Antibodies or Antigen-Binding Fragments, Composition, Use and Method for Producing an Antibody or Antigen-Binding Fragment

Abstract

Antibodies are described that bind to the apple 3 domain of human coagulation factor xi and inhibit activation of fxi by coagulation factor xia, as well as activation of fix by fxia.

Description

Antibodies or Antigen-Binding Fragments, Composition, Use and Method for Producing an Antibody or Antigen-Binding Fragment CROSS-REFERENCE TO RELATED ORDERS

[001] This application claims the benefit of U.S. Provisional Application No. 62 / 349,888, filed June 14, 2016, which is incorporated herein by reference in its entirety. BACKGROUND OF THE INVENTION (1) Field of the invention

[002] The present invention relates to antibodies that bind to the apple 3 domain of human coagulation factor XI (FXI) and inhibit the activation of FXI by coagulation factor XIIa as well as the activity of FXIa on Factor IX (FIX). (2) Description of the Related Technique

[003] Thromboembolic disorders, including both venous and arterial thrombosis, remain a major cause of morbidity and mortality in the Western world despite the availability of numerous classes of anticoagulants, such as vitamin K antagonists (VKAs), heparins, and direct thrombin inhibitors (Weitz et al., Chest 2008, 133: 234S-256S; Hawkins, Pharmacotherapy 2004, 24:62S-65S). These drugs are effective in reducing the risk of thrombosis, but they are associated with multiple limitations. For example, VKAs (e.g., warfarin) were the basis for oral anticoagulation; however, the management of VKA therapy is complicated due to its significant risk of hemorrhage, slow onset and compensation of action, and multiple food and drug interactions (Hawkins, op. cit.; Ansell J et al., Chest 2008, 133:160S-198S).Oral anticoagulants other than vitamin K antagonists (NOACs, including rivaroxaban, apixaban, edoxaban, and dabigatran) have demonstrated at least non-inferior efficacy compared to warfarin. Petition 870260051334, dated 05 / 28 / 2026, page 17 / 164 2 / 141 fewer food and drug interactions and no need for monitoring. However, NOACs still increase the risk of bleeding as demonstrated by the nearly 15% annual incidence of clinically relevant major or non-major bleeding in their registry experiences for stroke prevention in atrial fibrillation (Connolly et al., N Engl J Med 2009, 361:1139-1151; Patel et al., N Engl J Med 2011, 365:883-891; Granger et al., N Engl J Med 2011, 365:981-992; Giugliano et al., N Engl J Med 2013, 369:2093-2104). This is largely attributed to the fact that NOACs target proteins (coagulation Factor Xa (FXa) and thrombin) that are essential for normal coagulation (hemostasis). New therapies with improved safety profiles in the prevention and treatment of thrombotic diseases or disorders are therefore an unmet need.

[004] In the classic cascade model of the blood coagulation cascade (Fig. 1A), coagulation is triggered by the extrinsic pathway (activated by tissue factor (TF)) or the intrinsic pathway (activated by contact), both feeding into the common pathway that culminates in the generation of thrombin and fibrin formation (Furie & Furie, Cell 1988, 53:505-518; Gailani & Renne, J Thromb Haemost 2007, 5:1106-1112). The extrinsic cascade is initiated when TF, which is present in subendothelial and atherosclerotic lesions, becomes exposed to flowing blood and forms a complex with coagulation Factor VIIa (FVIIa). The TF-FVIIa complex (extrinsic tenase complex) then triggers the common pathway, i.e., activation of FX to form FXa, which in turn converts prothrombin to thrombin. The TF-FVIIa complex can also activate coagulation factor IX (FIX) to form FIXa. FIXa in complex with coagulation factor VIII (FVIIIa) (intrinsic tenase complex) can cleave the FX substrate as well.The intrinsic cascade is initiated when FXIIa is formed through contact activation of negatively charged surfaces (e.g., collagen and...). Petition 870260051334, dated 05 / 28 / 2026, page 18 / 164 3 / 141 glycosaminoglycans) and propagates thrombin generation by sequential activation of FXI, FIX, FX, and prothrombin. Thrombin, as the terminal protease in the coagulation cascade, can further contribute to FXIa generation by direct activation of FXI in a feedback mechanism. Platelets, another important hemostatic component in whole blood, can be activated by thrombin and can subsequently support FXIa formation as well. FXI-dependent amplification of thrombin generation can indirectly regulate fibrinolysis through activation of thrombin-activatable fibrinolysis inhibitor (TAFI). FXI thus interacts with various components in the hemostatic system and plays an essential role in blood coagulation and thrombosis (Gailani & Renne op. cit.; Emsley et al., Blood 2010, 115:2569-2577).

[005] Coagulation Factor XI (FXI) is a dimer composed of identical 80 kDa subunits, and each subunit starting from the N-terminus consists of four apple domains (A1, A2, A3, and A4) and a catalytic domain (See Fig. 1B). FXI is a zymogen that circulates in complex with high molecular weight kininogen (HK). HK binds to the A2 domain in FXI and is a physiological cofactor for FXIIa activation from FXI to FXIa. The remaining apple domains in FXI also mediate important physiological functions. For example, the FIX binding exosite is located at A3, while the FXIIa binding site is at A4. Residues that are critical for FXI dimerization are also located at A4 (Emsley et al., op. cit.).

