the severity of symptoms of such disorders. In addition, courses include amelioration of existing uncontrolled or unwanted symptoms, prevention of additional symptoms, and amelioration or prevention of the underlying causes of such symptoms. Therefore, courses mean that a beneficial result has been achieved for a human or animal patient who has a disorder, disease, or symptom, or has the potential to develop such a disorder, disease, or symptom. As used herein, a "therapeutically effective amount" refers to the amount or quantity of a given substance that is sufficient to achieve a desired effect in a patient being treated. For example, this amount may be the amount necessary to inhibit the activation of FXI or the amount necessary to inhibit blood coagulation for at least 192 to 288 hours, as determined by the aPTT test. At the time of administration to the patient, a dose is typically used that achieves the target tissue concentrations that have demonstrated a desired effect in vitro. As used herein, "thrombosis" refers to the formation or presence of a blood clot (also called a blood clot) within a blood vessel, which obstructs the flow of blood through the circulatory system. Thrombosis is usually caused by an abnormality in the composition of the blood, the quality of the vessel wall, or the nature of the blood flow. A blood clot is usually formed due to an injury to the vessel wall (such as a wound or disease) and is caused by a slowing or stasis of blood flow past the point of injury. In some cases, abnormalities in blood clotting cause the formation of a blood clot. As used herein, "without risk of hemostasis" means little or no detectable bleeding in a subject or patient following administration to the subject or patient of an antibody or graftable component to an antigen disclosed herein. In the case of targeting factor XI, inhibiting the conversion of factor XI to factor XIa or the activation of factor XI by factor XIa without hemostasis results in inhibition of blood coagulation and associated blood clot formation. Conversely, inhibition of factor XI conversion or activity prevents blood coagulation but also induces bleeding or increases the risk of bleeding. Brief description of the images Figures A1 and B1 show the coagulation cascade, FXI, FXI mAb, and four novel oral anticoagulants (NOACs). Figure A1 is a cartoon depicting FXI in the coagulation cascade (which consists of either intrinsic or extrinsic pathways). A mAb targeting FXI could exert a neutralizing function by blocking the activation of FXI by XIIa or thrombin, or the activation of FXIa on FIX. It is possible that the antibodies presented here exert dual blockade of FIX activation by FXIa. Four NOACs (i.e., rivaroxaban, apixaban, edoxaban, and dabigatran) that target either FXa or thrombin are shown. Figure 1B shows the structure of the FXI domain. FXI is a bipartite consisting of 80 kDa identical subunits, each subunit starting at an N-terminus consisting of four apple domains (1, 2, 3, and 4) and a catalytic or stimulatory domain (CAT). The antibodies presented here bind to apple domain 3. Figure 2 shows the structure of factor XI and the apple 3 domain, along with peptides that are protected from deuterium incorporation by the identified anti-FXI antibodies of the 18611-αFXI family and P18623-αFXI family. Arginine residue 184, a critical residue in the outer binding site of FIX, is shown. Peptides in the apple 3 domain with no difference in deuterium incorporation are in light gray. Peptides for which no data are available are in dark gray. The stimulatory domain is not shown. Figures A3 and B3 are heat maps of the difference in deuterium labeling of FXI amino acid residues detected by anti-FXI antibodies, respectively. LC / (105L)(1E)(P228S) HC 4LGg 18611- αFXI / kappa light chain and LC / (1Q)( P228S) HC 4LGg P 18623 αFXI heavy chain are linked together. Figures 4A, 4B, and 4C show the amino acid sequences of the HC and LC domains of the P18611-αFXI and 18611-αFXI family antibodies. The heavy chain and light chain CDRs are designated as 1.HC-CDR, 2HC-CDR, 3HC-CDR, 1LC-CDR, 2LC-CDR, and 3LC-CDR, respectively. Figures A5 and B5 show the amino acid sequences of the LC and HC domains of the P18623 αFXI family antibodies. The heavy chain and light chain are designated as 1.HC-CDR, 2.HC-CDR, 3.HC-CDR, 1.LC-CDR, 2.LC-CDR, and 3.LC-CDR, respectively. Figure 6 shows the results of an activated partial thromboplastin time (aPTT) assay of kappa LC(A)-LC / (105L)(1E)(P228S) HC 4LGg 18611-αFXI / kappa (A) LC / (1Q)( P228S) HC 4LGg P 18623 αFXI and kappa (B) light chain in human plasma, expressed as the percentage increase from baseline. Figure 7 shows the results of an activated partial thromboplastin time (aPTT) assay of LC / (105L)(1E)(P228S) HC 4LGg 18611- αFXI / / kappa light chain (A) and kappa light chain (B) in cynomolgus monkey plasma, expressed as a percentage increase from baseline. Figure 8 shows the results of an activated partial thromboplastin time (aPTT) assay of LC / (105L)(1E)(P228S) HC 4LGg 18611- αFXI / / kappa light chain (A) and LC / (1Q)( P228S) HC 4LGg P 18623 αFXI kappa light chain (B) in rhesus monkey plasma, expressed as a percentage increase from baseline. Figure 9 shows a composite of aPTT results for LC / (105L)(1E)(P228S) HC 4LGg 18611- αFXI / kappa in human plasma, cynomolgus monkey, and rhesus monkey plasma expressed as percent increase from baseline. Figure 10 shows a composite of the results of LC / (1Q)( P228S) HC 4LGg P 18623 αFXI kappa in human plasma, cynomolgus monkey, and rhesus monkey plasma expressed as percent increase from baseline. Figure 11 shows BIAcore spectra indicating the binding kinetics of LC / (1Q)(P228S) HC 4LGg P 18623 αFXI / kappa light chain to human, cynomolgus and rhesus monkey FXI and other non-human and human ancestral blood coagulation cascade proteins. Figure 12 shows BIAcore spectra showing the binding kinetics of LC / (1Q)(P228S) HC 4LGg P 18623 αFXI / kappa light chain to human, cynomolgus and rhesus monkey FXI and other non-human and human ancestral blood coagulation cascade proteins. Figure 13 shows a schematic of the cynomolgus monkey AV shunt test design. Anesthetized monkeys, previously caesarean or surgical fluid drainage tube placed in their femoral vein, were given either LC / (1Q)(P228S) HC 4LGg P 18623 αFXI / or kappa light chain (antibody) at 0.1-01.0 mg / kg by intravenous bolus injection (test substance delivery). An AV shunt or shunt passage was inserted as described in the text (AV shunt inlet). Blood flowed through the AV shunt for 40 min. Contact between the blood and the silk thread suspended in the tube induced blood clot formation. Blood clots were weighed as described in the text. Blood samples were collected to measure circulating levels of antibody, apt, and PT (asterisks). Figures 14-14 show the effect of LC / (1Q)( P228S) HC 4LGg P 18623 αFXI / kappa light chain (antibody) on AV shunt clot formation, aPTT, and PT in the cynomolgus monkey AV shunt model. In Figure 14A, clot weight was measured after two consecutive shunts in the same animal. Animals were given vehicle during the first shunt (shunt #1), followed by antibody (0.1-01.0 mg / kg IV) during the second shunt (shunt #2) as indicated. Increasing the two antibodies resulted in smaller clot formation. The percent inhibition of clot weight (Figure 14B) and the percent change in aPTT (Figure 14C) increased with increasing antibody plasma concentration. Conversely, PT (Figure D14) remained almost unchanged at all antibody concentrations. Figure 15 shows a schematic of a cynomolgus monkey bleeding time template. Bleeding times or patterns on the buccal mucosa (inner lip), fingertip, and tail tip at baseline (pretreatment) were determined in anesthetized monkeys and after application of Treatment #1 (vehicle) and Treatment #2 (vehicle or LC / (1E)( P228S) HC 4LGg P 18623 αFXI / kappa, 10 mg / kg IV). Blood samples were collected as indicated for measurement of αFXI-(1E)( P228S) HC 4LGg P 18623 αFXI / kappa light chain, aPTT, and PT levels. Figures F16-A16 show the effect of (1E)( P228S) HC 4LGg P 18623 αFXI / kappa light chain on bleeding times measured in cynomolgus monkeys. Bleeding times were measured on the inner lip (Figures A16, D16), between the toes (Figures B16, E16), and at the tip of the tail (Figures C16, F16). The treatment effects of ((1E)( P228S) HC 4LGg P 18623 αFXI / kappa light chain-vs LC) on bleeding times were assessed by comparing absolute bleeding times (left panels) and percent changes in bleeding times (right panels), with vehicle-vehicle as treatments #1 and #2 in study session #1, and vehicle- (1E)( P228S) HC 4LGg P 18623 αFXI / kappa light chain- as treatments #1 and #2 in study session #2, using a one-tailed paired Student's t-test. Figure A17 shows the concentration-time profile following administration of (1E)( P228S) HC 4LGg P 18623 αFXI / kappa light chain in rhesus monkeys. The plasma concentration-time profile for (1E)( P228S) HC 4LGg P 18623 αFXI / kappa light chain in rhesus monkeys is shown. Four animals were included in each dose group. Each line represents a mean for a particular group. Figure B17 shows aPTT-time characteristic plots in rhesus monkeys. The aPTT-time characteristic plots for (1E)( P228S) HC 4LGg P 18623 αFXI / kappa light chain are shown for each dose group. Four animals were included in each dose group. Each symbol represents an aPTT-time plot from one animal at each time point. Each line represents a mean for a particular group. Detailed description of the invention The present invention provides anticoagulant factor XI antibodies that bind to the apple 3 domain of coagulation factor XI (FXI). These anti-FXI antibodies are inhibitors of FXI activation by factor XIIa and are useful for inhibiting blood coagulation and associated blood clot formation without the risk of bleeding (antithrombotic effects). For example, anti-FXI antibodies can be used to treat and prevent thromboembolic events (VTE), prevent stroke due to uncoordinated contraction of the arterial muscle fibers (SPAF), or treat and prevent certain thromboembolic disorders associated with medical devices (e.g., stents, endovascular stent grafts, catheters (cardiac or venous), continuous flow assist devices (CF-LVADS), dialysis for toxic effects, cardiopulmonary bypass and extracorporeal membrane oxygenation (ECMO), and ventricular assist devices (VADS)).Therefore, the anti-FXI antibodies provided herein are useful for treating a disorder or disease related to the blockage of blood vessels by a blood clot in a patient or individual in need of such treatment. FXI is a symmetrical or identical protease (a serine protease is a type of peptidases, or enzymes that cleave peptide bonds in proteins, identified by the presence of a serine residue in the active site of the enzyme and involved in a wide range of bodily functions, including blood coagulation, inflammation, and digestive enzymes—translator's note) that has the domain structure shown in Figure B1 and is an integral component of the intrinsic pathway of the blood coagulation cascade. The FXI zymogen can be cleaved by factor XIIA to its active form, FXIa. FXIa then activates factor IX, ultimately initiating thrombin production and blood clot formation. The anti-FXI antibodies presented here prevent the conversion of FXI to FXIa (see Figure 1A). Anti-FXI antibody molecules were obtained from a fully synthetic human IgG / kappa library or source displayed on the surface of an engineered yeast strain. The source was screened by FXI or FXIa to identify antibodies that bind with sub-nanomolar affinity to human FXI and non-human primate (NHP) FXI and do not bind to human or NHP plasma kallikrein (a protein that shares 56% identity with FXI), or to other human coagulation cascade proteins (FII / / IIa, FVII / VIIa, FIX / IXa, FX / Xa, and FXII / XIIa). Two antibodies were identified that had these properties: P18611-αFXI and P18623-αFXI. These antibodies are fully human antibodies that contain a human kappa (k) light chain and a human γ1 (γ1) LgG heavy chain. The antibodies selectively bind to the zymogen epitope comprising SEQ ID NOs: 82 and 83, located in the 3-chain domain of FXI. These antibodies also bind with comparable affinity to the FXI zymogen. The P18611-αFXI family of antibodies includes heavy chain (HC) complementarity determining regions (CDRs) 1, 2, and 3, which have the amino acid sequences shown in SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, respectively, and light chain (LC) CDRs 1, 2, and 3, which have the amino acid sequences shown in SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7, respectively. A P18611-αFXI family contains antibodies that include a heavy chain variable domain (HC) that includes the amino acid sequence shown in SEQ ID NO: 21 or 22, and a light chain variable domain (LC) that includes the amino acid sequence shown in SEQ ID NO: 25. The 18611-αFXI family antibodies comprise heavy chain (HC) complementarity determining regions (CDRs) 1, 2, and 3, which have the amino acid sequences shown in SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 4, respectively, and light chain (LC) CDRs 1, 2, and 3, which have the amino acid sequences shown in SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7, respectively. An αFXI-18611 family contains antibodies that include a heavy chain variable domain (HC) that includes the amino acid sequence shown in SEQ ID NO: 23 or 24, and a light chain variable domain (LC) that includes the amino acid sequence shown in SEQ ID NO: 25. The P18623-αFXI family of antibodies includes heavy chain (HC) complementarity determining regions (CDRs) 1, 2, and 3, which have the amino acid sequences shown in SEQ ID NO: 8, SEQ ID NO: 9, and SEQ ID NO: 10, respectively, and light chain (LC) CDRs 1, 2, and 3, which have the amino acid sequences shown in SEQ ID NO: 11, SEQ ID NO: 12, and SEQ ID NO: 13, respectively. A P13716-αFXI family contains antibodies that include a heavy chain variable domain (HC) that includes the amino acid sequence shown in SEQ ID NO: 28 or 29, and a light chain variable domain (LC) that includes the amino acid sequence shown in SEQ ID NO: 30. Antibodies in this family are derived from a different lineage than previous families. The present invention further provides anti-FXI antibodies comprising at least six CDRs of an anti-FXI antibody of the P18611-αFXI family, the 18611-αFXI family, or the αFXI-18623p family, or embodiments thereof, wherein one or more of the six CDRs has one, two, or three amino acid substitutions, additions, or deletions, or combinations thereof, and also includes methods of using the antibodies to treat anti-thrombotic effects, e.g., SPAF. In particular aspects or embodiments, the anti-FXI antibodies comprise at least the heavy chain variable domain of an anti-FXI antibody from the P18611-αFXI family, the 18611-αFXI family, or the P18623-αFXI family or a variant thereof, wherein the variable domain comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, or deletions, or a combination thereof. In particular aspects, the anti-FXI antibodies comprise at least the variable domain of the light chain of an anti-FXI antibody from the P18611-αFXI family, the 18611-αFXI family, or the αFXI-18623p family, or a variant thereof, wherein the variable domain comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, or deletions, or a combination thereof. In certain aspects or embodiments, the anti-FXI antibodies comprise at least the heavy chain variable domain of an anti-FXI antibody of the P18611-αFXI family, the 18611-αFXI family, or the αFXI-18623p family or a variant thereof, wherein the variable domain comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, or deletions or a combination thereof, and comprise a light chain variable of an anti-FXI antibody of the P18611-αFXI family, the 18611-αFXI family, or the 18623-αFXI family or a variant thereof, wherein the variable domain comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, or deletions. It is the substitution, addition, or deletion of amino acids or a combination of them. In particular embodiments, the antibodies described herein comprise at least six CDRs from an anti-FXI antibody of the P18611-αFXI family, the 18611-αFXI family, or the P18623-αFXI family, or embodiments thereof, wherein one or more of the CDRs contain one, two, or three amino acid substitutions, additions, or deletions, or a combination thereof, and further comprise a heavy chain (HC) that is a human IgG 3, IgG 2, IgG 1, or IgG 4 isotype, and the light chain (LC) thereof can be of the kappa or lambda type. In other embodiments, the antibodies comprise at least six CDRs of an anti-FXI antibody of the P18611-αFXI family, the 18611-αFXI family, or the P18623-αFXI family, or embodiments thereof, wherein one or more of the CDRs comprises one, two, or three amino acid substitutions, additions, or deletions, or a combination thereof, and may further be of the IgM, IgD, IgA, or IgE type. In particular embodiments, the human IgG 3, IgG 2, IgG 1, or IgG 4 isotype may comprise 9, 8, 7, 6, 5, 4, 3, 2, or 10 amino acid substitutions, additions, or deletions, or a combination thereof. In particular embodiments, the antibodies can comprise at least six CDRs from an