[006] In recent years, multiple lines of research have demonstrated that FXI plays an essential role in the pathological process of blood clot formation with a relatively small contribution to hemostasis and is thus a promising target for thrombosis. Key data supporting this notion are summarized as follows: (1) in the Phase II antisense oligonucleotide assay of Petition 870260051334, dated 05 / 28 / 2026, page 19 / 164 4 / 141 FXI (ASO) at Ionis Pharmaceuticals Inc. (Buller et al., N Engl J Med 2015, 372:232-240), ASO FXI produced a significant reduction in venous thromboembolism (VTE), with a trend toward less bleeding, compared to enoxaparin, in patients undergoing total knee arthroplasty; (2) Human genetic and epidemiological studies (Duga et al., Semin Thromb Hemost 2013; Chen et al., Drug Discovery Today 2014; Key, Hematology Am Soc Hematol Education Program 2014, 2014:66-70) indicated that severe FXI deficiency (hemophilia C) confers a reduced risk of ischemic stroke and deep vein thrombosis; conversely, increased FXI levels are associated with a higher risk for VTE and ischemic stroke; and (3) Numerous lines of preclinical studies have demonstrated that inhibition or loss of function of FXI(a) mediates deep thromboprotection without compromising hemostasis (Chen et al. op. cit.).It is observed that the monoclonal antibodies 14E11 and 1A6 produced a significant reduction in blood clotting in the baboon AV shunt thrombosis model (US Patent No. 8,388,959; US Patent No. 8,236,316; Tucker et al., Blood 2009, 113:936-944; Cheng et al., Blood 2010, 116:3981-3989). Furthermore, 14E11 (as it cross-reacts with mouse FXI) provided protection in an experimental mouse model of acute ischemic stroke (Leung et al., Transl Stroke Res 2012, 3:381-389). Additional mAbs targeting FXI have also been reported in preclinical models to validate FXI as an antithrombotic target with minimal risk of bleeding (van Montfoort et al., Thromb Haemost 2013, 110; Takahashi et al., Thromb Res 2010, 125:464-470; van Montfoort, Ph.D. Thesis, University of Amsterdam, Amsterdam, Netherlands, November 14, 2014).FXI inhibition is therefore a promising strategy for novel antithrombotic therapy with an improved risk-benefit profile compared to current standard-of-care anticoagulants. Petition 870260051334, dated 05 / 28 / 2026, page 20 / 164 5 / 141

[007] There is currently a large unmet medical need for antithrombotic therapies for patients who have severe or end-stage renal disease (ESRD). Approximately 650,000 patients in the US have severe renal disease or ESRD, and these patients suffer an extremely high incidence of thrombotic and thromboembolic complications (MI, stroke / TIA, peripheral arterial disease (PAD), vascular access failure). Patients with ESRD are also more likely to experience bleeding events than the general population. Since anticoagulation of any kind is not commonly prescribed in patients with ESRD (due to the risk of bleeding and lack of data for non-vitamin K antagonist oral anticoagulants (NOACs) in ESRD), there is a need for an antithrombotic therapy that has an acceptable risk-benefit profile in these patients. BRIEF SUMMARY OF THE INVENTION

[008] The present invention provides human antibodies capable of selectively binding to coagulation factor XI (anti-FXI antibodies) and inhibiting blood coagulation and associated thrombosis, preferably without compromising hemostasis. Compositions include anti-coagulation factor XI antibodies capable of binding to a defined epitope of the apple 3 (A3) domain of coagulation factor XI. These antibodies exhibit neutralizing activity by inhibiting the conversion of FXI in zymogen form to its activated form, FXIa, under the action of FXIIa, and inhibiting FXIa-mediated activation of FIX. The antibodies are useful for inhibiting FXI, which can confer a clinically relevant antithrombotic effect with a reduced risk of hemorrhagic complications and consequently an expanded therapeutic index compared to the inhibition of more downstream coagulation factors such as FXa and thrombin.Therefore, these antibodies provide a therapeutic method for the prevention of thromboembolic complications, for example, stroke prevention. Petition 870260051334, dated 05 / 28 / 2026, page 21 / 164 6 / 141 atrial fibrillation (APF).

[009] An underserved cohort at risk of vascular thrombosis that may benefit from FXI inhibition is the population with severe end-stage renal disease (ESRD), in whom non-vitamin K antagonist oral anticoagulants (NOACs) are not typically used due to concerns regarding bleeding, which have led to a lack of clinical trial experience. The antibodies here provide a novel anticoagulant therapy for the prevention of thrombotic complications in patients with ESRD. The antibodies here may provide clinically relevant antithrombotic efficacy accompanied by an acceptable risk of bleeding in patients with ESRD.

[010] In addition to ESRD and SPAF, FXI inhibition may also be indicated in additional patient segments that are at high risk of thrombosis. These include: 1) venous thromboembolism (VTE) prophylaxis in orthopedic surgery and / or secondary prevention of VTE; 2) reduction of revascularization and / or reduction of Major Adverse Limb Events (MALE) in PAD; 3) adjuvant therapy in ACS.

[011] The present invention provides an antibody or antigen-binding fragment comprising at least the six complementarity-determining regions (CDRs) of an anti-FXI antibody of the aFXI-18623p family, aFXI-18611p family, or aFXI-18611 family, or at least the six complementarity-determining regions (CDRs) of an anti-FXI antibody of the aFXI-18623p family, aFXI-18611p family, or aFXI-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 aFXI18623 family comprises a variable heavy chain (HC) region having the amino acid sequence shown in SEQ ID NO: 28 or 29 and a variable LC region having the amino acid sequence shown in SEQ ID NO: 30; an antibody of Petition 870260051334, dated 05 / 28 / 2026, page 22 / 164 The 7 / 141 aFXI-18611p family comprises a variable HC region having the amino acid sequence shown in SEQ ID NO: 21 or 22 and a variable light chain (LC) region having the amino acid sequence shown in SEQ ID NO: 25; and the aFXI-18611 family antibody comprises a variable HC region having the amino acid sequence shown in SEQ ID NO: 23 or 24 and a variable LC region having the amino acid sequence shown in SEQ ID NO: 25. In additional embodiments, the antibody or antigen-binding fragment binds to the apple 3 domain of coagulation factor XI (FXI) and inhibits FXI activation and / or Factor XIa-mediated activation of Factor IX.

[012] In further aspects or embodiments of the invention, the six CDRs comprise or consist of CDR1, CDR2, and CDR3 of the HC of an anti-FXI antibody of the aFXI-18623p family, aFXI-18611p family, or aFXI-18611 family and CDR1, CDR2, and CDR3 of the LC of the aFXI-18623p family, aFXI-18611p family, or aFXI-18611 family, wherein an antibody of the aFXI-118623 family comprises a variable HC region having the amino acid sequence shown in SEQ ID NO: 28 or 29 and a variable LC region having the amino acid sequence shown in SEQ ID NO: 30; An antibody of the aFXI-18611p family comprises a variable heavy chain (HC) region having the amino acid sequence shown in SEQ ID NO: 21 or 22 and a variable light chain (LC) region having the amino acid sequence shown in SEQ ID NO: 25;And, an antibody of the aFXI-18611 family comprises a variable HC region having the amino acid sequence shown in SEQ ID NO: 23 or 24 and a variable LC region having the amino acid sequence shown in SEQ ID NO: 25. In further embodiments, the antibody or antigen-binding fragment binds to the apple 3 domain of coagulation factor XI (FXI) and inhibits FXI activation and / or Factor XIa-mediated activation of Factor IX.

[013] In additional aspects or embodiments of the invention, the antibody or Petition 870260051334, dated 05 / 28 / 2026, page 23 / 164 The antigen-binding fragment 8 / 141 comprises a variable HC region having an amino acid sequence selected from the group of amino acid sequences consisting of SEQ ID NO: 21, 22, 23, and 24; and a variable LC region having the amino acid sequence shown in SEQ ID NO: 25; wherein the framework of the variable HC region may comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, deletions, or combinations thereof, and the framework of the variable LC region may comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, deletions, or combinations thereof.

[014] In further aspects or embodiments of the invention, the antibody or antigen-binding fragment comprises a variable HC region having an amino acid sequence selected from the group of amino acid sequences consisting of SEQ ID NO: 21, 22, 23, and 24; and a variable LC region having the amino acid sequence shown in SEQ ID NO: 25.

[015] In further aspects or embodiments of the invention, the antibody or antigen-binding fragment comprises a variable HC region having an amino acid sequence selected from the group of amino acid sequences consisting of SEQ ID NO: 28 and 29; and a variable LC region having the amino acid sequence shown in SEQ ID NO: 30; wherein the framework of the variable HC region may comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, deletions, or combinations thereof and the framework of the variable LC region may comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, deletions, or combinations thereof.

[016] In further aspects or embodiments of the invention, the antibody or antigen-binding fragment comprises a variable HC region having an amino acid sequence selected from the group of sequences of Petition 870260051334, dated 05 / 28 / 2026, page 24 / 164 9 / 141 amino acids consisting of SEQ ID NO: 28 and 29; and a variable LC region having the amino acid sequence shown in SEQ ID NO: 30.

[017] In further aspects or embodiments of the invention, the antibody comprises a constant heavy chain domain of the human IgG1, IgG2, IgG3, or IgG4 isotype. In further aspects, the constant domain may comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, deletions, or combinations thereof. In particular aspects, the constant domain may comprise a C-terminal lysine or may lack a C-terminal lysine.

[018] In further aspects or embodiments of the invention, the antibody comprises a constant heavy chain domain of the human IgG1 or IgG4 isotype. In another aspect, the constant heavy chain domain is of the IgG4 isotype and further includes a substitution of the serine residue at position 228 (EU numbering) with proline, which corresponds to position 108 of SEQ ID NO: 16 or 17 (Serine at position 108).

[019] In further aspects or embodiments of the invention, the antibody comprises a constant HC domain comprising the amino acid sequence shown in SEQ ID NO: 16, 17, 18, or 19.

[020] In additional aspects or embodiments of the invention, the antibody comprises a constant domain of human kappa or lambda type light chain.

[021] In further aspects or embodiments of the invention, the antibody comprises a constant LC domain comprising the amino acid sequence shown in SEQ ID NO: 20.

[022] In further aspects or embodiments of the invention, the antibody or antigen-binding fragment comprises a HC having an amino acid sequence selected from the group of amino acid sequences consisting Petition 870260051334, dated 05 / 28 / 2026, p. 25 / 164 10 / 141 in SEQ ID NO: 33, 35, 37, 39, 45, 47, 49, 51, 57, 59, 61, 63, 69, 71, 73, and 75; and a LC having the amino acid sequence shown in SEQ ID NO: 26.

[023] In further aspects or embodiments of the invention, the antibody or antigen-binding fragment comprises a HC having an amino acid sequence selected from the group of amino acid sequences consisting of SEQ ID NO: 41, 43, 53, 55, 65, 67, 77, and 79; and a LC having the amino acid sequence shown in SEQ ID NO: 31.

[024] The present invention further provides an antibody or antigen-binding fragment comprising (a) a variable heavy chain (HC) domain having the amino acid sequence shown in SEQ ID NO: 28 and a variable light chain (LC) domain having the amino acid sequence shown in SEQ ID NO: 30; (b) a variable heavy chain (HC) domain having the amino acid sequence shown in SEQ ID NO: 29 and a variable light chain (LC) domain having the amino acid sequence shown in SEQ ID NO: 30; (b) a variable heavy chain (HC) domain having the amino acid sequence shown in SEQ ID NO: 21 and a variable light chain (LC) domain having the amino acid sequence shown in SEQ ID NO: 25; (c) a variable heavy chain (HC) domain having the amino acid sequence shown in SEQ ID NO: 22 and a variable light chain (LC) domain having the amino acid sequence shown in SEQ ID NO: 25;(d) a variable heavy chain (HC) domain having the amino acid sequence shown in SEQ ID NO: 23 and a variable light chain (LC) domain having the amino acid sequence shown in SEQ ID NO: 25, or (e) a variable heavy chain (HC) domain having the amino acid sequence shown in SEQ ID NO: 24 and a variable light chain (LC) domain having the amino acid sequence shown in SEQ ID NO: 25.;

[025] In additional embodiments, the antibody or binding fragment to Petition 870260051334, dated 05 / 28 / 2026, page 26 / 164 The 11 / 141 antigen binds to the apple 3 domain of coagulation factor XI (FXI) and inhibits FXI activation and / or Factor XIa-mediated activation of Factor IX.