anti-FXI antibody of the P18611-αFXI family, the 18611-αFXI family, or the P18623-αFXI family, or embodiments thereof, wherein one or more of the CDRs contain one, two, or three amino acid substitutions, additions, or deletions, or a combination thereof, and further comprise a heavy chain (HC) constant domain that is of the 4IgG isotype. A 4IgG framework provides an antibody that has little or no effector function or utility. In another aspect or embodiment of the invention, the antibodies can comprise at least six CDRs of an anti-FXI antibody of the P18611-αFXI family, the 18611-αFXI family, or the P18623-αFXI family, or embodiments thereof, wherein one or more of the CDRs contain one, two, or three amino acid substitutions, additions, or deletions, or a combination thereof, and further comprise a heavy chain (HC) constant domain that is of the 1IgG isotype.In another aspect of the invention, the antibodies can comprise at least the heavy chain variable domain (HC) or the light chain variable domain (LC) of an anti-FXI antibody of the P18611-αFXI family, the 18611-αFXI family, or the P18623-αFXI family, or variants thereof, wherein the light chain and heavy chain variable domains independently comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, or deletions, or combinations thereof, and further comprise a heavy chain constant domain (HC) that is of the 4IgG isotype.In another aspect of the invention, the antibodies can comprise at least the heavy chain (HC) and light chain (LC) variable domains of an anti-FXI antibody of the P18611-αFXI family, the 18611-αFXI family, or the P18623-αFXI family, or variants thereof, wherein the light chain and heavy chain variable domains independently comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, or deletions, or combinations thereof, and further comprise a heavy chain (HC) constant domain that is of the 4IgG isotype. Additionally, antibodies of the present invention include, but are not limited to, monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), biparatopic antibodies, fully human antibodies, and multigenic antibodies. Generally, the amino acid sequence of the heavy chain of an antibody such as 1lgG or 4lgG includes a lysine at the C-terminus of the heavy chain constant domain. In some embodiments, to improve the homogeneity of an antibody product, an antibody may be produced that is a C-terminal lysine. The anti-FXI antibodies of the present invention include embodiments in which the C-terminal lysine is present as well as embodiments in which the C-terminal lysine is absent. For example, a 1lgG heavy chain constant domain can have the amino acid sequence shown in SEQ ID NO: 18 or 19 and a 4lgG heavy chain constant domain can have the amino acid sequence shown in SEQ ID NO: 16 or 17. In certain embodiments, the N-terminal amino acid of the heavy chain can be a glutamine residue. In certain embodiments, the N-terminal amino acid of the heavy chain can be a glutamic acid residue. In certain embodiments, the N-terminal amino acid of the heavy chain is a modified glutamic acid residue. Additionally, the present invention provides anti-FXI antigen-binding components comprising at least six CDRs of an anti-FXI antibody of the P18611-αFXI family, the 18611-αFXI family, or the P18623-αFXI family, or embodiments thereof, wherein one or more of the CDRs contain one, two, or three amino acid substitutions, additions, or deletions, or combinations thereof. Additionally, the present invention provides anti-FXI Fab fragments comprising at least six CDRs from an anti-FXI antibody of the P18611-αFXI family, the 18611-αFXI family, or the P18623-αFXI family, or embodiments thereof, wherein one or more of the CDRs contain one, two, or three amino acid substitutions, additions, or deletions, or combinations thereof. Additionally, the present invention provides anti-FXI antibodies comprising at least six CDRs from an anti-FXI antibody of the P18611-αFXI family, the 18611-αFXI family, or the P18623-αFXI family, or embodiments thereof, wherein one or more of the six CDRs comprises one, two, or three amino acid substitutions, additions, or deletions, or combinations thereof, as well as antigen-binding moieties thereof, including an Fc region, and methods of using them. Additionally, the present invention provides anti-FXI Fab' components comprising at least six CDRs from an anti-FXI antibody of the P18611-αFXI family, the 18611-αFXI family, or the P18623-αFXI family, or embodiments thereof, wherein one or more of the six CDRs comprises one, two, or three amino acid substitutions, additions, or deletions, or a combination thereof. Furthermore, the present invention provides an anti-FXI F(ab')2 comprising at least six CDRs from an anti-FXI antibody of the P18611-αFXI family, the 18611-αFXI family, or the P18623-αFXI family, or embodiments thereof, wherein one or more of the six CDRs comprises one, two, or three amino acid substitutions, additions, or deletions, or a combination thereof. Additionally, the present invention provides anti-FXI Fv components comprising at least six CDRs from an anti-FXI antibody of the P18611-αFXI family, the 18611-αFXI family, or the P18623-αFXI family, or embodiments thereof, wherein one or more of the six CDRs comprises one, two, or three amino acid substitutions, additions, or deletions, or a combination thereof. Additionally, the present invention provides anti-FXI scFv components comprising at least six CDRs from an anti-FXI antibody of the P18611-αFXI family, the 18611-αFXI family, or the P18623-αFXI family, or embodiments thereof, wherein one or more of the six CDRs comprises one, two, or three amino acid substitutions, additions, or deletions, or combinations thereof. Additionally, the present invention provides anti-FXI domain antibodies comprising at least three heavy chain CDRs or three light chain CDRs from an anti-FXI antibody of the P18611-αFXI family, the 18611-αFXI family, or the P18623-αFXI family, or embodiments thereof, wherein one or more of the heavy chain or light chain CDRs comprises one, two, or three amino acid substitutions, additions, or deletions, or combinations thereof. In one embodiment of the invention, the domain antibody is a single-domain antibody or nanobody. In one embodiment of the invention, a domain antibody is a Nanobody comprising at least CDRs of the P18611-αFXI family, the 18611-αFXI family, or the P18623-αFXI family, or embodiments thereof, wherein one or more of the CDRs have one, two, or three amino acid substitutions, additions, or deletions, or a combination thereof. Additionally, the invention provides bivalent anti-FXI antibodies comprising at least six CDRs from an anti-FXI antibody of the P18611-αFXI family, the 18611-αFXI family, or the P18623-αFXI family, or embodiments thereof, such that one or more of the six CDRs comprise one, two, or three amino acid substitutions, additions, or deletions, or combinations thereof. Additionally, the present invention provides bispecific antigen-binding antibodies and components that have binding selectivity for FXI and other antigens of interest, as well as methods of using them. Biparatopic antibodies are antibodies that have binding selectivity for different epitopes on an antigen. In addition, the present invention provides biparatopic antibodies that have a first heavy / light chain pair from a first antibody that comprises at least six CDRs from an anti-FXI antibody of the P18611-αFXI family, the 18611-αFXI family, or the P18623-αFXI family, or embodiments thereof, such that one or more of the six CDRs comprise one, two, or three amino acid substitutions, additions, or deletions, or a combination thereof, and a second heavy / light chain pair from a second antibody that has binding selectivity for an FXI epitope that is different from the epitope recognized by the first heavy / light chain pair. The present invention further provides antibodies and anti-FXI antigen-binding components comprising a first heavy / light chain pair of an antibody comprising at least six CDRs of an antibody of the P18611-αFXI family or the 18611-αFXI family or embodiments thereof, wherein one or more of the CDRs comprises one, two, or three amino acid substitutions, additions, or deletions, or a combination thereof, and a second heavy / light chain pair of an antibody comprising at least six CDRs of an antibody of the P18623-αFXI family or embodiments thereof, wherein one or more of the CDRs comprises one, two, or three amino acid substitutions, additions, or deletions, or a combination thereof. Additionally, the present invention provides anti-FXI diabodies comprising at least six CDRs of an anti-FXI antibody of the P18611-αFXI family, the 18611-αFXI family, or the P18623-αFXI family, or embodiments thereof, wherein one or more of the six CDRs comprises one, two, or three amino acid substitutions, additions, or deletions, or combinations thereof. An antibody comprising at least six CDRs from an anti-FXI antibody of the P18611-αFXI family, the 18611-αFXI family, or the P18623-αFXI family, or embodiments thereof, such that one or more of the CDRs have one or more amino acid substitutions, additions, or deletions, or combinations thereof, can be modified such that it retains at least 10% of its FXI binding activity (compared to the parent antibody, i.e., an antibody of the corresponding P18611-αFXI family, the 18611-αFXI family, or the P18623-αFXI family), when the activation is expressed on a molar basis. Preferably, an antibody or antigen-binding fragment of the invention retains at least 20%, 50%, 80%, 90%, 95%, or 100% or more of the binding affinity for FXI as the parent antibody. It is also contemplated that an antibody or antigen-binding fragment of the invention may have conservative or non-conservative amino acid substitutions (referred to as "conservative variables" or "constant-function variables" of the antibody), which do not inherently alter its biological activities. Additionally, the present invention provides isolated anti-FXI antibodies comprising at least six CDRs of an anti-FXI antibody of the P18611-αFXI family, the 18611-αFXI family, or the P18623-αFXI family, or embodiments thereof, wherein one or more of the six CDRs comprises one, two, or three amino acid substitutions, additions, or deletions, or combinations thereof, and antigen-binding moieties thereof and methods of use thereof, as well as immunoglobulin chains of isolated polypeptides thereof and isolated polynucleotides encoding such polypeptides, and isolated carriers comprising such polynucleotides. Additionally, the present invention provides anti-FXI monoclonal antibodies comprising at least six CDRs from an anti-FXI antibody of the P18611-αFXI family, the 18611-αFXI family, or the P18623-αFXI family, or embodiments thereof, wherein one or more of the six CDRs comprises one, two, or three amino acid substitutions, additions, or deletions, or combinations thereof, and antigen-binding moieties thereof, as well as monoclonal compositions comprising the majority of isolated monoclonal antibodies. Additionally, the present invention provides polygenic anti-FXI antibodies comprising at least six CDRs from an anti-FXI antibody of the P18611-αFXI family, the 18611-αFXI family, or the P18623-αFXI family, or embodiments thereof, wherein one or more of the six CDRs comprises one, two, or three amino acid substitutions, additions, or deletions, or a combination thereof. The present invention encompasses fully human anti-FXI antibodies comprising at least six CDRs from an anti-FXI antibody of the P18611-αFXI family, the 18611-αFXI family, or the P18623-αFXI family, or embodiments thereof, wherein one or more of the six CDRs comprises one, two, or three amino acid substitutions, additions, or deletions, or combinations thereof, and antigen-binding moieties thereof, and methods of using them. In one embodiment of the invention, a fully human antibody or antigen-binding fragment thereof is the product of isolation from a transgenic or polygenic animal (the term transgenic is used when an animal has one or more genes derived from a plant or other animal—translator's note), for example, a mouse (e.g., a HUMAB mouse, for example, U.S. Patent Nos.: 5,545,806- 5,569,825- 5,625,126- 5,633,425- 5,661,016- 5,770,429- 5,789,650- 5,814,318- 5,874,299 and 5,877.397; and Hardin et al. (1995), New York Academic Science Annals, 546 536: 764; or a XENOMOUSE, e.g., Green and Sarin, 1999, Journal of Immunological Methods, 231: 11–23), which has been genetically modified to contain fully human immunoglobulin genes; or is the product of isolation from a xenophage or virus that expresses fully human anti-FXI antibody immunoglobulin chains or an antigen-binding fragment thereof. In some embodiments, different constant domains can be fused to the VL and VH regions derived from the CDRs provided herein. For example, if a particular desired application of an antibody (or component) of the present invention requires altered effector functions, a heavy chain constant domain other than human IgG1 can be used, or a hybrid IgG / IgG4 can be employed. Although human IgG antibodies confer long half-lives and effector functions, such as complement activation and antibody-dependent cytotoxicity, such activities may not be suitable for all antibody applications. In such instances, for example, a human IgG constant domain can be used. The present invention includes anti-FXI antibodies and antigen-binding components thereof that comprise a IgG constant domain, for example, human IgG anti-FXI antibodies and components, and methods of using them. In one embodiment, the IgG constant domain can be derived from a native human IgG constant domain (Swiss Treaty Annex, No. 1).01861P), at a position corresponding to position 228 in the EU system and position 241 in the Cobat system, in which the native N at position 108 (108SER) of the heavy chain constant domain is replaced by proline (Pro), to prevent the formation of potential intra-chain disulfide bonds between the cysteine ​​at position 106 (106Cys) and the cysteine ​​at position (109Cys), which correspond to positions 226Cys and 229Cys in the EU system and positions 239Cys and 242Cys in the Cobat system, and which could interfere with the formation of the appropriate extra-chain disulfide bond. See Engel et al., Molecular Immunology, 30: 10 (1993); See also (Shurman et al., Molecular Immunology, 38: 1-8 (2001); SEQ ID NOS: 14 and 41).In other examples, a modified IgG constant domain is modified to reduce the effector functions that can be used, for example, an IgG isotype can include substitutions of IgG residues 233-236 and IgG residues 4 at positions 327, 330 and 331 to greatly reduce ADCC and CDC (Armour et al., European Journal of Immunology, 29(8): 2613-24 (1999); Shields et al., Journal of Biological Chemistry, 276(9): 6591-604 (2001)). In another embodiment, the IgG heavy chain is genetically modified to lack the N-glycoprotein nuclease from the asparagine (Asn) residue around position 297. The common sequence for producing N-glycoprotein is the sequence Asn-Xaa-Ser / Thr (where Xaa is any amino acid except Pro); in IgG the common sequence for producing N-glycoprotein is the sequence Asn-Ser-Thr.The modification can be accomplished by replacing the Asn codon at position 297 in the nucleic acid molecule encoding the heavy chain with a codon for another amino acid, for example, Gln. Conversely, the Ser codon can be exchanged for the Pro codon, or the Thr codon can be replaced with any codon except the Ser codon. Such modified IgG molecules may have little or no detectable effector function. Instead, all three codons are modified. In one embodiment of the present invention, the anti-FXI monoclonal antibodies comprise at least six CDRs from an anti-FXI antibody of the P18611-αFXI family, the 18611-αFXI family, or the P18623-αFXI family, or embodiments thereof, such that one or more of the six CDRs having one, two, or three amino acid substitutions, additions, or deletions, or combinations thereof, comprise a complete tetramer structure having two light chains and two heavy chains, as well as constant regions. The variable regions of each light / heavy chain pair form the antigen-binding site or region. Thus, generally, a complete antibody has two binding regions. With the exception of bispecific antibodies, generally, the two binding regions are identical. In particular embodiments, the present invention provides the anti-FXI antibodies shown in Table 1. Table 1 Antibody Family Heavy Chain (HC) Sequence ID Number: Light Chain (LC) Sequence ID Number: αFXI-18611p αFXI-18611p IgG4 HC (S228P)(Q1)(M105) / Kappa Light Chain 33 26 αFXI-18611p IgG4 HC (S228P)(E1)(M105) / Kappa Light Chain 35 26 αFXI-18611p IgG1 HC (Q1)(M105) / Kappa Light Chain 45 26 αFXI-18611p IgG1 HC (E1)(M105) / Kappa Light Chain 47 26 αFXI-18611p IgG4 HC (S228P)(Q1)(M105)(K-) / Kappa Light Chain 57 26 αFXI-18611p IgG4 HC (S228P)(E1)(M105)(K-) / Kappa light chain 59 26 αFXI-18611p IgG1 HC (Q1)(M105)(K-) / Kappa light chain 69 26 αFXI-18611p IgG1 HC (E1)(M105)(K-) / Kappa light chain 71 26 αFXI-18611 αFXI-18611 IgG4 HC (S228P)(Q1)(L105) / Kappa light chain 37 26 αFXI-18611 IgG4 HC (S228P)(E1)(L105) / Kappa light chain 39 26 αFXI-18611 IgG1 HC (Q1)(L105) / Kappa light chain 49 26 