[026] In particular embodiments, the variable regions of HC and LC may comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, deletions, or combinations thereof.

[027] In particular embodiments, the constant domains of HC and LC may comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, deletions, or combinations thereof. In particular aspects, the constant domain may comprise a C-terminal lysine or may lack a C-terminal lysine.

[028] In particular embodiments, the variable regions of HC and LC may comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, deletions, or combinations thereof, and the constant domains of HC and LC may comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, deletions, or combinations thereof. In particular aspects, the constant domain may comprise a C-terminal lysine or may lack a C-terminal lysine.

[029] In additional aspects or embodiments of the invention, the antibody further comprises a constant HC domain comprising the amino acid sequence shown in SEQ ID NO: 16, 17, 18, or 19 or a variant thereof comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, deletions, or combinations thereof.

[030] In additional aspects or embodiments of the invention, the antibody further comprises a constant LC 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, deletions, or combinations thereof. Petition 870260051334, dated 05 / 28 / 2026, p. 27 / 164 12 / 141

[031] In another aspect or embodiment of the invention, the antibody or antigen-binding fragment comprises (a) a variable heavy chain (HC) domain having the amino acid sequence shown in SEQ ID NO: 28 and a variable light chain (LC) domain having the amino acid sequence shown in SEQ ID NO: 30; (b) a variable heavy chain (HC) domain having the amino acid sequence shown in SEQ ID NO: 29 and a variable light chain (LC) domain having the amino acid sequence shown in SEQ ID NO: 30; (c) a variable heavy chain (HC) domain having the amino acid sequence shown in SEQ ID NO: 21 and a variable light chain (LC) domain having the amino acid sequence shown in SEQ ID NO: 25; (d) a variable heavy chain (HC) domain having the amino acid sequence shown in SEQ ID NO: 22 and a variable light chain (LC) domain having the amino acid sequence shown in SEQ ID NO: 25;(e) a variable heavy chain (HC) domain having the amino acid sequence shown in SEQ ID NO: 23 and a variable light chain (LC) domain having the amino acid sequence shown in SEQ ID NO: 25; (f) a variable heavy chain (HC) domain having the amino acid sequence shown in SEQ ID NO: 24 and a variable light chain (LC) 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 framework of the variable HC region comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, deletions, or combinations thereof; or, (h) a variant of (a), (b), (c), (d), (e), (f), or (g) wherein the framework of the variable region of LC comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, deletions, or combinations thereof.

[032] The present invention further provides an antibody comprising (a) a heavy chain (HC) having a constant domain and a variable domain wherein the variable domain comprises a determining region of Petition 870260051334, dated 05 / 28 / 2026, page 28 / 164 13 / 141 heavy chain complementarity (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; (b) 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) 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;or (c) 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) 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. In further embodiments, the antibody or antigen-binding fragment binds to the apple 3 domain of coagulation factor XI (FXI) and inhibits FXI activation and / or Factor XIa-mediated activation of Factor IX.

[033] In further aspects or embodiments of the invention, the antibody comprises a constant heavy chain domain of the human IgG1, IgG2, IgG3, or IgG4 isotype. In further aspects, the constant domain may comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, deletions, or combinations thereof when compared to the amino acid sequence of the native constant heavy chain domain for the human IgG1, IgG2, IgG3, or IgG4 isotype. In particular aspects, the constant domain may comprise a C-terminal lysine or may lack a C-terminal lysine. Petition 870260051334, dated 05 / 28 / 2026, page 29 / 164 14 / 141

[034] In further aspects or embodiments of the invention, the antibody comprises a constant heavy chain domain of the human IgG1 or IgG4 isotype. In another aspect, the constant heavy chain domain is of the IgG4 isotype and further includes a substitution of the serine residue at position 228 (EU numbering) with proline, which corresponds to position 108 of SEQ ID NO: 16 or 17 (Serine at position 108).

[035] In further aspects or embodiments of the invention, the antibody comprises a constant domain of IgG4 heavy chain comprising the amino acid sequence shown in SEQ ID NO: 16 or 17. In further aspects, the constant domain may comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, deletions, or combinations thereof.

[036] In further aspects or embodiments of the invention, the antibody comprises a constant domain of IgG1 heavy chain comprising the amino acid sequence shown in SEQ ID NO: 18 or 19. In further aspects, the constant domain may comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, deletions, or combinations thereof.

[037] The present invention further provides an antibody or antigen-binding fragment 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 (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; or (b) a light chain (LC) having a constant domain and a variable domain wherein the variable domain comprises a light chain comprising a light chain complementarity-determining region (LC-CDR) 1 having a Petition 870260051334, dated 05 / 28 / 2026, page 30 / 164 15 / 141 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. In additional embodiments, the antibody or antigen-binding fragment binds to the apple 3 domain of coagulation factor XI (FXI) and inhibits FXI activation and / or Factor XIa-mediated activation of Factor IX.

[038] In further aspects or embodiments of the invention, the light chain (LC) comprises a human kappa light chain or human lambda light chain or variant 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 to the apple 3 domain of coagulation factor XI (FXI) and inhibits FXI activation and / or Factor XIa-mediated activation of Factor IX. In further aspects or embodiments of the invention, the antibody comprises a constant light chain domain comprising the amino acid sequence shown in SEQ ID NO: 20.

[039] In further aspects or embodiments of the invention, the antibody comprises a constant IgG4 heavy chain domain comprising the amino acid sequence shown 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, deletions, or combinations thereof, wherein the antibody or antigen-binding fragment binds to the apple 3 domain of coagulation factor XI (FXI) and inhibits FXI activation and / or Factor XIa-mediated activation of Factor IX.

[040] In further aspects or embodiments of the invention, the antibody comprises a constant IgG1 heavy chain domain comprising the amino acid sequence shown in SEQ ID NO: 18 or 19 or a variant thereof comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 substitutions, additions, Petition 870260051334, dated 05 / 28 / 2026, page 31 / 164 16 / 141 amino acid deletions, or combinations thereof, in which the antibody or antigen-binding fragment binds to the apple 3 domain of coagulation factor XI (FXI) and inhibits FXI activation and / or Factor XIa-mediated activation of Factor IX.