αFXI-18611 IgG1 HC (E1)(L105) / Kappa light chain 51 26 αFXI-18611 IgG4 HC (S228P)(Q1)(L105)(K-) / Kappa light chain 61 26 αFXI-18611 IgG4 HC (S228P)(E1)(L105)(K-) / Kappa light chain 63 26 αFXI-18611 IgG1 HC(Q1)(L105)(K-) / Kappa light chain 73 26 αFXI-18611 IgG1 HC (E1)(L105)(K-) / Kappa light chain 75 26 αFXI-18623p αFXI-18623p IgG4 HC (S228P)(Q1) / Kappa light chain 41 31 αFXI-18623p IgG4 HC (S228P)(E1) / Kappa light chain 43 31 αFXI-18623p IgG1 HC (Q1) / Kappa light chain 53 31 αFXI-18623p IgG1 HC (E1) / Kappa light chain 55 31 αFXI-18623p IgG1 HC (S228P)(Q1)(K-) / Kappa light chain 65 31 αFXI-18623p IgG4 HC (S228P)(E1)(K-) / Kappa light chain 67 31 αFXI-18623p IgG1 HC (Q1)(K-) / Kappa light chain 77 31 αFXI-18623p IgG1 HC (E1)(K-) / Kappa light chain 79 31 Epitope mapping by hydrogen deuterium exchange mass spectrometry (HDX-MS), as described in Example 3, has shown that anti-FXI antibodies containing the light chain and heavy chain CDRs bind to a specific epitope on the apple 3 domain comprising SEQ ID NO: 82 and SEQ ID NO: 83. Thus, the antibodies presented here bind to the apple 3 domain of FXI and prevent FXIIa from activating FXI, and also act as allosteric inhibitors of FIX activation by FXIa. Epitope mapping suggested that the “footprint” of the P18623-αFXI family on the apple 3 domain overlaps with the FIX-binding site on FXIa. Medicinal ingredients and uses To prepare pharmaceutical compositions or neutralizing and inert compositions of anti-FXI antibodies or their conjugates, the antibody or conjugate to the antigen thereof is mixed with a pharmaceutically acceptable carrier or vehicle. See, for example, Remington Pharmaceutical Sciences and the United States Pharmaceutical Code: National Manual, Mack Publishing Company, Easton, PA (1984) and the United States Pharmaceutical Code (USP) 12601, Twin Brook Parkway, Rockville, MD 20852-1790, USA, which is updated continuously on the Internet. Pharmaceutical and diagnostic agents or compounds can be prepared by mixing with acceptable carriers, vehicles or stabilizers, as, for example, vacuum-frozen powders, heterogeneous solutions, aqueous solutions or particulate solutions (e.g., Hardman et al. (2001), Pharmacological Basis of Therapeutics, Osgoodman and Gilman, McGraw-Hill, New York, NY, Gennaro, (2000), Remington: Science and Practice of Pharmacy, Lippincott, Williams, and Wilkins, New York, NY, Avis, et al. (eds.) (1993) Pharmaceutical Dosage Forms: Non-Oral Therapy, Marcel Dekker, New York, Lieberman, et al. (eds.) (1990), Pharmaceutical Dosage Forms: Tablets, Marcel Dekker, New York, Lieberman, et al. (eds.) (1990), Pharmaceutical Dosage Forms: Dispersed Systems, Marcel Dekker, New York, See Weiner and Katkasky (2000) Toxicity and Safety of Carriers, Marcel Dekker Co., New York, NY). In another embodiment, a composition comprising an antibody or antibody component as disclosed herein is administered to a patient according to the Physicians' Desk Reference 2017 (Thomson Health & Medicine, 75th ed., (November 1, 2002)). The mode of administration of the drug can vary. Suitable routes of administration of the drug are preferably parenteral or subcutaneous. Other routes of administration of the drug can include oral, transmucosal, intradermal, direct intraventricular, intravenous, intranasal, inhalation, inhalation into the lungs, or intra-arterial. In certain embodiments, the anti-FXI antibody or antigen-binding fragment thereof can be administered to a patient by a route of administration, such as injection. In other embodiments of the invention, the anti-FXI antibody or antigen-binding fragment thereof, or pharmaceutical compositions thereof, can be administered to a patient intravenously, subcutaneously, intrathecally, or by delivery by inhalation, dusting. Administration of the drug by non-invasive methods (e.g., orally, e.g., in a tablet, capsule, or pill) is also within the scope of the invention. The compositions can be administered by medical devices known in the art. For example, a pharmaceutical composition of the invention can be administered to a patient by injection with a hypodermic needle, including, for example, a prefilled syringe or an autoinjector. The pharmaceutical compositions disclosed herein can also be administered by a needleless subcutaneous injection device, such as those disclosed in U.S. Patent Nos. 6,620,135; 6,096,002; 5,399,163; 5,383,851; 5,312,335; 5,064,413; 4,941,880; 4,790,824; or 4,596,556. The pharmaceutical compositions disclosed herein can also be administered by spraying or diffusion. Examples of known implantable modules or devices for administering pharmaceutical compositions include: U.S. Patent No. 4,487,603, which discloses a micro-dispenser pump for dispensing a drug at a controlled rate; U.S. Patent No. 4,447,233, which discloses a drug injection pump for delivering a drug at a precise injection rate; U.S. Patent No. 4,447,224, which discloses a variable flow rate implantable injection device for continuous drug delivery; and U.S. Patent No. 4,439,196, which discloses an osmotic or osmotic drug delivery system having multi-compartment compartments. Many other such delivery systems, and implantable or graftable modules are well known to those skilled in the art. The drug regimen for administering the drug depends on several factors, including the serum or tissue circulating rate of the therapeutic antibody, the level of symptoms, the extent of the therapeutic antibody's ability to elicit an immune response, and the availability of target cells in the biological compartment. Preferably, the drug regimen for administering the drug delivers a sufficient amount of the therapeutic antibody to the patient to have an ameliorating effect on the target disease state, while simultaneously minimizing undesirable side effects. Consequently, the amount of biological drug delivered depends to some extent on the therapeutic antibody being administered and the severity of the condition being treated.Guidance in selecting appropriate doses of therapeutic antibodies in (e.g., Warzynczek (1996), Antibody Therapy, Society for Biological Sciences Press, Ltd., England, Krasina (editor) Monoclonal Antibodies, Cytokines, and Osteoarthritis, Marcel Dekker, New York, NY, Buck (editor) (1991) Monoclonal Antibodies and Peptide Therapy in Immune Disorders, Marcel Dekker, New York, NY, Baert, et al., (2003) New England Journal of Medicine, 348: 601-608; Milgram et al. (1999) New England Journal of Medicine, 341: 1966-1973; Islamon et al. (2001), New England Journal of Medicine, 344: 783-792; Benjaminowitz et al. (2000), New England Journal of Medicine New England Journal of Medicine, 342: 613-619; Gash et al. (2003) New England Journal of Medicine, 348: 24-32; Lipsky et al. (2000) New England Journal of Medicine, 343: 1594-1602). Dosage regimens are adjusted to provide the most optimal and desirable response (e.g., a therapeutic response). For example, a single large tablet may be administered, multiple divided doses may be administered over time, or the dose may be increased or decreased as appropriate, depending on the emergent indications of the therapeutic condition. In particular, it is advantageous to formulate non-edible compositions in dosage unit form for convenience of administration and uniformity of dosage. Dosage unit form, as used herein, refers to physically discrete units suitable as unitary dosages for the individual to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with a pharmaceutically acceptable carrier.The specifications of the dosage unit forms described herein are directly dependent on and dictated by (a) the unique properties of the antibody or antigen-binding moiety and the particular therapeutic effect to be achieved, and (b) the inherent limitations of the science or art of making compounds, such as active molecules for treating allergies in individuals. (e.g., Yang and Sarin, (2003), New England Journal of Medicine, 349: 427-434; Herold and Sarin, (2002), New England Journal of Medicine, 346: 1692-1698), Liu and Sarin (1999) Journal of Psychology, Neurosurgery and Neurology, 67: 451-456; Portilji et al., (2003) Cancer Immunotherapy and Immunology, 52: 133-144). Required supplies Other objects provided are kits comprising one or more components, including, but not limited to, an anti-FXI antibody or antigen-binding moiety, as discussed herein, in combination with one or more other components, including, but not limited to, another therapeutic agent, as discussed herein. The antibody or moiety or therapeutic agent can be formulated and combined into a pharmaceutical composition as a pure composition or in combination with a pharmaceutically acceptable carrier. In one embodiment, the kit comprises an anti-FXI antibody or antigen-binding fragment thereof or a pharmaceutical composition thereof in one container (e.g., in a sample vial or a sterile plastic sample container) and another therapeutic agent in another container (e.g., in a sample vial or a sterile plastic sample container). In another embodiment, the kit comprises a composition of the invention comprising an anti-FXI antibody or antigen-binding fragment thereof or a pharmaceutical composition thereof in combination with one or more other therapeutic agents, optionally formulated in a pharmaceutical composition and in a common excipient. If the kit includes a pharmaceutical composition for non-oral administration to a patient, the kit can include a device for carrying out such administration. For example, the kit can include one or more hypodermic needles or other injection devices as discussed above. Thus, the present invention includes kits as needed that contain an injection device and an anti-FXI antibody or antigen-binding moiety thereof, for example, where the injection device includes the antibody or its conjugate or where the antibody or its conjugate is in a separate container. The device may include an instruction manual or guide that includes information about the drug ingredients and dosage forms contained in the device. In general, such information assists patients and physicians in the effective and safe use of the drug ingredients and dosage forms provided. For example, the following information about a device of the invention may be included in the instruction manual or guide: drug kinetics, drug effects on the structure of living organisms, clinical studies, efficacy parameters, overdose, appropriate dosage and administration, method of supply, appropriate storage conditions, references, manufacturer / distributor information, and patent information. Methods for making antibodies and components that can be linked to their antigens The anti-FXI antibodies and antigen-binding fragments thereof disclosed herein can also be produced genetically engineered. In this embodiment, the nucleic acids encoding the antibody molecules can be injected into a carrier (plasmid or viral) and virally transfected or transferred to a host cell, where they can be expressed and secreted from the host cell. There are several methods for producing genetically engineered antibodies that are known in the art. Mammalian cell lines that are available as hosts for expression of the antibodies or components disclosed herein are well known in the art and include many immortalized cell lines available from the American Type Culture Collection (ATCC). Among others, these include Chinese hamster ovary (CHO) cells, NSO, 2SP cells, HeLa cells, baby hamster kidney (BHK) cells, monkey kidney (COS) cells, human liver cancer cells (e.g., 2HEP G), 549A cells, 3T3 cells, human embryonic kidney (293-HEK) cells, and a number of other cell lines. Cell lines that are of particular advantage are selected by determining which cell lines have higher expression levels.Other cell lines that may be used include insect cell lines, such as 9SF cells, amphibian cells, bacterial cells, plant cells, filamentous fungal cells (e.g., Trichoderma reisi), and yeast cells (e.g., Saccharomyces cerevisiae or P. pasteuriza). In particular aspects, the host cell can be a prokaryotic host cell, such as E. coli. When recombinant gene expression vectors comprise a nucleic acid molecule encoding the heavy chain or antigen-binding portion or component thereof, and the light chain or antigen-binding portion thereof are introduced into host cells, antibodies are produced by culturing the host cells under conditions and for a period of time sufficient to allow expression of the antibody in the host cells or, more conveniently, secretion of the antibody into the culture medium in which the host cells are grown. The antibodies can be recovered from the culture medium and then purified or processed to produce the antibodies of the invention. In particular aspects, host cells are transfected with an expression vector comprising a nucleic acid molecule encoding a heavy chain and a light chain, comprising at least the heavy and light chains of the CDRs of an anti-FXI antibody of the P18611-αFXI family, the 18611-αFXI family, or the P18623-αFXI family or embodiments thereof, wherein one or more of the CDRs has one, two, or three amino acid substitutions, additions, or deletions, or a combination thereof, and, wherein the heavy chain or light chain variable framework region comprises 9, 8, 7, 6, 5, 4, 3, 2, 1, 0, or 10 amino acid substitutions, additions, or deletions, or a combination thereof. In particular aspects, host cells are provided with a first expression vector, which comprises a nucleic acid molecule encoding a heavy chain and comprising at least the heavy chain CDRs of an anti-FXI antibody of the P18611-αFXI family, the 18611-αFXI family, or the P18623-αFXI family or embodiments thereof, wherein one or more of the six CDRs has one, two or three amino acid substitutions, additions, or deletions or a combination thereof, and, wherein the heavy chain or light chain framework variable region comprises 9.8.7.6.5.4.3.2.1.0 or 10 amino acid substitutions, additions, or deletions or a combination thereof, and a second expression vector, which comprises a nucleic acid molecule encoding a light chain and comprising at least the light chain CDRs of an anti-FXI antibody of the P18611-αFXI family, the 18611-αFXI family, or the P18623-αFXI family or embodiments thereof, in which one or more of the six CDRs has one, two, or three amino acid substitutions, additions, or deletions or a combination thereof, or in which the heavy chain or light chain variable framework region comprises 9,8,7,6,5,4,3,2,1,0 or 10 amino acid substitutions, additions, or deletions or a combination thereof. In certain embodiments, the heavy chain and light chain are expressed as a fusion protein in which the N-termini of the heavy chain and the light chain are linked to a leader or conductor sequence to facilitate transport of the antibody through the secretory or efflux pathway. Examples of leader sequences that can be used include MSVPTQVLGLLLLWLTDARC (SEQ ID NO: 14) or MEWSWVFLFFLSVTTGVHS (SEQ ID NO: 15). The heavy chain of the antibody of the example herein can be encoded by a nucleic acid molecule having the nucleotide sequence shown in the sequence identification numbers: 78, 76, 74, 72, 70, 68, 66, 64, 62, 60, 58, 56, 54, 52, 50, 48, 46, 44, 42, 40, 38, 36, 34 or 80. The light chain of the antibody of the example herein can be encoded by a nucleic acid molecule having the nucleotide sequence shown in SEQ ID NOS: 27 or 32. In addition, the present invention provides a plasmid vector (Plasmids are circular double-stranded DNA molecules that are different from chromosomal DNA. They are usually found in bacteria and sometimes in eukaryotic organisms. Their size varies from 1 to over 400 kbp—translator's explanation) or a virus that comprises a nucleic acid molecule having the amino acid sequence shown in the sequence ID numbers: 78, 76, 74, 72, 70, 68, 66, 64, 62, 60, 58, 56, 54, 52, 50, 48, 46, 44, 42, 40, 38, 36, 34 or 80. In addition, the present invention provides a plasmid or viral vector comprising a nucleic acid molecule encoding the heavy chain of an anti-FXI antibody of a P18611-αFXI family, a 18611-αFXI family, or a P18623-αFXI family, or embodiments thereof, wherein one or more CDRs have one, two, or three amino acid substitutions, additions, or deletions, or a combination thereof, or wherein the heavy chain or light chain variable framework region comprises 9.8.7.6.5.4.3.2.1.0 or 10 amino acid substitutions, additions, or deletions or combinations thereof, and a nucleic acid molecule encoding the light chain of an anti-FXI antibody of the P18611-αFXI family, the 18611-αFXI family, or the P18623-αFXI family, or embodiments thereof, wherein one or more of the six CDRs have one, two, or three amino acid substitutions, additions, or deletions or combinations thereof, or wherein the heavy chain or light chain variable framework region comprises 9,8,7,6,5,4,3,2,1,0 or 10 amino acid substitutions, additions, or deletions or combinations thereof. Furthermore, the present invention provides a plasmid or viral vector comprising a nucleic acid molecule encoding the heavy chain of an anti-FXI antibody of the P18611-αFXI family, the 18611-αFXI family, or the P18623-αFXI family, and a plasmid or viral vector comprising a nucleic acid molecule encoding the light chain of an anti-FXI antibody