[041] The present invention further provides an antibody or antigen-binding fragment 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 (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; and (b) a light chain (LC) having a constant domain and a variable domain wherein the variable domain comprises a light chain complementarity-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. In additional embodiments, the antibody or antigen-binding fragment binds to the apple 3 domain of coagulation factor XI (FXI) and inhibits FXI activation and / or Factor XIa-mediated activation of Factor IX.

[042] In further aspects or embodiments of the invention, the light chain 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, deletions, or combinations thereof, wherein the antibody or antigen-binding fragment binds to the apple 3 domain of coagulation factor XI (FXI) and inhibits FXI activation and / or antigen-mediated activation. Petition 870260051334, dated 05 / 28 / 2026, page 32 / 164 17 / 141 Factor XIa of Factor IX. In further aspects or embodiments of the invention, the antibody comprises a constant light chain domain comprising the amino acid sequence shown in SEQ ID NO: 20.

[043] In further aspects or embodiments of the invention, the antibody comprises a constant heavy chain domain of the IgG1, IgG2, IgG3, or IgG4 isotype or variant thereof comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, deletions, or combinations thereof compared to the amino acid sequence of the native IgG1, IgG2, IgG3, or IgG4 isotype, wherein the antibody or antigen-binding fragment binds to the apple 3 domain of coagulation factor XI (FXI) and inhibits FXI activation and / or Factor XIa-mediated activation of Factor IX. In further aspects, the constant domain may comprise a C-terminal lysine or may lack a C-terminal lysine.

[044] In further aspects or embodiments of the invention, the antibody comprises a constant heavy chain domain of the human IgG1 or IgG4 isotype or variant 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 to the apple 3 domain of coagulation factor XI (FXI) and inhibits FXI activation and / or Factor XIa-mediated activation of Factor IX. In another aspect, the constant heavy chain domain is of the IgG4 isotype and further includes a substitution of the serine residue at position 228 (EU numbering) with proline, which corresponds to position 108 of SEQ ID NO: 16 or 17 (Serine at position 108).

[045] In further aspects or embodiments of the invention, the antibody comprises a constant IgG4 heavy chain domain comprising the amino acid sequence shown in SEQ ID NO: 16 or 17 or a variant thereof comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 substitutions, additions, Petition 870260051334, dated 05 / 28 / 2026, page 33 / 164 18 / 141 amino acid deletions, or combinations thereof, in which the antibody or antigen-binding fragment binds to the apple 3 domain of coagulation factor XI (FXI) and inhibits FXI activation and / or Factor XIa-mediated activation of Factor IX.

[046] In further aspects or embodiments of the invention, the antibody comprises a constant IgG1 heavy chain domain comprising the amino acid sequence shown 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, deletions, or combinations thereof, wherein the antibody or antigen-binding fragment binds to the apple 3 domain of coagulation factor XI (FXI) and inhibits FXI activation and / or Factor XIa-mediated activation of Factor IX.

[047] The present invention further provides an antibody or antigen-binding fragment 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 (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; and (b) a light chain (LC) having a constant domain and a variable domain wherein the variable domain comprises a light chain complementarity-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. In further embodiments, the antibody or antigen-binding fragment binds to the apple 3 domain of factor XI of Petition 870260051334, dated 05 / 28 / 2026, page 34 / 164 19 / 141 coagulation (FXI) and inhibits FXI activation and / or Factor XIa-mediated activation of Factor IX.

[048] In further aspects or embodiments of the invention, the light chain 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, deletions, or combinations thereof, wherein the antibody or antigen-binding fragment binds to the apple 3 domain of coagulation factor XI (FXI) and inhibits FXI activation and / or Factor XIa-mediated activation of Factor IX. In further aspects or embodiments of the invention, the antibody comprises a constant light chain domain comprising the amino acid sequence shown in SEQ ID NO: 20.

[049] In further aspects or embodiments of the invention, the antibody comprises a constant heavy chain domain of the IgG1, IgG2, IgG3, or IgG4 isotype or variant thereof comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, deletions, or combinations thereof compared to the amino acid sequence of the native IgG1, IgG2, IgG3, or IgG4 isotype, wherein the antibody or antigen-binding fragment binds to the apple 3 domain of coagulation factor XI (FXI) and inhibits FXI activation and / or Factor XIa-mediated activation of Factor IX. In further aspects, the constant domain may comprise a C-terminal lysine or may lack a C-terminal lysine.

[050] In further aspects or embodiments of the invention, the antibody comprises a constant heavy chain domain of the human IgG1 or IgG4 isotype or variant 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 to the apple 3 domain of coagulation factor XI (FXI) and inhibits FXI activation and / or antigen-mediated activation. Petition 870260051334, dated 05 / 28 / 2026, page 35 / 164 20 / 141 by Factor XIa of Factor IX. In another aspect, the constant heavy chain domain is of the IgG4 isotype and also includes a substitution of the serine residue at position 228 (EU numbering) with proline, which corresponds to position 108 of SEQ ID NO: 16 or 17 (Serine at position 108).

[051] In further aspects or embodiments of the invention, the antibody comprises a constant IgG4 heavy chain domain comprising the amino acid sequence shown 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, deletions, or combinations thereof, wherein the antibody or antigen-binding fragment binds to the apple 3 domain of coagulation factor XI (FXI) and inhibits FXI activation and / or Factor XIa-mediated activation of Factor IX.

[052] In further aspects or embodiments of the invention, the antibody comprises a constant IgG1 heavy chain domain comprising the amino acid sequence shown 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, deletions, or combinations thereof, wherein the antibody or antigen-binding fragment binds to the apple 3 domain of coagulation factor XI (FXI) and inhibits FXI activation and / or Factor XIa-mediated activation of Factor IX.

[053] The present invention further provides an antibody or antigen-binding fragment 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 (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 sequence of Petition 870260051334, dated 05 / 28 / 2026, page 36 / 164 21 / 141 amino acids shown in SEQ ID NO: 10; and (b) a light chain (LC) having a constant domain and a variable domain wherein the variable domain comprises a light chain complementarity-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. In further embodiments, the antibody or antigen-binding fragment binds to the apple 3 domain of coagulation factor XI (FXI) and inhibits FXI activation and / or Factor XIa-mediated activation of Factor IX.

[054] In further aspects or embodiments of the invention, the light chain comprises a human kappa light chain or human lambda light chain or variant 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 to the apple 3 domain of coagulation factor XI (FXI) and inhibits FXI activation and / or Factor XIa-mediated activation of Factor IX. In further aspects or embodiments of the invention, the antibody comprises a constant light chain domain comprising the amino acid sequence shown in SEQ ID NO: 20.

[055] In further aspects or embodiments of the invention, the antibody comprises a constant heavy chain domain of the IgG1, IgG2, IgG3, or IgG4 isotype or variant thereof comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, deletions, or combinations thereof compared to the amino acid sequence of the native IgG1, IgG2, IgG3, or IgG4 isotype, wherein the antibody or antigen-binding fragment binds to the apple 3 domain of coagulation factor XI (FXI) and inhibits FXI activation and / or Factor XIa-mediated activation of Factor IX. In further aspects, the domain Petition 870260051334, dated 05 / 28 / 2026, page 37 / 164 The 22 / 141 constant may comprise a C-terminal lysine or may lack a C-terminal lysine.

[056] In further aspects or embodiments of the invention, the antibody comprises a constant heavy chain domain of the human IgG1 or IgG4 isotype or variant 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 to the apple 3 domain of coagulation factor XI (FXI) and inhibits FXI activation and / or Factor XIa-mediated activation of Factor IX. In another aspect, the constant heavy chain domain is of the IgG4 isotype and further includes a substitution of the serine residue at position 228 (EU numbering) with proline, which corresponds to position 108 of SEQ ID NO: 16 or 17 (Serine at position 108).

[057] In further aspects or embodiments of the invention, the antibody comprises a constant IgG4 heavy chain domain comprising the amino acid sequence shown 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, deletions, or combinations thereof, wherein the antibody or antigen-binding fragment binds to the apple 3 domain of coagulation factor XI (FXI) and inhibits FXI activation and / or Factor XIa-mediated activation of Factor IX.

[058] In further aspects or embodiments of the invention, the antibody comprises a constant heavy chain domain of IgG1 comprising the amino acid sequence shown 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, deletions, or combinations thereof, wherein the antibody or antigen-binding fragment binds to the apple 3 domain of coagulation factor XI (FXI) and inhibits FXI activation and / or Factor XIa-mediated activation of Petition 870260051334, dated 05 / 28 / 2026, page 38 / 164 23 / 141 Factor IX.

[059] In further aspects or embodiments of the invention, 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 (i) an HC framework and heavy chain complementarity-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 complementarity-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) a HC framework and heavy chain complementarity-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) a variant of (i), (ii), or (iii) in which 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) a variant of (i), (ii), (iii), or (iv) in which 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 and light chain framework comprising a light chain complementarity-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 a; Petition 870260051334, dated 05 / 28 / 2026, page 39 / 164 24 / 141 amino acid sequence shown in SEQ ID NO: 13; (ii) an LC framework and light chain complementarity-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) a variant of (i) or (ii) in which 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) a 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) a HC of (a) and an LC of (b); wherein the antibody binds to the apple 3 domain of coagulation factor XI (FXI) and inhibits FXI activation and / or Factor XIa-mediated activation of Factor IX.

[060] In additional aspects or embodiments of the invention, 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.

[061] In additional aspects or embodiments of the invention, the antibody of claim 18 or 19, wherein the constant domain of LC comprises the amino acid sequence shown in SEQ ID NO: 20.

[062] 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.

[063] The present invention further provides an antibody comprising a heavy chain having the amino acid sequence shown in SEQ ID NO: 35 and a light chain having the amino acid sequence shown in SEQ ID NO: 26.

[064] The present invention further provides an antibody comprising Petition 870260051334, dated 05 / 28 / 2026, p. 40 / 164 25 / 141 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.

[065] The present invention further 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.

[066] The present invention further 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.

[067] The present invention further 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.

[068] The present invention further 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.

[069] The present invention further 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.

[070] The present invention further 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. Petition 870260051334, dated 05 / 28 / 2026, p. 41 / 164 26 / 141

[071] 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: 26.

[072] 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.

[073] The present invention further provides an antibody comprising a heavy chain having the amino acid sequence shown in SEQ ID NO: 71 and a light chain having the amino acid sequence shown in SEQ ID NO: 26.

[074] 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.

[075] 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.

[076] 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.

[077] 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: Petition 870260051334, dated 05 / 28 / 2026, p. 42 / 164 27 / 141 31.

[078] 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.

[079] 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.

[080] 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.

[081] 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.

[082] 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.

[083] The present invention further 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.

[084] The present invention further provides an antibody comprising a heavy chain having the amino acid sequence shown in SEQ ID NO: Petition 870260051334, dated 05 / 28 / 2026, p. 43 / 164 28 / 141 and a light chain having the amino acid sequence shown in SEQ ID NO: 31.

[085] 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.

[086] 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.

[087] The present invention further provides an 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, 45, 47, 49, 51, 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: 39, 41, 43, 53, 55, 57, 65, 67, 69, 77, or 79 and a light chain having the amino acid sequence shown in SEQ ID NO: 31, provided that the antibody or antigen-binding fragment does not comprise murine or rat amino acid sequences.

[088] In another embodiment, the antibody or antigen-binding fragment does not comprise non-human amino acid sequences.

[089] In another embodiment, the antibody comprises (i) a human IgG1 constant domain or a variant or modified derivative thereof or (ii) a human IgG4 constant domain or a variant or modified derivative thereof.

[090] In another embodiment, the constant domain of IgG1 or IgG4 is Petition 870260051334, dated 05 / 28 / 2026, page 44 / 164 29 / 141 a variant comprising at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, deletions, or combinations thereof.