of the P18611-αFXI family, the 18611-αFXI family, or the P18623-αFXI family.In addition, the present invention provides a host cell comprising one or more plasmid or viral vectors comprising a nucleic acid molecule encoding the heavy chain of an anti-FXI antibody of a P18611-αFXI family, a 18611-αFXI family, or a P18623-αFXI family, or embodiments thereof, wherein one or more CDRs have one, two, or three amino acid substitutions, additions, or deletions, or a combination thereof, or wherein the heavy chain or light chain variable framework region comprises 9,8,7,6,5,4,3,2,1,0 or 10 amino acid substitutions, additions, or deletions, or a combination thereof, and a nucleic acid molecule encoding the light chain of an anti-FXI antibody of a P18611-αFXI family, a 18611-αFXI family, or embodiments thereof, wherein one or more CDRs have one, two, or three amino acid substitutions, additions, or deletions, or a combination thereof, and 18611-αFXI, or the P18623-αFXI family, or embodiments thereof, wherein one or more of the six CDRs have one, two, or three amino acid substitutions, additions, or deletions, or a combination thereof, or wherein the heavy chain or light chain framework variable region comprises 9.8.7.6.5.4.3.2.1.0 or 10 amino acid substitutions, additions, or deletions, or combinations thereof. In particular embodiments, the host cell is a host cell from a Chinese hamster ovary (CHO) cell or a human embryonic kidney 293 cell. Proteins can be recovered from the culture medium using standard protein purification methods. In addition, expression of the antibodies of the invention (or other identical moieties thereof) from cell lines can be enhanced using a number of well-known techniques. For example, the glutamine synthetase gene expression system (GS system) is a common method for enhancing expression under certain conditions. In general, glycoproteins produced in a particular cell line or polygenic animal will have a polyprotein production pattern that is specific to the glycoproteins produced in the cell line or polygenic animal (see, e.g., Krast et al., Biotechnology Journal, 161: 336-348 (2012)). Thus, the particular pattern of an antibody will depend on the particular cell line or polygenic animal used to produce the antibody. However, all antibodies encoded by the nucleic acid molecules provided herein, or comprising the amino acid sequences provided herein, are within the scope of the present invention, regardless of the glycoprotein production pattern that the antibodies may have. The following examples are intended to enhance a further understanding of the present invention. General methods Standard methods in molecular biology are described in (Sambrook, Fritich, and Maniatis (1982 and 1989, 2nd ed., 2001, 3rd ed.), Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Laboratory Press, New York; Sambrook and Rachel (2001), Molecular Cloning, 3rd ed., Cold Spring Harbor Laboratory Press, New York; Woo (1993), Engineered DNA, Vol. 217, Academic Press, San Diego, California). Also standard methods are in (Ausbel et al. (2001) Current Treatises in Molecular Biology, Vols. 1-4, John Wiley & Sons, Inc.).Sons, New York, NY), which describes cloning in bacterial cells and DNA mutagenesis (Volume 1), cloning in mammalian cells and yeast (Volume 2), glycoprotein fusion and protein expression (Volume 3), and bioinformatics (Volume 4). Methods for protein purification, including antibody and antigen precipitation, chromatography, electrophoresis, centrifugation, and crystallization, have been described (Cleggan et al. (2000) Current Transactions in Protein Science, Vol. 1, John Wiley & Sons, New York. Chemical analysis, chemical modification, pretranslational modification, production of fusion proteins, and production of polycoproteins from proteins have been described (see, for example, Cleggan et al. (2000) Current Transactions in Molecular Biology, Vol. 3, John Wiley & Sons, New York, NY, pp. 16.0.5–16.22.17; Sigma-Aldrich (2001), Products for Life Sciences Research, St. Louis, MO; pp. 45–89; Amersham Pharmaceutical Biotechnology (2001), BioDirectory, Piscataway, NJ, pp. 384–391).The production, purification, and analysis of polyclonal and monoclonal antibodies have been described (Cleggan et al., (2001) Current Trends in Immunology, Vol. 1, John Wiley & Sons, New York; Harlow and Lane (1999) Use of Antibodies, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York; see Harlow and Lane, supra). Standard techniques for the detection of active and inactive ligand / receptor interactions are available (see, for example, Cleggan et al., (2001) Current Protocols in Immunology, Vol. 4, John Wiley & Sons, New York). Monoclonal, polyclonal, and humanized antibodies can be prepared (e.g., Shepherd and Dean (eds.) (2000), Monoclonal Antibodies, Oxford University Press, New York, NY; Kanterman and Doble (eds.) (2001), Antibody Engineering, Cold Spring Harbor Laboratory Press, New York, pp. 139–243; Carpenter et al. (2000), 274:27371–27378; Baca et al. (1997), Journal of Biological Chemistry, 272:10678–10684; Shasaya et al. (1989), Nature, 342:877–883; Foote and Winter (1992) Journal of Molecular Biology, 224:487–499; U.S. Patent No. See United States, No. 6,329,511). An alternative to humanization or human adaptation is the use of human antibody libraries or banks displayed in xenobiotic or humanized libraries in polygenic mice (Wagan et al., (1996), Nature Biotechnology, 14: 309–314; Barbas (1995), Nature Medicine, 1: 837–839; Mendez et al., (1997), Nature Genetics, 15: 146–156; Hoogenboom and Kams (2000), Immunology Today, 21: 371–377; Barbas et al., (2001), Xenobiotic Display: A Laboratory Guide, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Kay et al. (1996) Xenobiotic Display of Peptides and Proteins: A Laboratory Guide, Academic Press, San Diego, CA, De Bruin et al., (1999), Nature Biotechnology, 17: 397- 399). Antibodies can be conjugated, for example, to small drug molecules, enzymes, liposomes, and polyethylene glycol (PEG). Antibodies are useful for therapeutic, diagnostic, delivery, or other purposes, and include antibodies conjugated to, for example, dyes, radioisotopes, enzymes, or metals, for example, colloidal gold (see, for example, Dussal et al., (1991), Journal of Immunology, 146: 169-175; Gibellini et al., (1998), Journal of Immunology, 160: 3891-3898; Hessing and Bishop (1999), Journal of Immunology, 162: 2804-2811; Evertz et al., (2002), Journal of Immunology, 168: 883-889). Methods for flow cytometry, including fluorescence-activated cell sorting (FACS), are available (see, for example, Owens et al., (1994), Principles of Flow Cytometry for Clinical Laboratory Applications, John Wiley & Sons, Hoboken, NJ; Givan (2001), Flow Cytometry, 2nd ed.; Wiley-Lee, Hoboken, NJ; Shapiro (2003), Applied Flow Cytometry, John Wiley & Sons, Hoboken, NJ). Fluorescent reagents suitable for modifying nucleic acids, including primers or nucleic acid starting strands and probes, polypeptides, and antibodies, are available for use as, for example, diagnostic reagents (Molecular Probes Catalog (2003), Molecular Probes Inc., Eugene, OR; Sigma-Aldrich Catalog (2003), St. Louis, MO). Standard methods of histology of the immune system are described (see, for example, Müller-Harmlink (eds.) (1986), The Human Thymus: Histology and Pathology, Springer Verlag, New York, NY; Hyatt et al., (2000), Color Atlas of Histology, Lippincott, Williams, & Wilkins, Phila., PA; Lewis et al., (2002), Basic Histology: Histology and Atlas, McGraw-Hill, New York, NY). Software packages and databases are available for determining, for example, antigenic components, leader sequences, final protein conformation, essential domains, glycoprotein production sites, and sequence regulation (e.g., GeneBank, NTI Carrier Software (Informex, Bethesda, MD); GCG Viscosine Package (Excelris, San Diego, CA); D-Cypher (Time Logic, Crystal Bay, NV; Mann et al., (2000) Bioinformatics 16: 741–742; Mann et al., (2000) Bioinformatics Application Note, 16: 741–742; Ren et al., (2002) Biomedical Methods Computer Program, 68: 177–181; von Heijen (1983) European Journal of Biochemistry, 133: 17–21; von Heijen (1986) Nucleic Acids Research, 14: 4683-4690). Human FXI and FIX zymogens can be obtained from Hematology Technologies, Essex Junction, VT; high molecular weight (HMW) kinogen can be obtained from Enzyme Research Laboratories, South Bend, IN; and ellagic acid can be obtained from Pacific Hematology, ThermoFisher, Waltham, MA. Example 1 In this example, the binding kinetics of anti-FXI antibodies LC / (105L)(1E)(P228S) HC 4LGg 18611- αFXI / / kappa light chain and LC / (1Q)( P228S) HC 4LGg P 18623 αFXI / kappa light chain to both human FXI zymogen and non-human primate (NHP) FXI zymogen were measured using the following assay. Human FXI / FXIa binding kinetics assay protocol Essentially, the binding and adsorption kinetics of the protein-protein interaction between anti-FXI antibodies and FXI or FXIa zymogen were performed using ProteOn XPR36 (Bio-Rad), an SPR (surface plasmon resonance)-based optical biosensor, as follows. A low-density GLC sensor chip was completely washed with 0.5% sodium dodecyl sulfate, 50 mM sodium hydroxide, and 100 mM hydrochloric acid for 60 seconds at a flow rate of 30 µL / sec, through the vertical and horizontal flow channels. The alginate chip surface was then activated for all six vertical flow channels (6L - 1L) with 1 x EDC / sNHS at a flow rate of 30 µL / sec for 150 seconds. A mouse Fc-biased polyclonal anti-human IgG antibody (capture antibody) was diluted to 1.25 µg / mL in 10 mM sodium acetate, pH 5.0, and then injected into all six horizontal flow channels for 300 s at a flow rate of 25 uL / sec to bind approximately 300 reaction units (RU) of the capture antibody to the activated surface of the chip in each flow channel by amine coupling to the internal lysine. Next, 1 M ethanolamine HCl was injected into all six flow channels to inactivate any remaining reactive amines on the surface. Anti-FXI antibodies were then infused at a rate of 25 µL / min for 60 s at a concentration of 5 µg / mL in 10 mM sodium acetate, pH 0.5 into a separate flow channel containing capture antibody (5 µL, 4 µL, 3 µL).2L or 6L) were injected to achieve saturated capture levels approximately equal to 80 RU; a 1 L vertical gerial channel was injected with 10 mM sodium acetate, pH 5.0 (buffer only), as a reference control. After capturing the anti-FXI antibodies, the mobile buffer (4.7 pH.20% 005 / 0.2 mM CaCl5.n-1) was injected into all horizontal flow channels (A1-A6) for 5 min and allowed to elute for 20 min at 25 µL / min to remove any non-selectively bound anti-FXI antibodies from the chip surface. Then, to measure the binding rate (Ka) of human FXI or FXa to the anti-FXI antibodies, a titration of 6-fold of human FXI or FXIa (Nm0.4,0.2,0.1,5.0,25.0, 0 diluted in running buffer) was injected horizontally onto all six vertical channels for 8 min; then the bound zymogen was allowed to dissociate in running buffer for 60 min at a flow rate of 25 µL / min to measure the efflux rate (Kd). Binding and gravimetric kinetics (KD) were determined using the instrument-specific software (Bio-Rad), as shown in Table 2. Kinetic assay protocol for FXIa / FXI zymogen binding in non-human ancestors The binding kinetics and active adsorption and protein-protein interactions between anti-FXI antibodies and FXI zymogen or FXIa from non-human primates (NHP: cynomolgus and rhesus) were determined using ProteOn XPR36 (Bio-Rad), an SPR (surface resonance amplification)-based optical biosensor. A low-density GLC sensor chip was rinsed with 0.5% sodium dodecyl-disulfate, 50 mM sodium hydroxide, and 100 mM hydrochloric acid for 60 seconds at a flow rate of 30 µL / sec on all vertical and horizontal flow channels. The alginate chip surface was activated with 1 EDC / sNHS on all six flow channels (6L-1L) at a flow rate of 30 µL / sec for 150 seconds. A mouse Fc-biased anti-human IgG polyclonal antibody (capture antibody) was diluted to 30 µg / mL in 1 mM sodium acetate, pH 0.5, and then injected into all six horizontal flow channels for 150 s at a flow rate of 25 µL / sec to allow approximately 4500 reaction units (RU) of the capture antibody to bind to the activated surface of the chip in each flow channel by amine coupling to the internal lysine. Then, 1 M ethanolamine HCl was injected into all six flow channels to neutralize or inactivate any remaining reactive amines on the surface. Then, anti-FXI antibodies were added at a rate of 25 µL / min for 60 seconds at a concentration of 0.415 µg / mL in running buffer (4.7 pH.20% P0.005 / 0.2 mM CaCl5.n-1), into a separate vertical flow channel that was filled with capture antibody (5 µL.4 µL.3L, 2L, or 6L) were injected to achieve saturated capture levels approximately equal to 40 RU; the 1L vertical flow channel was injected with running buffer alone as a reference control. After capture of anti-FXI antibodies, running buffer was injected into all horizontal flow channels (6A-1A) for 5 min and allowed to elute for 20 min at 25 µL / min to remove any non-selectively bound anti-FXI antibodies from the chip surface. Then, to measure the binding rate (Ka) of non-human primate (NHP) FXI to anti-FXI antibodies, a 6-point titration of FXI or NHP FXIa (0.4, 0.2, 0.1, 5.0, 25.0 Nm diluted in running buffer) was injected horizontally into all six vertical channels for 8 min; The zymogen conjugated to FXI or FIXa was then allowed to dissociate for 60 min in mobile buffer at a flow rate of 25 µL / min to measure the efflux rate (Kd). The binding kinetics and affinity (KD) were determined using the instrument-specific software (Bio-Rad). The results are shown in Table 2. Table 2 Binding of P18623-αFXI and mAb 18611-αFXI to FXI / XIa Target N Mean FXI KD ± SD pM Mean FXIa KD ± SD pM 18611-αFXI P18623-αFXI 18611-αFXI P18623-αFXI Human 3 38 ± 100 22.6 ± 2.2 55.4 ± 12.2 37.4 ± 10.4 Cynomolgus monkey 3 70 ± 180 13.0 ± 5.7 89.2 ± 10.4 19.5 ± 0.6 Rhesus monkey 3 52.9 ± 9.6 72.2 ± 31.7 175 ± 62.6 149 ± 3.8 18611- = LC / (105L)(1E)(P228S) HC 4LGg 18611- αFXI / ) / kappa light chain P18623-αFXI = LC / (1Q)( P228S) HC 4LGg P 18623 αFXI / kappa light chain Example 2 Effect of anti-FXI antibodies on the activation of FXI to FXIa by FXIIa in the presence of high molecular weight (HMW) kininogen and ellagic acid To measure the effects of anti-FXI antibodies LC / (105L)(1E)(P228S) HC 4LGg 18611- αFXI / / kappa light chain and LC / (1Q)( P228S) HC 4LGg P 18623 αFXI) / kappa light chain on FXI zymogen activation, dual enzyme assays that measure the cleavage of a tripeptide fluorophore (GPR-AFC) can be used to determine whether the antibodies themselves inhibit FXI activation. For these assays, anti-FXI antibodies were preincubated or treated with FXI zymogen for 1 h. FXI activation to FXIa is induced by adding FXIIa in the presence of an HMW kininogen and ellagic acid. The catalytic activity of FXIa on the tri-peptide fluorophore substrate is then measured as an indication of zymogen activation. A duplicate assay is also performed as a control in the absence of HMW kininogen.An 11-point titration of anti-FXI antibodies starting at a concentration of 1 µM was performed with a 3-fold dilution sequence, with human FXI (Hematology Technologies, Inc., Cat # HCXI-0150, final concentration NM30) and a HMW kininogen (Enzyme Research Laboratories, Cat # HK, final concentration 280 nM). 4.7 pH and 8000-PEG% 1.0.2 mM CaCl 5 mM, 150 mM NaCl, 150 mM HEPES were pre-treated for 2 hours at 25°C in a Corning 3575 non-crosslinkable surface microplate. The activation reaction was then initiated by adding Pacific Hematology APTT-XL reagent containing ellagic acid (ThermoFisher Sciences, Cat # 100403, initial concentration 100 µM, final concentration 2 µM) and freshly diluted coagulation factor XIIa (Enzyme Research Corporation, Cat # HFXIIa, final concentration, Pm50). The reaction was continued for 1 hour at 25°C and then quenched by the addition of 1 µM corn trypsin inhibitor (Hematology Technologies, Cat # CTI-01). The newly activated FXIa enzymatic activity was detected by measuring the dissociation rate of the Z-GPR-AFC substrate by continuous fluorescence monitoring at 400 / 505 nm for 10 min using a Tecan Infinite M 200 plate reader (Sigma, MG 10-0980 Cat # C, final concentration 150 µM).The percent inhibition for each data point was recalculated from the RFU / min data and analyzed using GraphPad Prism software by solving the four-parameter equation of log(inhibitor) versus reaction. The results are shown in Table 3. Activation of FXI to FXIa by FXIIa in the absence of HMW kininogen and ellagic acid Dose titrations of 11 anti-FXI antibodies of this invention, starting at a concentration of 1 µM with a 3-fold dilution sequence, were pretreated with human FXI (Hematology Technologies, Inc., Cat # HCXI-0150, final concentration 30 nM) in 4.7 pH and 8000-PEG% 1.0.2 mM CaCl, 5 mM NaCl, 150 mM HEPES for two hours at 25°C in a Corning 3575 non-crosslinkable surface microplate. The activation reaction was then initiated by the addition of freshly diluted factor XIIa coagulation reagent (Enzyme Research, Inc., Cat # HFXIIa, final concentration, 15 nM). The reaction was continued for 1 h at 25°C until quenched by the addition of 1 µM of corn trypsin inhibitor (Hematology Technologies, Cat # CTI-01). The newly activated FXIa enzymatic activity was detected by measuring the rate of dissociation of the Z-GPR-AFC substrate (Sigma, MG 10-0980 Cat # C, final concentration 150 µM) by continuous monitoring of fluorescence at 400 / 505 nm for 10 min using a Tecan Infinite M 200 plate reader.The percent inhibition for each data point was recalculated from the RFU / min data and analyzed using the four-parameter log(inhibitor) versus reaction equation solution with GraphPad Prism software. The results are shown in Table 3. Table 3 Effect of P18623-αFXI and 18611-αFXI on FXI activation by FXIIa Antibody N FXIIa Activation + HK Inhibition (IC 50 , nM) FXIIa HK Activation without inhibition (IC 50 , nM) 18611- αFXI 3 7 . 6 ± 3 . 5 34 ± 20 P18623-αFXI 3 6 . 0 ± 1 . 1 14 ± 9 . 5 18611- = LC / (105L)(1E)(P228S) HC 4LGg 18611- αFXI / ) / kappa light chain P 18623- αFXI = LC / (1 Q )( P 228 S ) HC 4 LGg P 18623 αFXI / kappa light chain ± SD, n=3 Data are given as mean IC 50 Together, these mechanistic theories demonstrate that these anti-FXI antibodies essentially neutralize FXI by preventing FXI activation by FXIIa and by inhibiting the catalytic activity of FXIa on the native substrate. Example 3 Epitope mapping of anti-FXI antibodies by hydrogen deuterium exchange mass spectrometry The contact sites of / (105L)(1E)(P228S) HC 4LGg 18611 / kappa light chain and αFXI- / (1Q)( P228S) HC 4LGg P 18623 αFXI / kappa light chain to human FXI were determined using hydrogen deuterium exchange mass spectrometry (HDX-MS). HDX-MS measures the amount of deuterium incorporation into the protein amide backbone and the changes induced by hydrogen solvent irradiation. A comparison of the deuterium exchange levels in antigen-only and antibody-only samples was performed to identify regions that may be in contact with the antibody. Human factor XI has the amino acid sequence shown in SEQ ID NO: 81. The factor XI dinucleotide was pretreated with antibodies before being incubated in deuterium buffer. The contribution of deuterium to factor XI was measured by mass spectrometry. The regions of human factor XI that were protected from deuterium entry are the A-epitope DIFPNTVF (factor XI residues 185–192; SEQ ID NO: 82) and the B-epitope PSTRIKKSKALSG (factor XI residues 247–259; SEQ ID NO: 83). Figures A3 and B3 show heat maps of the difference in deuterium incorporation of factor XI amino acid residues bound by the antibodies / (105L)(1E)(P228S) HC 4LGg 18611 / kappa light chain and LC / (1E)( P228S) HC 4LGg P 18623 αFXI / kappa light chain, respectively. These amino acid sequences are located in the apple 3 domain of factor XI (Figure 2). No significant changes were observed upon deuterium incorporation in the Sib 1, 2, 4, or catalytic domains, indicating that they are not involved in the binding of 18623 αFXI. Therefore, the epitope recognized by / (P228S)HC 4LGg P 18623 αFXI / kappa light chain consists of epitope A and epitope B. Example 4 FIX is an intrinsic protein substrate of FXIa, the active protease of the FXI zymogen. FXIa activates FIX to FIXa, which perpetuates the coagulation cascade. Inhibition of FIX activation by FXIa is a potential mechanism of action (MOA) for FXI mAbs. To investigate this mechanism of action, FXIa enzymatic assays were performed using the full-length zymogen. FXIa protease acts on a small tripeptide substrate. Anti-FXI antibodies were pre-treated with human FXIa (Sexio's Dysfunction, Exten, PA, Cat # 4011A, final concentration PM100) in 4.7 pH and 8000%-PEG 1.0.2 mM CaCl5, 150 mM NaCl, 50 mM HEPES50 for two hours at 25°C in Corning 3575 non-crosslinkable microplates. FXIa enzymatic activity was detected by continuous fluorescence monitoring at 400 / 505 nm for 10 minutes using a Tecan Infinite M 200 microplate reader, by measuring the dissociation rate of the Z-GPR-AFC substrate (Sigma, MG-0980 Cat # C, final concentration µM100). The final concentration of the titration dose of 11 antibodies was started with a 3-fold dilution series from 1 µM. The percent inhibition for each data point was recalculated from the RFU / min data and analyzed using a four-parameter log(inhibitor) versus reaction equation solution with GraphPad Prism software. The results are shown in Table 4. Activation of FIX to FIXa by FXIa FIX is an intrinsic protein substrate of FXIa, the active protease of the FXI zymogen. FXIa activates FIX to FIXa, which perpetuates the coagulation cascade. Inhibition of FIX activation by FXIa is a potential mechanism of action for FXI mAbs. To investigate this mechanism of action, FXIa enzymatic assays were performed using the full-length zymogen. Dose titrations of 11 anti-FXI antibodies, starting at 1 µM with a 3-fold dilution sequence, were pretreated with human FXIa (Sexio Defect, Cat # A4011, final concentration PM100) in pH 4.7 and 1.0.2 mM CaCl 5 mM, 150 mM NaCl, 50 mM HEPES 8000%-PEG for 2 h at 25°C in a Corning 3575 non-binding microplate. The activation reaction was then initiated by the addition of FIX (Hematology Technologies, Cat # HCIX-C-0040, final concentration, 300 nm). The reaction was continued for 1 h at 25°C until quenched by the addition of 100 nM of anti-FXI antibody directed to the catalytic region on the FXI light chain (anti-FXI antibody 04H-007W-D076, reported in WO 21316766). The newly activated FXIa enzymatic activity was detected by measuring the rate of dissociation of the GGR-AFC-cyclohexyl substrate (CPC Sciences, Cat # 839493, final concentration 300 µM) by continuous monitoring of fluorescence at 505 / 400 nm for 10 min using a Tecan Infinite M 200 plate reader.The percent inhibition for each data point was recalculated from the RFU / min data and analyzed using the four-parameter log(inhibitor) versus reaction equation solution with GraphPad Prism software. The results are shown in Table 4. Table 4 Effect of P18623-αFXI and 18611-αFXI on the catalytic activity of FXIa antibody N FXIa IC 50 nM (tripeptide sublayer) FXIa IC 50 nM (native full-length sublayer) 18611-αFXI 3 > 1000 1.0 ± 0.3 P18623-αFXI 3 > 1000 0.4 ± 0. 2 18611- = LC / (105L)(1E)(P228S) HC 4LGg 18611- αFXI / ) / kappa light chain P18623-αFXI = LC / (1Q)( P228S) HC 4LGg P 18623 αFXI / kappa light chain Data are given as mean ±SD, n= 3 IC 50 As shown in Table 4, the antibodies did not inhibit the catalytic function of FXIa in an enzymatic assay using a synthetic tripeptide fluorophore substrate, but both antibodies were potent inhibitors in an assay using the native full-length substrate. These data are consistent with the antibodies acting as allosteric, i.e. competitive inhibitors of FIX activation by FXIa, and with the epitope mapping results from Example 3, which indicate that the “footprints” of the antibodies on the apple 3 domain overlap with the FIX-binding exons of FXIa. Example 5 Autoactivation of FXI to FXIa in dextran sulfate Dose titrations of 11 anti-FXI antibodies of this invention, starting at a concentration of 1 µM with a 3-fold dilution sequence, were pre-treated with human FXI (Hematology Technologies, Inc., # 0150-hcxi cat, final concentration 30 nM) in pH 7 and 1% PEG-8000. 0.2 mM CaCl 5 mM, 150 mM NaCl, 50 mM HEPES for two hours at 25°C in a Corning 3575 non-crosslinkable surface microvessel. The auto-activation reaction was then initiated by the addition of dextran sulfate (acros, # 433240250 cat, approximate MW, 800 kDa, final concentration, 1 nM). The reaction was continued for 1 h at 25 °C until the newly activated FXIa enzymatic activity was detected by measuring the dissociation rate of the Z-GPR-AFC substrate (Sigma, MG 10-0980C #CAT, final concentration 150 µM) by continuous fluorescence monitoring at 400 / 505 nm for 10 min using a Tecan Infinite 200 µm laboratory plate reader.The percent inhibition for each data point was recalculated from the RFU / min data, and analyzed using the four-parameter log(inhibitor) versus reaction equation solution with GraphPad Prism software. The results are shown in Table 5. Table 5 Effect of P 18623-αfxi and 18611-αfxi on FXI autoactivation Antibody N Autoactivation IC 50 nM 18611-αfxi 2 3 . 3 ± 0 . 4 P 18623-αfxi 2 5 . 5 ± 4 . 0 / (105L)(1E)(P228S) HC 4LGg 18611- αFXI / ) / kappa light chain / (1Q)( P228S) HC 4LGg P 18623 αFXI)) / kappa light chain IC 50 are given as mean ±SD, n= 3 Example 6 The ability of anti-FXI antibodies to block blood clotting in vitro has been assessed using the activated partial thromboplastin time (aPTT) test. The activated partial thromboplastin time (aPPT) is a blood coagulation test that measures the activity of the intrinsic and common coagulation pathways. Activated partial thromboplastin time (aPTT) test The test was performed in sodium citrated plasma. Human plasma was obtained by collecting blood from healthy donors of both sexes into citrate tubes (Sarsted coagulation, 10 / nc9 ml). The blood was centrifuged at 1500 xg and the plasma was collected. The aPTT was measured on each donor, and those within the normal range (28–40 seconds) were pooled, divided into two equal parts, and stored at −80°C. Plasma from other species was also obtained commercially (Innovative Research, Novi, MI). Test samples were prepared by injecting inhibitors or carriers into the plasma with a sharp-pointed rod. These samples were incubated or cured on the sharp-pointed rod (60 min, RT) and then analyzed on a coagulation analyzer (Evolution STA-R, Estago Diagnostics, Parsippany, NJ).In general, the analyzer performs the following steps: FXII is activated by the addition of ellagic acid (Pacific Hematology, Thermo Fisher Sciences, Waltham, MA), and then the time required for blood to clot after recalcification of the samples is measured. Inhibition of FXI will prolong the aPTT clotting time. The results are shown in Table 6. Data are reported as the percent increase over the vehicle control clotting time and the concentration control time that causes a 100% (2-fold) or 50% (1.5-fold) increase in time. The aPTT results are shown in Figures 6, 7, 8, 9, and 10. Table 6 Human Antibody Cynomolgus Monkey Rhesus Monkey 2x (nM) 1.5 (nM) 2x (nM) 1.5 (nM) 2x (nM) 1.5 (nM) P 18623-αfxi 24 19 21 15 22 15 18611-αfxi 37 23 218 42 79 22 / (105L)(1E)(P228S) HC 4LGg 18611- αFXI / kappa / (1Q)( P228S) HC 4LGg P 18623 αFXI kappa Example 7 Surface plasmon resonance assay to assess the putative binding of anti-FXI monoclonal antibodies to human and non-human primate (NHP) coagulation cascade proteins. A surface plasmon resonance (SPR) assay (Biacore T200) was used to determine the potential for nonselective interactions of the anti-FXI mAbs, LC / (105L)(1E)(P228S) HC 4LGg 18611-αFXI / / kappa light chain and HC 4LGg P 18623 / (1Q)(P228S) HC 4LGg P 18623 αFXI) / kappa light chain, with other human and nonhuman primate (NHP) serum proteins (Table 7). Anti-FXI mAbs were captured on a 5 cm sensor chip and immobilized with capture or capture (GE Healthcare) anti-human IgG (Fc) at approximately 500 RU to minimize background interference from simultaneous lgs specificity in plasma-derived proteins.A negative control antibody, a monoclonal antibody (mAb) against respiratory syncytial virus (RSV), was used as a reference and to help reduce background binding to plasma proteins. Binding kinetics using analyte concentrations of FXI in nm. 5 was measured; all other serum coagulation proteins were used at an analyte concentration of 500 nM. Single-concentration injections (n=2) were performed at µL / min, 25ºC, HBS-EP+, pH 7.430. Table 7 Human and NHP (non-human precursors) plasma-derived engineered blood coagulation proteins Lot number / Vendor catalog number Common name Source 00AJF Merck, Sharp & Dohm Co., Ltd., Conniver, NJ, USA Recessive monkey plasma kallikrein Engineered protein with His-terminal C-tagged NCBI reference Sequence: EHH26351 65AJE Merck, Sharp & Dohm Co., Ltd., Conniver, NJ, USA Cynomolgus monkey plasma kallikrein Engineered protein with His-terminal C-tagged NCBI reference Sequence: XP_005556538.1 97AJY / HPK 1302 Research Laboratories Human plasma prekallikrein enzyme isolated from human plasma 98AJY / HPKa 1303 Research Laboratories Human plasma kallikrein enzyme isolated from Human Plasma 42AHG / HCP-0010 Hematology Technologies Corporation (α-Thrombin) Human Factor II Isolated from Human Plasma 50AHK / HCVII-0030 Hematology Technologies Corporation Human Factor VII Isolated from Human Plasma 51AHK HCVIIA-0031 Hematology Technologies Corporation Human Factor II Isolated from Human Plasma 38AHG / HCIX-0040 Hematology Technologies Corporation Human Factor IX Isolated from Human Plasma 14AJZ / HFIXa 1080 Research Laboratories Human Factor IXa Protease Enzyme Isolated from Human Plasma 15AJZ / HFX1010 Research Laboratories Human Factor X Enzyme Isolated from Human Plasma 18AJZ / HFXa 1011 Research Laboratories Human Factor Xa Protease Enzyme Isolated from Human Plasma 19AJZ / HFXII 1212 Research Laboratories Human Factor XII Enzyme Isolated from Human Plasma 20AJZ / HFXII 1212a Research Laboratories Human Factor XIIa Protease Enzyme Isolated from Human Plasma 23AIR / HCXI-0150-C Hematology Technologies Corporation Human FXI Isolated from Human Plasma 41AHG HCP-0010 Hematology Technologies Corporation Human Factor II (Prothrombin) Isolated from Human Plasma 82AJK / 2460-SE R&D Human FXI His-tagged Engineered protein with C-terminal His-tagged Mouse bone marrow tumor cell line, derived from NSO. NCBI reference PO3951 23AFE Merck, Sharp & Dohm, Conniver, NJ, USA Anti-RSV mAb IgG4 SEQ ID NO:84 (LC) andSequence ID: 85 (HC) The binding kinetics of anti-FXI monoclonal antibodies (mAbs), / (105L)(1E)(P228S) HC 4LGg 18611- αFXI / / kappa light chain and / (1Q)( P228S) HC 4LGg P 18623 αFXI) / kappa light chain to human, cynomolgus and rhesus monkey FIX, and other human and NHP (non-human primate) proteins as described above are shown in Figure 11 and Figure 12. Biacore T200 assay software was used to fit the data to a 1:1 binding model to determine the accumulation rate constant, Ka (M-1s-1, where “M” is molar and “s” is seconds) and the dissociation rate constant, Kd (s-1). These rate constants were used to calculate the dissociation equilibrium constant, KD (M). / (105L)(1E)(P228S) HC 4LGg 18611- αFXI / / kappa light chain and / (1Q)( P228S) HC 4LGg P 18623 αFXI) / kappa light chain recorded on the chip showed no cross-reactivity against FXI-deficient blood coagulation proteins (Figure 11 and Figure 12). These monoclonal antibodies showed the expected levels of tight binding to human and cynomolgus (and rhesus) proteins. Example 8 A shunt model of thrombosis or blood clot formation in vessels for the femoral (AV) veins of the cynomolgus monkey The in vivo antithrombotic efficacy of the antibody LC / (1Q)( P228S) HC 4LGg P 18623 αFXI / kappa light chain was determined in a cynomolgus monkey femoral vein (AV) thrombosis shunt model, developed at Merck, Sharp & Dohm Research Laboratories, Kenilworth, New Jersey, USA, and Palo Alto, California, USA. Methods: These studies used a sequential design, with each animal receiving 2 shunts over two consecutive experimental periods (see Figure 13, Study Outline). During the first and second experimental periods, monkeys were given either vehicle without antibody (20 mM sodium acetate, 9% sucrose, pH 5.5) or LC / (1Q)(P228S) HC 4LGg P 18623 αFXI) / kappa light chain antibody (dose range 0.01 to 1.0 mg / kg), respectively. The difference between the weight of blood clots measured during the first (vehicle) and second (antibody) periods of the experiment determined the degree of antithrombotic or antithrombotic efficacy. Thus, a greater reduction in clot weight upon administration of the (1Q)(P228S) HC 4LGg P 18623 αFXI / kappa light chain antibody would indicate a greater antithrombotic effect than administration of the vehicle or carrier. The use of the sequential or repeated pairwise method described above allows for a pre- and post-treatment assessment within an animal of the extent of the antithrombotic effect. Details of the AV shunt implantation procedure: To perform this model, anesthetized cynomolgus monkeys were fitted with venous and arterial casters in the femur. These casters allow for the insertion and removal of the shunt. The AV shunts consist of TYGON tubing with a slit with silk threads suspended in the opening of the tube. To insert the AV shunt, both the venous and arterial casters were closed to stop blood flow. An AV shunt was then placed between the two casters. The timing of caster insertion and removal is shown in Figure 13. Once the shunt was in place, the casters were opened and blood flowed through the shunt circuit, contacting the silk slit. The action of the blood contacting the slit increased blood clot formation. The AV shunt was left in place for 40 minutes. To remove the AV shunt, both the venous and arterial casters were closed to stop blood flow in the AV shunt. The shunt was then removed and cut transversely to access the silk gap and the blood clot. The blood clot was weighed.Data are reported as net clot weight, which is defined as the total clot weight minus the silk gap weight. Biomarkers of blood coagulation, activated partial thromboplastin time (aPTT) and prothrombin time (PT), as well as circulating plasma levels of the antibody (1Q)(P228S) HC 4LGg P 18623 αFXI) / kappa light chain, were measured from blood samples collected during the experiment, as shown in Figure 13. aPTT and PT were measured from thawed and frozen (-80°C) citrated plasma collected from cynomolgus monkeys using a Sta Compact Max coagulation analyzer (Stago Diagnostics). For the aPTT assay, fifty microfilters of plasma were mixed with 50 µL of ellagic acid mixture (APTT-XL, Pacific Stop Bleeding; Fisher Diagnostics, cat#0402-10) at 37°C for 3 min. Fifty microfilters of 0.025M calcium chloride (Sta – CaCl2 0.025M, Stago Diagnostics, cat#00367) were added to the mixture, and the time required for blood clot formation was measured.For the PT test, fifty microfilters of plasma were incubated at 37°C for 4 min. The time required for blood clot formation was initiated by the addition of 100 µL of thromboplastin reagent (Neoplastin Cl Plus 10, Stago Diagnostics, cat#00667). Plasma was assayed as follows. A total 4hlgG immunoassay based on electrochemical fluorescence was performed to quantify antibody in cynomolgus monkey plasma. The test was initiated with goat anti-human IgG(H+L) containing vitamin B from butyl (B319-80A #CAT) as the capture reagent, and mouse anti-human IgG (Fc specific) containing sulfoTAG from Southern Biotechnology (9190-01#CAT) for the detection reagent. The accuracy of the test was confirmed and the lower limit of quantification of the test was determined to be 40 ng / lm, with a minimum required cut-off of 100. Figures D14-A14 summarize the effects of presenting the / (1Q)( P228S) HC 4LGg P 18623 αFXI / kappa light chain antibody on intravascular blood clot formation (Figure A14, Figure B14), APTT (Figure 14c), and PT (Figure D14). Table 8 summarizes the effect of a / (1Q)( P228S) HC 4LGg P 18623 αFXI / kappa light chain antibody on blood clot weight in the cynomolgus AV shunt model. Table 9 summarizes the effect of a / (1Q)( P228S) HC 4LGg P 18623 αFXI / kappa light chain antibody on aPTT and PT in the cynomolgus monkey AV shunt model. Table 8 Effect of αFXI-18623p IgG4 HC (S228P)(E1) / kappa light chain antibody on blood clot weight in the cynomolgus monkey AV shunt model Antibody dose (mg / kg) Shunt No. 1 (vehicle) Shunt No. 1 (antibody) Percentage inhibition of blood clot weight Antibody concentration (µg / mL) 1 0. 