[091] In another embodiment, the constant domain of IgG1 or IgG4 is a variant comprising at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, deletions, or combinations thereof.

[092] In another embodiment, the constant domain of IgG4 is a variant comprising at least one serine substitution at position 228 (EU numbering) or position 108 as shown here with a proline residue.

[093] In another embodiment, the constant domain of IgG1 or IgG4 is a variant that at least lacks a lysine at the C-terminus.

[094] In another embodiment, the antibody or antigen-binding fragment comprises variable domain sequences comprising a framework characteristic of human antibodies.

[095] The present invention further provides 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, 45, 47, 49, 51, 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: 39, 41, 43, 53, 55, 57, 65, 67, 69, 77, or 79 and a light chain having the amino acid sequence shown in SEQ ID NO: 31.

[096] In another embodiment, the antibody or antigen-binding fragment does not comprise non-human amino acid sequences.

[097] In another embodiment, the antibody comprises (i) a human IgG1 constant domain or a variant or modified derivative thereof or (ii) a human IgG4 constant domain or a variant or modified derivative thereof Petition 870260051334, dated 05 / 28 / 2026, page 45 / 164 30 / 141 same.

[098] In another embodiment, the constant domain of IgG1 or IgG4 is a variant comprising at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, deletions, or combinations thereof.

[099] In another embodiment, the constant domain of IgG1 or IgG4 is a variant comprising at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, deletions, or combinations thereof.

[0100] In another embodiment, the constant domain of IgG4 is a variant comprising at least one serine substitution at position 228 (EU numbering) or position 108 as shown here with a proline residue.

[0101] In another embodiment, the constant domain of IgG1 or IgG4 is a variant that at least lacks a lysine at the C-terminus.

[0102] In another embodiment, the antibody or antigen-binding fragment comprises variable domain sequences comprising a framework characteristic of human antibodies.

[0103] The present invention further provides an 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 or antigen-binding fragment does not comprise murine or rat amino acid sequences. In particular embodiments, epitope binding is determined by hydrogen / deuterium exchange mass spectrometry.

[0104] In another embodiment, the antibody or antigen-binding fragment does not comprise non-human amino acid sequences.

[0105] In another embodiment, the antibody comprises (i) a constant domain of human IgG1 or a variant or modified derivative thereof or (ii) Petition 870260051334, dated 05 / 28 / 2026, page 46 / 164 31 / 141 a constant domain of human IgG4 or a variant or modified derivative thereof.

[0106] In another embodiment, the constant domain of IgG1 or IgG4 is a variant comprising at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, deletions, or combinations thereof.

[0107] In another embodiment, the constant domain of IgG1 or IgG4 is a variant comprising at least 1, 2, 3, or 4 amino acid substitutions, additions, deletions, or combinations thereof.

[0108] In another embodiment, the constant domain of IgG4 is a variant comprising at least one serine substitution at position 228 (EU numbering) or position 108 as shown here with a proline residue.

[0109] In another embodiment, the constant domain of IgG1 or IgG4 is a variant that at least lacks a lysine at the C-terminus.

[0110] In another embodiment, the antibody or antigen-binding fragment comprises variable domain sequences comprising a framework characteristic of human antibodies.

[0111] 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 IgG1 constant domain or a variant or modified derivative thereof or (ii) a human IgG4 constant domain or a variant or modified derivative thereof. In particular embodiments, epitope binding is determined by hydrogen / deuterium exchange mass spectrometry.

[0112] In another embodiment, the constant domain of IgG1 or IgG4 is a variant comprising at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 Petition 870260051334, dated 05 / 28 / 2026, page 47 / 164 32 / 141 amino acid substitutions, additions, deletions, or combinations thereof.

[0113] In another embodiment, the constant domain of IgG1 or IgG4 is a variant comprising at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, deletions, or combinations thereof.

[0114] In another embodiment, the constant domain of IgG4 is a variant comprising at least one serine substitution at position 228 (EU numbering) or position 108 as shown here with a proline residue.

[0115] In another embodiment, the constant domain of IgG1 or IgG4 is a variant that at least lacks a lysine at the C-terminus.

[0116] In another embodiment, the antibody or antigen-binding fragment comprises variable domain sequences comprising a framework characteristic of human antibodies.

[0117] The present invention further provides an isolated nucleic acid molecule encoding either the variable light chain domain or the variable heavy chain domain of either of the aforementioned antibodies or antigen-binding fragments.

[0118] The present invention further 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 IgG1 constant domain or a variant or modified derivative thereof or (ii) a human IgG4 constant domain or a variant or modified derivative thereof. In particular embodiments, epitope binding is determined by hydrogen / deuterium exchange mass spectrometry.

[0119] In another embodiment, the constant domain of IgG1 or IgG4 is a variant comprising at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 Petition 870260051334, dated 05 / 28 / 2026, p. 48 / 164 33 / 141 amino acid substitutions, additions, deletions, or combinations thereof.

[0120] In another embodiment, the constant domain of IgG1 or IgG4 is a variant comprising at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, deletions, or combinations thereof.

[0121] In another embodiment, the constant domain of IgG4 is a variant comprising at least one serine substitution at position 228 (EU numbering) or position 108 as shown here with a proline residue.

[0122] In another embodiment, the constant domain of IgG1 or IgG4 is a variant that at least lacks a lysine at the C-terminus.

[0123] In another embodiment, the antibody or antigen-binding fragment comprises variable domain sequences comprising a framework characteristic of human antibodies.

[0124] The present invention further provides an isolated nucleic acid molecule encoding either the variable light chain domain or the variable heavy chain domain of either of the aforementioned antibodies or antigen-binding fragments.

[0125] The present invention further provides a composition comprising the antibody or antigen-binding fragment of any of the aforementioned antibodies or antigen-binding fragments and a pharmaceutically acceptable carrier or diluent.

[0126] The present invention further provides a method of 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 of the antibodies or antigen-binding fragments mentioned above.