772 0. 1%100 13. 29 1. 0 0. 957 0. 1%100 42. 2%1. 0 0. 974 0. 1007 -3%17. 0 03. 0 0. 927 0. 935 -1%54. 0 04. 0 0. 909 0. 887 -2%79. 0 05. 0 0. 607 0. 472 22% 91. 0 05. 0 0. 710 0. 147 79% 03 .1 05. 0 688 66 90% 83 .0 Table 9 Effect of αFXI-18623p IgG4 HC (S228P)(E1) / kappa / LC antibody on aPTT and PT in the cynomolgus monkey AV shunt model Antibody dose (mg / kg) Percentage change in aPTT Percentage change in PT Antibody concentration (µg / mL) 1% 143% 13. 29 1. 0% 93% 142. 2 01. 0% 4% 3% 17. 0% 03. 0% 10% 154. 0% 04. 0% 5% 2- 79. 0% 05. 0% 17% 2 91. 0% 05. 0% 21% 0% 03. 1 05. 0% 42% 3% 83. 0 As shown in Figures 14A and 14B and in Table 8, the αFXI-18623p IgG4 HC (S228P)(E1) / kappa light chain antibody exhibited a dose- and plasma concentration-dependent decrease with full efficacy (90-100, reduction in blood clots) observed at plasma {antibody} concentrations greater than 1 µg / mL (approximately 10 nM). As shown in Figure 14C and Table 9, the antibody exhibited a dose- and plasma concentration-dependent increase in aPTT. A plasma concentration of 2.4 µg / mL (~17 nM) of αFXI-18623p IgG4 HC (S228P)(E1) / kappa light chain antibody caused a 93% increase in aPTT, while 29 µg / mL (~200 nM) of αFXI-18623p IgG4 HC (S228P)(E1) / kappa light chain antibody (at the highest dose tested) caused a 143% increase in aPTT. In contrast to aPTT, as shown in Figure 14D and Table 9, PT changed by less than 10% over the antibody concentrations evaluated, consistent with a selective effect of FXI inhibition on the intrinsic coagulation pathway. Example 9 Cynomolgus monkey bleeding time pattern model The bleeding tendency of the anti-FXI monoclonal antibody αFXI-18623p IgG4 HC (S228P)(E1) / kappa light chain was determined in vivo in a cynomolgus monkey bleeding time pattern model, developed at Merck, Sharp, & Dohm Research Laboratories, Kenilworth, NJ, USA, and Palo Alto, CA, USA. This model, along with triple antiplatelet therapy, has previously been used to demonstrate significant increases in bleeding time patterns in various body sites (Saie et al., J. Eur. Pharmacol. 758: 107-114 (2015)). To implement this model, the bleeding pattern times were determined using spring-loaded lancet pressure to induce bleeding on the buccal mucosa (inner lip), between the toes, and at the end of the tail at different time points. Bleeding time test: Bleeding time test was performed in anesthetized cynomolgus monkeys as follows. Each test area (inner lip, between the toes, or end of the tail) was examined to identify a suitable location for creating a slit to induce bleeding. To induce or force bleeding, a spring-loaded lancet was placed firmly and firmly over the selected test site and activated to create a uniform linear incision. The characteristics of the lancet determined the dimensions of the incision. Blood was allowed to flow freely from the incision site until it stopped after monitoring for 30 seconds. This determined the bleeding time (BT). The bleeding time was recorded for each bleeding site. During the identification of bleeding times, warm neutral lactated Ringer's solution was poured over the incision at the end of the tail, and the interdigital space was placed in neutral lactated Ringer's solution. The use of lactated Ringer's solutions improved the visualization of blood flow at these sites. Methods: Each study consisted of 30 min of bleeding time (BT) pattern tests at three experimental sites (see study outline in Figure 15). The first BT determined the baseline or onset of bleeding. The second BT occurred 70 min after a 3-min IV injection of 17.4 ml / kg of vehicle or vehicle without compound (20 mM sodium acetate, 9% sucrose, pH 5.5) (treatment #1). The third BT occurred 70 min after a 3-min IV injection (17.4 ml / kg) of vehicle without compound or αFXI-18623p IgG4 HC (S228P)(E1) / kappa light chain (10 mg / kg) (treatment #2). Bleeding was monitored and bleeding time was recorded as described above. The time to cessation of bleeding was recorded for each site. Periodic blood samples were collected to determine plasma levels of αFXI-18623p IgG4 HC (S228P)(E1) / kappa light chain antibody, aPTT, and PT. Each experimental animal had two study arms or sections. In study arm #1, the carrier followed by another carrier or section constitutes Treatment #1 and Treatment #2, respectively. In study arm #2, the carrier or section followed by 10 mg / kg of αFXI-18623p IgG4 HC (S228P)(E1) / kappa light chain constitutes Treatment #1 and Treatment #2, respectively. The 70-minute period between the end of the test substance injection and the start of the bleeding time assessment represents the timing in the AV shunt model for determining clot mass (shunt implantation 30 minutes after treatment + 40 minutes of blood flow through the shunt). The mg / kg IV dose of 10 trials of αFXI-18623p IgG4 HC (S228P)(E1)- / kappa light chain was estimated to be approximately 10 times the predicted human Cmax for αFXI-18623p IgG4 HC (S228P)(E1)- / kappa light chain, based on the non-human PK / PD modeling studies previously described. The coagulation biomarkers of activated partial thromboplastin time (aPTT) and prothrombin time (PT) as well as circulating plasma levels of αFXI-18623p IgG4 HC (S228P)(E1)- / kappa light chain were measured from blood samples collected throughout the experiment, as shown in Figure 15. aPTT and PT were measured from thawed and frozen (-80°C) citrated plasma collected from the animals using a Sta-R Evolution coagulation analyzer (Stago Diagnostics). The coagulation analyzer measures the time required for blood clot formation using an electromagnetic clot detection system. For the aPTT test, the analyzer mixes 50 µL of plasma with 50 µL of ellagic acid (APTT-XL, Pacific Hemostasis; Fisher Diagnostics, Cat # 10-0402) in a cuvette at 37°C for 3 minutes. Then 50 µL of M025.0 Calcium Chloride (M025.2– CaCl Sta, Stago Diagnostics, Cat #00367) was added to the mixture to initiate blood clotting and the time required for clot formation was measured. For the PT test, 50 µL of plasma was incubated at 37°C for 4 min; clotting was initiated by the addition of 100 µL of dissolved thromboplastin reagent (Trinickelate, PT Excel, TCoag; CAT #1106T). A comprehensive hIgG4 immunoassay based on electrochemical fluorescence was performed to quantify the αFXI-18623p IgG4 HC (S228P)(E1) / kappa light chain antibody in rhesus monkey plasma. The assay was initiated with goat anti-human IgG(H+L) containing vitamin B butyl from Southern Biotechnology (Cat # B319-80A) as the capture reagent, and mouse anti-human huIgG (Fc specific) containing sulfoTAG from Southern Biotechnology (CAT # 9190-01) as the detection reagent. The assay was validated and the lower limit of quantification of the assay was determined to be 40 ng / mL with a minimum required cutoff of 100. Figures F16-A16 Effects of using a carrier or carrier and mg / kg IV αFXI-18623p IgG4 HC (S228P)(E1) 10 / kappa light chain in six cynomolgus monkeys show bleeding time patterns on the inner lip (Figures A16 and D16), between the toes (Figures B16 and E16), and the tip of the tail (Figures C16 and F16). Effects on bleeding times were assessed by comparing absolute bleeding times (left panels) and percent change in bleeding times (right panels) with vehicle-vehicle as treatments #1 and #2 in study arm #1, and vehicle-αFXI-18623p IgG4 HC (S228P)(E1) / kappa light chain as treatments #1 and #2 in study arm #2. Comparisons of both carriers relative to the absolute bleeding times of αFXI-18623p IgG4 HC (S228P)(E1) / kappa light chain as well as comparisons of the percent changes in bleeding times of carrier-carrier relative to the αFXI-18623p IgG4 HC (S228P)(E1) / kappa light chain carrier did not identify any significant changes in bleeding times at any of the test sites with the use of αFXI-18623p IgG4 HC (S228P)(E1) / kappa light chain at this test dose. Plasma concentrations of αFXI-18623p IgG4 HC (S228P)(E1) / kappa light chain with The experimental dose in the cynomolgus monkey bleeding time study was 2.17±7.290 (mean SEM) (MN193802 ~) μg / ml. Plasma aPTT values ​​were initially 5.0±0.31 seconds, which increased to 6.1±3.71 seconds after the addition of αFXI-18623p IgG4 HC (S228P)(E1) IV mg / kg 10 kappa light chain (a 2.3-fold increase). Plasma PT values ​​were initially 1.0±7.12 seconds, which increased to 1.0±6.12 seconds after the addition of mg / kg 10 kappa light chain (a no significant increase). Example 10 Evaluation of pharmacokinetics (PK) and pharmacodynamics (PD) of αFXI-18623p IgG4 HC (S228P)(E1) / kappa light chain after several stages of administration in rhesus monkeys. PKPD properties of αFXI-18623p IgG4 HC (S228P)(E1) / kappa light chain were identified in vivo in rhesus monkeys. The aim was to evaluate the PK properties and establish a PK / PD relationship after two full weekly doses. Study method: Rhesus monkeys (four animals per dose group) were given vehicle-free compound (IV) (10 mM sodium acetate, pH 5.5, 7% sucrose, 80% PS 02.0) or αFXI-18623p IgG4 HC (S228P)(E1) / kappa light chain at five dose levels of 3, 1, 3.0, 1.0, and 6 mg / kg. The study duration was 22 days and 5.1 mL of blood was collected for drug levels and activated partial thromboplastin time (aPTT). The prothrombin time (aPTT) and circulating plasma levels of αFXI-18623p IgG4 HC (S228P)(E1) / kappa light chain were measured from blood samples collected throughout the trial, as shown in Table 10. Table 10 Blood sample collection table Collection type PK time Day-3; Day 0: Pre-dose (-1 hour) and 30 minutes, 3 hours, 6 hours, 24 hours (Day 1), 48 (Day 2) 96 (Day 4) Day 7: Pre-dose and 1 hour, 6 hours, 24 hours, (Day 8), 48 hours (Day 9), 96 hours (Day 11), 168 hours, (Day 14) 264 hours, (Day 18) and 528 hours (Day 22) after the second dose PD (aPTT assessment) Day-3; Day 0: Pre-dose (-1 hour) and 30 minutes, 3 hours, 6 hours, 24 hours (day 1), 48 (day 2) 96 (day 4) Day 7: Pre-dose and 1 hour, 6 hours, 24 hours, (day 8), 48 hours (day 9), 96 hours (day 11), 168 hours, (day 14) 264 hours, (day 18) and 528 hours (day 22) after the second dose aPTT or activated partial thromboplastin time (aPTT) was measured from thawed and frozen (-80°C) citrated plasma collected from animals using a Sta-R Evolution coagulation analyzer (Stago Diagnostics). The coagulation analyzer measures the time required for blood clot formation using an electromagnetic mechanical clot detection system. For the aPTT test, the analyzer mixes 50 µL of plasma with 50 µL of ellagic acid (APTT-XL, Pacific Stop Bleeding; Fisher Diagnostics, CAT# 0402-10) in a cuvette, which is then incubated or treated at 37°C for 3 minutes. Then 50 µL of M025. 0 Calcium chloride (M025.2– CaCl Sta, Stago Diagnostics, 00367#cat) was added to the mixture to initiate blood coagulation, and then the time required for blood clot formation was measured. A comprehensive hIgG immunoassay based on electrochemical fluorescence was performed to quantify the αFXI-18623p IgG4 HC (S228P)(E1) / kappa light chain antibody in rhesus monkey plasma. The assay was initiated with goat anti-IgG(H+L) containing vitamin B from butyl (B319-80A#CAT) as the capture reagent, and mouse anti-huIgG (Fc-specific) containing sulfoTAG from Southern Biotechnology (01-9190#CAT) as the detection reagent. The assay was validated and the lower limit of quantification of the assay was achieved with a minimum required dilution of 100, the amount of It was determined to be 41 ng / ml. Separate animal plasma concentration-time data for αFXI-18623p IgG4 HC (S228P)(E1) / kappa light chain were analyzed using non-separable (NCA) methods (Gabrielsen and Wiener, 2000). All PK parameters were calculated using Phoenix 3.6. WinNonlin (version 395.0.3.6); Sertara, LP, St. Louis, MO, 2012). Samples used by the non-separable analysis model that had concentration values ​​below the limit of quantification ( <LLOQ) از تحلیل PK و محاسبات داده های میانگین مستثنی شدند. به منظور نمایش مصور، مقادیر کمتر از LLOQ برای نمودار های مجزای غلظت-زمانِ حیوان ها به میزان ½ از حداقل غلظتِ قابلِ گزارش تنظیم شدند. A sigmoid or circular Emax response (PK / PD) model was used to characterize the relationship between exposure or radiation and aPTT using GraphPad Prism software version 00. 7 (GraphPad Software Inc.). In this model, the Emax value corresponds to the half-maximal effective concentration. The variability is reported as 95% confidence intervals (CI) for the 50EC values ​​as provided by the software. Results. The individual concentration-time profiles for αFXI-18623p IgG4 HC (S228P)(E1) / kappa light chain are shown in Figure A17. Nonlinearity was observed for all PK parameters. The mean clearance values ​​decreased from approximately 8 mL / kg / day for the lowest dose tested (0.1 mg / kg) to approximately 4 mL / kg / day for the highest dose tested ( mg / kg). The aPTT concentration-time profiles are shown in Figure B17. A dose-dependent increase in aPTT was observed. The relationship between plasma concentrations of αFXI-18623p IgG4 HC (S228P)(E1) / kappa light chain and aPTT was best described by a circular or sigmoid Emax model, which adequately described this relationship. The estimated EC50 value for αFXI-18623p IgG4 HC (S228P)(E1) / kappa light chain was approximately 3.6 µg / mL. Although the present invention has been described herein with respect to the embodiments described, it is to be understood that the invention is not limited thereto. Those of ordinary skill in the art, having access to the teachings set forth herein, will recognize other modifications and embodiments that fall within the scope of the invention. Accordingly, the present invention is limited only by the appended claims herein. What is claimed: 1. An antibody or antigen-binding fragment comprising: (i) at least six complementarity determining regions (CDRs) of an anti-FXI antibody of the P 18623 αFXI family, the P 18611-αFXI family, or the 18611-αFXI family, or (ii) at least six complementarity determining regions (CDRs) of an anti-FXI antibody of the P18623-αFXI family, the P 18611-αFXI family, or the 18611-αFXI family, wherein one or more of the six CDRs have one, two, or three amino acid substitutions, additions, or deletions, or a combination thereof, wherein an antibody of the 18623 αFXI family comprises a heavy chain variable region (HC) having the amino acid sequence shown in SEQ ID NO: 28 or 29 and a light chain variable region (LC) having the amino acid sequence shown in SEQ ID NO: 30; An antibody of the P18623-αFXI family comprises a heavy chain variable region (HC) having the amino acid sequence shown in SEQ ID NO: 21 or 22 and a light chain variable region (LC) having the amino acid sequence shown in SEQ ID NO: 25; and An antibody of the 18611-αFXI family comprises a heavy chain variable region (HC) having the amino acid sequence shown in SEQ ID NO: 23 or 24 and a light chain variable region (LC) having the amino acid sequence shown in SEQ ID NO: 25. The antibody or antigen-binding fragment of claim 1, wherein the six CDRs include CDR 1, CDR 2 and CDR 3 from the heavy chain of an anti-FXI antibody of the P18623-αFXI family. , P 18611-αFXI family, or 18611-αFXI family and 1CDR, 2CDR and 3CDR of the light chain of an anti-FXI antibody of the P18623-αFXI family , P family 18611-αFXI, or 18611-αFXI family. 2. The antibody or antigen-binding portion of claim 2, wherein the antibody or antigen-binding portion comprises CDR 1, CDR 2, and CDR 3 of the heavy chain variable region having the amino acid sequence shown in SEQ ID NO: 28 or 29, CDR 1, CDR 2, and CDR 3 of the heavy chain variable region having the amino acid sequence shown in SEQ ID NO: 21, 22, 23, or 24, and CDR 1, CDR 2, and CDR 3 of the light chain variable region having the amino acid sequence shown in SEQ ID NO: 25. 3. The antibody or antigen-binding portion of any one of claims 1 to 3, wherein the antibody comprises a heavy chain constant region comprising the amino acid sequence set forth in SEQ ID NO: 16, 17, 18 or 19. 4. The antibody or antigen-binding fragment of any one of claims 1 to 4, wherein the antibody comprises a heavy chain constant region comprising the amino acid sequence set forth in SEQ ID NO: 20. 5. The antibody or antigen-binding fragment of claim 1 or 3, wherein the antibody or antibody fragment comprises: (a) a heavy chain variable domain (HC) having the amino acid sequence shown in SEQ ID NO: 28 and a light chain variable domain (LC) having the amino acid sequence shown in SEQ ID NO: 30; (b) a heavy chain variable domain (HC) having the amino acid sequence shown in SEQ ID NO: 29 and a light chain variable domain (LC) having the amino acid sequence shown in SEQ ID NO: 30; (c) a heavy chain variable domain (HC) having the amino acid sequence shown in SEQ ID NO: 21 and a light chain variable domain (LC) having the amino acid sequence shown in SEQ ID NO: 25; (d) a heavy chain variable domain (HC) having the amino acid sequence shown in SEQ ID NO: 22 and a light chain variable domain (LC) having the amino acid sequence shown in SEQ ID NO: 25; (e) a heavy chain variable domain (HC) having the amino acid sequence shown in SEQ ID NO: 23 and a light chain variable domain (LC) having the amino acid sequence shown in SEQ ID NO: 25; (f) a heavy chain variable domain (HC) having the amino acid sequence shown in SEQ ID NO: 24 and a light chain variable domain (LC) having the amino acid sequence shown in SEQ ID NO: 25; (g) a variant of (a), (b), (c), (d), (e) or (f), wherein the heavy chain variable framework region comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, or deletions, or a combination thereof; or (h) A variant of (a), (b), (c), (d), (e), (f) or (g), wherein the light chain variable framework region comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, or deletions, or a combination thereof. 6. The antibody or antigen-binding portion of claim 6, wherein the antibody further comprises a heavy chain (HC) constant region comprising the amino acid sequence shown in SEQ ID NO: 16, 17, 18, or 19. 7. The antibody or antigen-binding fragment of claim 6, wherein the antibody further comprises a light chain (LC) constant region comprising the amino acid sequence shown in SEQ ID NO: 20. 8. The antibody or antigen-binding fragment of claim 1, 2, 3, 4, 5, 6, 7, or 8, wherein the antibody or antigen-binding fragment binds to the 3 domain of blood coagulation factor XI (FXI) and inhibits the activation of FXI and / or the activation of factor IX by factor XIa. 9. The antibody or antigen-binding fragment of claim 1 or 3, wherein the antibody comprises: (a) a heavy chain having a constant domain and a variable domain, wherein the variable domain comprises a heavy chain complementarity determining region 1 (HC-CDR 1) having the amino acid sequence shown in SEQ ID NO: 1, a heavy chain complementarity determining region 2 (HC-CDR 2) having the amino acid sequence shown in SEQ ID NO: 2, and a heavy chain complementarity determining region 3 (HC-CDR 3) having the amino acid sequence shown in SEQ ID NO: 3 or 4; and (b) a light chain having a constant domain and a variable domain, wherein the variable domain comprises a light chain complementarity determining region 1 (LC-CDR) having the amino acid sequence shown in SEQ ID NO: 5, a light chain complementarity determining region 2 (LC-CDR) having the amino acid sequence shown in SEQ ID NO: 6, and a light chain complementarity determining region 3 (LC-CDR) having the amino acid sequence shown in SEQ ID NO: 7. 11. The antibody or binding moiety of claim 10, wherein the antibody comprises a heavy chain constant domain comprising the amino acid sequence shown in SEQ ID NO: 16, 17, 18, or 19. 12. The antibody or binding moiety of claim 10, wherein the antibody comprises a light chain constant domain comprising the amino acid sequence shown in SEQ ID NO: 20. 13. The antibody or antigen-binding fragment of claim 1 or 3, wherein the antibody comprises: (a) a heavy chain having a constant domain and a variable domain, wherein the variable domain comprises a heavy chain having a heavy chain complementarity determining region 1 (HC-CDR 1) having the amino acid sequence shown in SEQ ID NO: 8, a heavy chain complementarity determining region 2 (HC-CDR 2) having the amino acid sequence shown in SEQ ID NO: 9, and a heavy chain complementarity determining region 3 (HC-CDR 3) having the amino acid sequence shown in SEQ ID NO: 10; and (b) a light chain having a constant domain and a variable domain, wherein the variable domain comprises a light chain complementarity determining region 1 (LC-CDR) having the amino acid sequence shown in SEQ ID NO: 11, a light chain complementarity determining region 2 (LC-CDR) having the amino acid sequence shown in SEQ ID NO: 12, and a light chain complementarity determining region 3 (LC-CDR) having the amino acid sequence shown in SEQ ID NO: 13. 14. The antibody or antigen-binding fragment of claim 13, wherein the antibody comprises a heavy chain constant domain comprising the amino acid sequence shown in SEQ ID NO: 16, 17, 18, or 19. 15. The antibody or antigen-binding fragment of claim 13, wherein the antibody comprises a light chain constant domain comprising the amino acid sequence shown in SEQ ID NO: 20. 16. The antibody or antigen-binding fragment of claim 1 or 3, wherein the antibody comprises: A heavy chain having the amino acid sequence shown in SEQ ID NO: 73,71,69,63,61,59,57,51,49,47,45,39,37,35,33 or 75, and variants thereof include 9,8,7,6,5,4,3,2,1 or 10 amino acid substitutions, additions, or deletions, or combinations thereof; and A light chain having the amino acid sequence shown in SEQ ID NO: 26, and variants thereof comprising 9, 8, 7, 6, 5, 4, 3, 2, 1 or 10 amino acid substitutions, additions, or deletions, or combinations thereof, such that the antibody or antigen-binding portion binds to the 3-domain of blood coagulation factor XI (FXI) and prevents activation of FXI or activation of factor IX by factor XIa. 17. The antibody or antigen-binding fragment of claim 1 or 3, wherein the antibody comprises: A heavy chain having the amino acid sequence shown in SEQ ID NO: 77,67,65,55,53,43,41 or 79, and variants thereof comprising 9,8,7,6,5,4,3,2,1 or 10 amino acid substitutions, additions, or deletions, or combinations thereof; and A light chain having the amino acid sequence shown in SEQ ID NO: 31, and variants thereof comprising 9, 8, 7, 6, 5, 4, 3, 2, 1 or 10 amino acid substitutions, additions, or deletions, or combinations thereof, such that the antibody or antigen-binding portion binds to the 3-domain of blood coagulation factor XI (FXI) and prevents activation of FXI or activation of factor IX by factor XIa. 18. An antibody that contains: (a) A heavy chain having a constant domain and a variable domain, such that the variable domain includes: (i) a heavy chain framework and a heavy chain complementarity determining region 1 (1 HC-CDR) having the amino acid sequence shown in SEQ ID NO: 8, a 2 HC-CDR having the amino acid sequence shown in SEQ ID NO: 9, and a 3 HC-CDR having the amino acid sequence shown in SEQ ID NO: 10; #x200f(#x200f#x200eii#x200e#x200f)#x200fa heavy chain framework and a heavy chain complementarity determining region 1 (1 HC-CDR) having the amino acid sequence shown in SEQ ID NO: 1, a 2 HC-CDR having the amino acid sequence shown in SEQ ID NO: 2, and a 3 HC-CDR having the amino acid sequence shown in SEQ ID NO: 3; #x200f(#x200f#x200eiii#x200e#x200f) #x200fa heavy chain framework and a heavy chain complementarity determining region (1 HC-CDR) having the amino acid sequence shown in SEQ ID NO: 1, a 2 HC-CDR having the amino acid sequence shown in SEQ ID NO: 2, and a 3 HC-CDR having the amino acid sequence shown in SEQ ID NO: 4; #x200f(#x200f#x200eiv#x200e#x200f)#x200fA variant of (i), (ii) or (iii), wherein at least one of the 2CDRs, 1CDR, or 3CDRs comprises 1, 2, or 3 amino acid substitutions, additions, or deletions, or a combination thereof; or #x200f(#x200f#x200ev#x200e#x200f)#x200fA variant of (i), (ii), (iii) or (iv), wherein the heavy chain framework comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, or deletions, or a combination thereof; #x200f(#x200f#x200eb#x200e#x200f)#x200fA light chain that has a fixed domain and a variable domain, such that the variable domain includes: #x200f(#x200f#x200ei#x200e#x200f)#x200f a light chain framework and a light chain complementarity determining region 1 (1 LC-CDR) having the amino acid sequence shown in SEQ ID NO: 11, a 2 LC-CDR having the amino acid sequence shown in SEQ ID NO: 12, and a 3 LC-CDR having the amino acid sequence shown in SEQ ID NO: 13; #x200f(#x200f#x200eii#x200e#x200f)#x200fa light chain framework and a light chain complementarity determining region 1 (1 LC-CDR) having the amino acid sequence shown in SEQ ID NO: 5, a 2 LC-CDR having the amino acid sequence shown in SEQ ID NO: 6, and a 3 LC-CDR having the amino acid sequence shown in SEQ ID NO: 7; #x200f(#x200f#x200eiii#x200e#x200f) #x200fA variant of (i) or (ii), wherein at least one of the 2CDRs, 1CDR, or 3CDRs comprises 1, 2, or 3 amino acid substitutions, additions, or deletions, or a combination thereof; or #x200f(#x200f#x200eiv#x200e#x200f)#x200fA variant of (i), (ii) or (iii), wherein the light chain framework comprises, 1,2,3,4,5,6,7,8,9 or 10 amino acid substitutions, additions, or deletions, or a combination thereof; or #x200f(#x200f#x200ec#x200e#x200f)#x200fA heavy chain from (a) and a light chain from (b); such that the antibody binds to the apple 3 domain of blood coagulation factor XI (FXI) and prevents FXI from being activated or factor IX from being activated by factor XIa. 19. The antibody of claim 18, wherein the heavy chain constant domain comprises the amino acid sequence shown in SEQ ID NO: 16, 17, 18, or 19. 20. The antibody of claim 18 or 19, wherein the light chain constant domain comprises the amino acid sequence shown in SEQ ID NO: 20. 21. An isolated nucleic acid molecule encoding the light chain variable domain or the heavy chain variable domain of any of the antibodies or antigen-binding portions of claims 1-20. 22. A composition comprising the antibody or antigen-binding fragment of any one of claims 1-20 and a pharmaceutically acceptable carrier or diluent. 23. An antibody or antigen-binding fragment of any one of claims 1-20 for use in treating a vascular thrombus formation disorder or disease in a subject, comprising administering an effective amount of the antibody or antigen-binding fragment of any one of claims 1-20. 24. Use of an antibody of any one of claims 1 to 20 for the manufacture of a medicament for treating a blood clot formation disorder or disease in the arteries. 25. An antibody of any one of claims 1-20 for use in treating a blood clot formation disorder or disease in a vessel. 26. A human antibody or antigen-binding fragment that binds to an epitope on blood coagulation factor XI (FXI), wherein the epitope, as determined by hydrogen deuterium exchange mass spectrometry (HDX-MS) analysis, comprises the amino acid sequences DIFPNTVF (SEQ ID NO: 82) and the amino acid sequence PSTRIKKSKALSG (SEQ ID NO: 83). 27. The human antibody of claim 26, wherein the antibody comprises (i) a constant or variable IgG1 or a modified derivative thereof or (ii) a constant or variable IgG4 or a modified derivative thereof. 28. The human antibody of claim 26, wherein the antibody comprises an IgG constant domain that, as shown herein, comprises a substitution of serine at position 228 (EU numbering) or position 108 with a proline residue. 29. A human antibody or antigen-binding fragment that blocks cross-linking or competes with an antibody comprising a heavy chain having the amino acid sequence shown in SEQ ID NO: 33, 35, 37, 39, 45, 47, 49, 51, 57, 59, 61, 63, 69, 71, 73 or 75 and a light chain having the amino acid sequence shown in SEQ ID NO: 26, or an antibody comprising a heavy chain having the amino acid sequence shown in SEQ ID NO: 77, 67, 65, 55, 53, 43, 41 or 79 and a light chain having the amino acid sequence shown in SEQ ID NO: 31. 30. The human antibody of claim 29, wherein the antibody comprises (i) a constant or variable IgG1 or a modified derivative thereof or (ii) comprises a constant or variable IgG4 or a modified derivative thereof. 31. The human antibody of claim 30, wherein the antibody comprises an IgG constant domain that, as shown herein, comprises a substitution of serine at position 228 (EU numbering) or position 108 with a proline residue. 32. A method for producing an antibody or antigen-binding fragment comprising: (i) a heavy chain variable domain comprising a heavy chain complementarity determining region 1 (1 HC-CDR) having the amino acid sequence shown in SEQ ID NO: 1, a 2 HC-CDR having the amino acid sequence shown in SEQ ID NO: 2, and a 3 HC-CDR having the amino acid sequence shown in SEQ ID NO: 3 or 4, or a 1 HC-CDR having the amino acid sequence shown in SEQ ID NO: 8, a 2 HC-CDR having the amino acid sequence shown in SEQ ID NO: 9, and a 3 HC-CDR having the amino acid sequence shown in SEQ ID NO: 10; or (ii) a light chain framework comprising a light chain complementarity determining region 1 (LC-CDR 1) having the amino acid sequence shown in SEQ ID NO: 5, a LC-CDR 2 having the amino acid sequence shown in SEQ ID NO: 6, and a LC-CDR 3 having the amino acid sequence shown in SEQ ID NO: 7, or a LC-CDR 1 having the amino acid sequence shown in SEQ ID NO: 11, a LC-CDR 2 having the amino acid sequence shown in SEQ ID NO: 12, and a LC-CDR 3 having the amino acid sequence shown in SEQ ID NO: 13, and the method comprising: providing a host cell comprising a nucleic acid molecule encoding a heavy chain and a nucleic acid molecule encoding a light chain; and culturing the host cell under conditions and for a time sufficient to produce the antibody or antigen-binding fragment. 33. The method of claim 32, wherein the heavy chain variable domain comprises the amino acid sequence SEQ ID NO: 21, 22, 23 or 24 and the heavy chain variable domain comprises the amino acid sequence SEQ ID NO: 25. 34. The method of claim 32, wherein the antibody comprises a heavy chain constant domain of the isotype It can be 3lgG, 2lgG, 1lgG or 4lgG. 35. The method of claim 32, wherein the antibody comprises a heavy chain constant domain of the 4IgG isotype. 36. The method of claim 32, wherein the antibody comprises a heavy chain constant domain comprising the amino acid sequence shown in SEQ ID NO: 16, 17, 18 or 19. 37. The method of claim 32, wherein the light chain comprises a human kappa light chain or a human lambda light chain. 38. The method of claim 32, wherein the antibody comprises a heavy chain constant domain comprising the amino acid sequence shown in SEQ ID NO: 20. 39. The method of claim 32, wherein the host cell is a Chinese hamster ovary cell or a human embryonic kidney 293 cell. 40. The method of claim 32, wherein the host cell is a yeast cell or a filamentous fungal cell. 41. A composition comprising any of the antibodies of claims 1 to 20, wherein the antibody or antigen-binding portion thereof is obtained from a host cell comprising a nucleic acid molecule encoding a heavy chain and a nucleic acid molecule encoding a light chain. 42. The composition of claim 41, wherein the antibody comprises a heavy chain constant domain of the 3IgG, 2IgG, 1IgG or 4IgG isotype. 43. The composition of claim 41, wherein the antibody comprises a heavy chain constant domain of the 4IgG isotype. 44. The composition of claim 41, wherein the antibody comprises a heavy chain constant domain comprising the amino acid sequence shown in SEQ ID NO: 16, 17, 18, or 19. 45. The composition of claim 41, wherein the light chain comprises a human kappa light chain or a human lambda light chain. 46. ​​The composition of claim 41, wherein the antibody comprises a heavy chain constant domain comprising the amino acid sequence shown in SEQ ID NO: 20. 47. The composition of claim 41, wherein the host cell is a Chinese hamster ovary cell or a human embryonic kidney 293 cell. 48. The composition of claim 41, wherein the host cell is a yeast cell or a filamentous fungal cell. Summary of the invention Antibodies that bind to coagulation factor XI in the human body's apple3 domain and inhibit the activity of FXI by coagulation factor XIIa and also the activity of FIX by FXIa, as described above.

Claims

ANTI-COAGULATION FACTOR XI ANTIBODIES WHAT IS CLAIMED: 1.An antibody or antigen binding fragment comprising: (i) at least the six complimentary determining regions (CDRs) of an anti-FXI antibody of the αFXI-18623p family, αFXI-18611p family, or αFXI-18611 family or (ii) at least the six complimentary determining regions (CDRs) an anti-FXI antibody of the αFXI-18623p family, αFXI-18611p family, or αFXI-18611 family wherein one or more of the six CDRs has one, two, or three amino acid substitutions, additions, deletions, or combinations thereof, wherein an antibody of the αFXI-18623 family comprises a heavy chain (HC) variable region having the amino acid sequence shown in SEQ ID NO:28 or 29 and an LC variable region having the amino acid sequence shown in SEQ ID NO:30; an antibody of the αFXI-18611p family comprises an HC variable region having the amino acid sequence shown in SEQ ID NO:21 or 22 and a light chain (LC) variable region having the amino acid sequence shown in SEQ ID NO:25;and an antibody of the αFXI-18611 family comprises an HC variable region having the amino acid sequence shown in SEQ ID NO:23 or 24 and an LC variable region having the amino acid sequence shown in SEQ ID NO:

25.

2. The antibody or antigen binding fragment of claim 1, wherein the six CDRs comprise CDR1, CDR2, and CDR3 of the HC of an anti-FXI antibody of the αFXI-18623p family, αFXI-18611p family, or αFXI-18611 family and CDR1, CDR2, and CDR3 of the LC of an anti-FXI antibody of the αFXI-18623p family, αFXI-18611p family, or αFXI-18611 family.; 3. The antibody or antigen binding fragment of claim 2, wherein the antibody or antigen binding fragment comprises CDR1, CDR2, and CDR3 of an HC variable domain having the amino acid sequence shown in SEQ ID NO:28 or 29 and CDR1, CDR2, and CDR3 of an LC variable domain having amino acid sequence shown in SEQ ID NO:30; or CDR1, CDR2, and CDR3 of an HC variable domain having the amino acid sequence shown in SEQ ID NO:21, 22, 23, or 24 and CDR1, CDR2, and CDR3 of an LC variable domain having amino acid sequence shown in SEQ ID NO:

25.

4. The antibody or antigen binding fragment of any one of claims 1 to 3, wherein the antibody comprises a HC constant domain comprising the amino acid sequence shown in SEQ ID NO:16, 17, 18, or 19.

5. The antibody or antigen binding fragment of any one of claims 1 to 4, wherein the antibody comprises a LC constant domain comprising the amino acid sequence shown in SEQ ID NO:

20.

6. The antibody or antigen binding fragment of claim 1 or 3, wherein the antibody or antibody fragment comprises: (a) a heavy chain (HC) variable domain having the amino acid sequence shown in SEQ ID NO: 28 and a light chain (LC) variable domain having the amino acid sequence shown in SEQ ID NO:30; (b) a heavy chain (HC) variable domain having the amino acid sequence shown in SEQ ID NO: 29 and a light chain (LC) variable domain having the amino acid sequence shown in SEQ ID NO:30; (c) a heavy chain (HC) variable domain having the amino acid sequence shown in SEQ ID NO: 21 and a light chain (LC) variable domain having the amino acid sequence shown in SEQ ID NO:25; (d) a heavy chain (HC) variable domain having the amino acid sequence shown in SEQ ID NO:22 and a light chain (LC) variable domain having the amino acid sequence shown in SEQ ID NO:25;(e) a heavy chain (HC) variable domain having the amino acid sequence shown in SEQ ID NO:23 and a light chain (LC) variable domain having the amino acid sequence shown in SEQ ID NO:25; (f) a heavy chain (HC) variable domain having the amino acid sequence shown in SEQ ID NO: 24 and a light chain (LC) variable domain having the amino acid sequence shown in SEQ ID NO:25; (g) variant of (a), (b), (c), (d), (e), or (f) wherein the HC variable region framework comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, deletions, or combinations thereof; or, (h) variant of (a), (b), (c), (d), (e), (f), or (g) wherein the LC variable region framework comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, deletions, or combinations thereof.; 7. The antibody or antigen binding fragment of claim 6, wherein the antibody further comprises a HC constant domain comprising the amino acid sequence shown in SEQ ID NO:16, 17, 18, 19.

8. The antibody or antigen binding fragment of claim 6, wherein the antibody further comprises a LC constant domain comprising the amino acid sequence shown in SEQ ID NO:

20.

9. The antibody or antigen binding fragment of claim 1, 2, 3, 4, 5, 6, 7, or 8, wherein the antibody or antigen binding fragment binds the apple 3 domain of coagulation factor XI (FXI) and inhibits activation of FXI and / or Factor XIa-mediated activation of Factor IX 10. The antibody or antigen binding fragment of claim 1 or 3, wherein the antibody comprises: (a) an HC having a constant domain and a variable domain wherein the variable domain comprises a heavy chain-complementary determining region (HC-CDR) 1 having the amino acid sequence shown in SEQ ID NO:1, a HC-CDR 2 having the amino acid sequence shown in SEQ ID NO:2, and a HC-CDR 3 having the amino acid sequence shown in SEQ ID NO:3 or 4; and (b) an LC having a constant domain and a variable domain wherein the variable domain comprises a light chain-complementary determining region (LC-CDR) 1 having the amino acid sequence shown in SEQ ID NO:5, a LC-CDR 2 having the amino acid sequence shown in SEQ ID NO:6, and a LC-CDR 3 having the amino acid sequence shown in SEQ ID NO:

7.

11. The antibody or antigen binding fragment of claim 10, wherein the antibody comprises an HC constant domain comprising the amino acid sequence shown in SEQ ID NO:16, 17, 18, or 19.

12. The antibody or antigen binding fragment of claim 10, wherein the antibody comprises an LC constant domain comprising the amino acid sequence shown in SEQ ID NO:

20.

13. The antibody or antigen binding fragment of claim 1 or 3, wherein the antibody comprises: (a) an HC having a constant domain and a variable domain wherein the variable domain comprises a heavy chain comprising a heavy chain-complementary determining region (HC-CDR) 1 having the amino acid sequence shown in SEQ ID NO:8, a HC-CDR 2 having the amino acid sequence shown in SEQ ID NO:9, and a HC-CDR 3 having the amino acid sequence shown in SEQ ID NO:10; and (b) an LC having a constant domain and a variable domain wherein the variable domain comprises a light chain-complementary determining region (LC-CDR) 1 having the amino acid sequence shown in SEQ ID NO:11, a LC-CDR 2 having the amino acid sequence shown in SEQ ID NO:12, and a LC-CDR 3 having the amino acid sequence shown in SEQ ID NO:

13.

14. The antibody or antigen binding fragment of claim 13, wherein the antibody comprises an HC constant domain comprising the amino acid sequence shown in SEQ ID NO:16, 17, 18, or 19.

15. The antibody or antigen binding fragment of claim 13, wherein the antibody comprises an LC constant domain comprising the amino acid sequence shown in SEQ ID NO:

20.

16. The antibody or antigen binding fragment of claim 1 or 3, wherein the antibody comprises: an HC having the amino acid sequence shown in SEQ ID NO:33, 35, 37, 39, 45, 47, 49, 51, 57, 59, 61, 63, 69, 71, 73, or 75, and variants thereof comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, deletions, or combinations thereof; and an LC having the amino acid sequence shown in SEQ ID NO: 26, and variants thereof comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, deletions, or combinations thereofwherein the antibody or antigen binding fragment binds the apple 3 domain of coagulation factor XI (FXI) and inhibits activation of FXI and / or Factor XIa-mediated activation of Factor IX.

17. The antibody or antigen binding fragment of claim 1 or 3, wherein the antibody comprises: an HC having the amino acid sequence shown in SEQ ID NO:41, 43, 53, 55, 65, 67, 77, or 79, and variants thereof comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, deletions, or combinations thereof;and an LC having the amino acid sequence shown in SEQ ID NO:31, and variants thereof comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, deletions, or combinations thereof, wherein the antibody or antigen binding fragment binds the apple 3 domain of coagulation factor XI (FXI) and inhibits activation of FXI and / or Factor XIa-mediated activation of Factor IX. 18.An antibody comprising: (a) a heavy chain (HC) having a constant domain and a variable domain wherein the variable domain comprises (i) an HC framework and heavy chain-complementary determining region (HC-CDR) 1 having the amino acid sequence shown in SEQ ID NO:8, an HC-CDR 2 having the amino acid sequence shown in SEQ ID NO:9, and an HC-CDR 3 having the amino acid sequence shown in SEQ ID NO:10;(ii) an HC framework and heavy chain-complementary determining region (HC-CDR) 1 having the amino acid sequence shown in SEQ ID NO:1, an HC-CDR 2 having the amino acid sequence shown in SEQ ID NO:2, and an HC-CDR 3 having the amino acid sequence shown in SEQ ID NO:3; (iii) an HC framework and heavy chain-complementary determining region (HC-CDR) 1 having the amino acid sequence shown in SEQ ID NO:1, an HC-CDR 2 having the amino acid sequence shown in SEQ ID NO:2, and an HC-CDR 3 having the amino acid sequence shown in SEQ ID NO:4; (iv) variant of (i), (ii), or (iii) wherein at least one of HC CDR 1, HC-CDR 2, or CDR 3 comprises 1, 2, or 3 amino acid substitutions, additions, deletions, or combinations thereof; or (v) variant of (i), (ii), (iii), or (iv) wherein the HC framework comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, deletions, or combinations thereof;(b) a light chain (LC) having a constant domain and a variable domain wherein the variable domain comprises (i) an LC framework and light chain comprising a light chain-complementary determining region (LC-CDR) 1 having the amino acid sequence shown in SEQ ID NO:11, an LC-CDR 2 having the amino acid sequence shown in SEQ ID NO:12, and an LC-CDR 3 having the amino acid sequence shown in SEQ ID NO:13; (ii) an LC framework and light chain-complementary determining region (LC-CDR) 1 having the amino acid sequence shown in SEQ ID NO:5, an LC-CDR 2 having the amino acid sequence shown in SEQ ID NO:6, and an LC-CDR 3 having the amino acid sequence shown in SEQ ID NO:7; (iii) variant of (i) or (ii) wherein at least one of LC CDR 1, LC-CDR 2, or LC-CDR 3 comprises 1, 2, or 3 amino acid substitutions, additions, deletions, or combinations thereof;or (iv) variant of (i), (ii), or (iii) wherein the LC framework comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, deletions, or combinations thereof; or (c) an HC from (a) and an LC from (b); wherein the antibody binds the apple 3 domain of coagulation factor XI (FXI) and inhibits activation of FXI and / or Factor XIa-mediated activation of Factor IX.; 19. The antibody of claim 18, wherein the HC constant domain comprises the amino acid sequence shown in SEQ ID NO:16, 17, 18, or 19.

20. The antibody of claim 18 or 19, wherein the LC constant domain comprises the amino acid sequence shown in SEQ ID NO:

20.

21. An isolated nucleic acid molecule encoding the light chain variable domain or the heavy chain variable domain of any of the antibodies or antigen binding fragments of claims 1-20.

22. A composition comprising the antibody or antigen binding fragment of any one of claims 1-20 and a pharmaceutically acceptable carrier or diluent.

23. The antibody or antigen binding fragment of any one of claims 1-20 for use in treating a thromboembolic disorder or disease in a subject, comprising administering to the subject an effective amount of the antibody or antigen binding fragment of any one of claims 1-20.

24. Use of an antibody of any one of claim 1-20 for the manufacture of a medicament for treating a thromboembolic disorder or disease.

25. An antibody of any one of claims 1-20 for the treatment of a thromboembolic disorder or disease.

26. A human antibody or antigen binding fragment that binds to an epitope on coagulation factor XI (FXI), wherein the epitope comprises the amino acid sequence DIFPNTVF (SEQ ID NO:82) and amino acid sequence PSTRIKKSKALSG (SEQ ID NO:83) as determined by use of hydrogen deuterium exchange mass spectrometry (HDX-MS) analysis.

27. The human antibody of claim 26, wherein the antibody comprises (i) a human IgG1 constant domain or variant or modified derivative thereof or (ii) a human IgG4 constant domain or variant or modified derivative thereof.

28. The human antibody of claim 26, wherein the antibody comprises an IgG4 constant domain comprising a substitution of the serine at position 228 (EU numbering) or position 108 as shown herein with a proline residue.

29. A human antibody or antigen binding fragment that cross-blocks or competes with the binding of an antibody comprising a heavy chain having the amino acid sequence shown in SEQ ID NO: 33, 35, 37,39, 45, 47, 49, 51, 57, 59, 61, 63, 69, 71, 73, or 75 and a light chain having the amino acid sequence shown in SEQ ID NO: 26; or an antibody comprising a heavy chain having the amino acid sequence shown in SEQ ID NO: 41, 43, 53, 55, 65, 67, 77, or 79 and a light chain having the amino acid sequence shown in SEQ ID NO:

31.

30. The human antibody of claim 29, wherein the antibody comprises (i) a human IgG1 constant domain or variant or modified derivative thereof or (ii) a human IgG4 constant domain or variant or modified derivative thereof.

31. The human antibody of claim 30, wherein, the antibody comprises an IgG4 constant domain comprising a substitution of the serine at position 228 (EU numbering) or position 108 as shown herein with a proline residue.

32. A method for producing an antibody or antigen binding fragment comprising: (i) a heavy chain variable domain comprising a heavy chain-complementary determining region (HC-CDR) 1 having the amino acid sequence shown in SEQ ID NO:1, a HC-CDR 2 having the amino acid sequence shown in SEQ ID NO:2, and a HC-CDR 3 having the amino acid sequence shown in SEQ ID NO:3 or 4 or an HC-CDR 1 having the amino acid sequence shown in SEQ ID NO:8, an HC-CDR 2 having the amino acid sequence shown in SEQ ID NO:9, and an HC-CDR 3 having the amino acid sequence shown in SEQ ID NO:10;and (ii) a light chain variable domain comprising a light chain-complementary determining region (LC-CDR) 1 having the amino acid sequence shown in SEQ ID NO:5, a LC-CDR 2 having the amino acid sequence shown in SEQ ID NO:6, and a LC-CDR 3 having the amino acid sequence shown in SEQ ID NO:7 or an LC-CDR 1 having the amino acid sequence shown in SEQ ID NO:11, an LC-CDR 2 having the amino acid sequence shown in SEQ ID NO:12, and an LC-CDR 3 having the amino acid sequence shown in SEQ ID NO:13, the method comprising: providing a host cell comprising a nucleic acid molecule encoding the heavy chain and a nucleic acid molecule encoding the light chain; and cultivating the host cell under conditions and a time sufficient to produce the antibody or antigen binding fragment.; 33. The method of claim 32, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:21, 22, 23, or 24 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:

25.

34. The method of claim 32, wherein the antibody comprises a heavy chain constant domain of the IgG1, IgG2, IgG3, or IgG4 isotype.

35. The method of claim 32, wherein the antibody comprises a heavy chain constant domain of the IgG4 isotype.

36. The method of claim 32, wherein the antibody comprises a heavy chain constant domain comprising the amino acid sequence shown in SEQ ID NO:16, 17, 18, or 19.

37. The method of claim 32, wherein the light chain comprises a human kappa light chain or human lambda light chain.

38. The method of claim 32, wherein the antibody comprises a light chain constant domain comprising the amino acid sequence shown in SEQ ID NO:

20.

39. The method of claim 32, wherein the host cell is a Chinese hamster ovary cell or a human embryo kidney 293 cell.

40. The method of claim 32, wherein the host cell is a yeast or filamentous fungus cell.

41. A composition comprising any one of the antibodies of claims 1-20, wherein the antibody or antigen binding fragment is obtained from a host cell comprising a nucleic acid molecule encoding the heavy chain and a nucleic acid molecule encoding the light chain.

42. The composition of claim 41, wherein the antibody comprises a heavy chain constant domain of the IgG1, IgG2, IgG3, or IgG4 isotype.

43. The composition of claim 41, wherein the antibody comprises a heavy chain constant domain of the IgG4 isotype.

44. The composition of claim 41, wherein the antibody comprises a heavy chain constant domain comprising the amino acid sequence shown in SEQ ID NO:16, 17, 18, or 19.

45. The composition of claim 41, wherein the light chain comprises a human kappa light chain or human lambda light chain.

46. The composition of claim 41, wherein the antibody comprises a light chain constant domain comprising the amino acid sequence shown in SEQ ID NO:

20.

47. The composition of claim 41, wherein the host cell is a Chinese hamster ovary cell or a human embryo kidney 293 cell.

48. The composition of claim 41, wherein the host cell is a yeast or filamentous fungus cell. ABSTRACT OF THE DISCLOSURE A ntibodies that bind the apple 3 domain of human coagulation Factor XI and inhibit activation of FXI by coagulation factor XIIa as well as activation of FIX by FXIa are described.

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