[0127] The present invention further provides a method of treating a thromboembolic disorder or disease in a subject comprising Petition 870260051334, dated 05 / 28 / 2026, page 49 / 164 34 / 141 administer to a subject in need thereof an effective amount of the antibody or antigen-binding fragments of any of the antibodies or antigen-binding fragments previously mentioned.

[0128] The present invention further takes into account the use of an antibody of any of the antibodies or antigen-binding fragments previously mentioned for the manufacture of a medicament to treat a thromboembolic disorder or disease.

[0129] The present invention further provides an antibody of any of the previously mentioned antibodies or antigen-binding fragments for the treatment of a thromboembolic disorder or disease.

[0130] The present invention further provides a method for producing an antibody or antigen-binding fragment comprising (i) a heavy chain having a constant domain and a variable domain wherein the variable domain comprises a heavy chain comprising a heavy chain complementarity-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 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) 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, 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 culturing the host cell under conditions and for a time sufficient to produce the antibody or fragment thereof; Petition 870260051334, dated 05 / 28 / 2026, page 50 / 164 35 / 141 antigen binding.

[0131] In additional aspects or embodiments of the invention, the antibody comprises a constant heavy chain domain of the IgG1, IgG2, IgG3, or IgG4 isotype.

[0132] In additional aspects or embodiments of the invention, the antibody comprises a constant heavy chain domain of the IgG4 isotype.

[0133] In further aspects or embodiments of the invention, the antibody comprises a constant heavy chain domain comprising the amino acid sequence shown in SEQ ID NO: 16, 17, 18, or 19.

[0134] In additional aspects or embodiments of the invention, the light chain comprises a human kappa light chain or a human lambda light chain.

[0135] In further aspects or embodiments of the invention, the antibody comprises a constant light chain domain comprising the amino acid sequence shown in SEQ ID NO: 20.

[0136] In additional aspects or embodiments of the invention, the host cell is a Chinese hamster ovary cell or a human embryonic renal cell.

[0137] In additional aspects or embodiments of the invention, the host cell is a yeast or filamentous fungus cell.

[0138] The present invention further provides a method for producing an antibody or antigen-binding fragment comprising (i) a heavy chain having a constant domain and a variable domain wherein the variable domain comprises a heavy chain comprising a heavy chain complementarity-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 or 4; and (ii) a light chain Petition 870260051334, dated 05 / 28 / 2026, page 51 / 164 36 / 141 having a constant domain and a variable domain wherein the variable domain comprises a light chain complementarity-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, 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 culturing the host cell under conditions and time sufficient to produce the antibody or antigen-binding fragment.

[0139] In additional aspects or embodiments of the invention, the antibody comprises a constant heavy chain domain of the IgG1, IgG2, IgG3, or IgG4 isotype.

[0140] In additional aspects or embodiments of the invention, the antibody comprises a constant heavy chain domain of the IgG4 isotype.

[0141] In further aspects or embodiments of the invention, the antibody comprises a constant heavy chain domain comprising the amino acid sequence shown in SEQ ID NO: 16, 17, 18, or 19.

[0142] In additional aspects or embodiments of the invention, the light chain comprises a human kappa light chain or a human lambda light chain.

[0143] In further aspects or embodiments of the invention, the antibody comprises a constant light chain domain comprising the amino acid sequence shown in SEQ ID NO: 20.

[0144] In additional aspects or embodiments of the invention, the host cell is a Chinese hamster ovary cell or a human embryonic kidney cell 293.

[0145] In additional aspects or embodiments of the invention, the cell Petition 870260051334, dated 05 / 28 / 2026, page 52 / 164 37 / 141 The host is a yeast cell or filamentous fungus.

[0146] A method for producing an antibody or antigen-binding fragment comprising (i) a variable heavy chain domain comprising a heavy chain complementarity-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 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 variable light chain domain comprising a light chain complementarity-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 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 culturing the host cell under conditions and for a time sufficient to produce the antibody or antigen-binding fragment.

[0147] In additional aspects or embodiments of the invention, the antibody comprises a constant heavy chain domain of the IgG1, IgG2, IgG3, or IgG4 isotype.

[0148] In additional aspects or embodiments of the invention, the antibody Petition 870260051334, dated 05 / 28 / 2026, page 53 / 164 38 / 141 comprises a constant heavy chain domain of the IgG4 isotype.

[0149] In further aspects or embodiments of the invention, the antibody comprises a constant heavy chain domain comprising the amino acid sequence shown in SEQ ID NO: 16, 17, 18, or 19.

[0150] In additional aspects or embodiments of the invention, the light chain comprises a human kappa light chain or a human lambda light chain.

[0151] In further aspects or embodiments of the invention, the antibody comprises a constant light chain domain comprising the amino acid sequence shown in SEQ ID NO: 20.

[0152] In additional aspects or embodiments of the invention, the host cell is a Chinese hamster ovary cell or a human embryonic kidney cell 293.

[0153] In additional aspects or embodiments of the invention, the host cell is a yeast or filamentous fungus cell.

[0154] The present invention further provides a composition comprising any of the aforementioned antibodies and a pharmaceutically acceptable carrier. In particular embodiments, the composition comprises a mixture of antibodies comprising a heavy chain having a C-terminal lysine and antibodies comprising a heavy chain lacking a C-terminal lysine. In particular embodiments, the composition comprises an antibody described herein in which the predominant antibody form comprises a heavy chain having a C-terminal lysine. In particular embodiments, the composition comprises an antibody described herein in which the predominant antibody form comprises a heavy chain lacking a C-terminal lysine. In particular embodiments, the composition comprises an antibody described herein in which about 100% of the antibodies in the composition comprise a heavy chain. Petition 870260051334, dated 05 / 28 / 2026, page 54 / 164 39 / 141 which lacks a C-terminal lysine. Definitions

[0155] As used herein, “antibody” refers to both a whole immunoglobulin, including recombinantly produced forms, and includes any form of antibody that exhibits the desired biological activity. Thus, it is used in the broadest sense and specifically covers, but is not limited to, monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), humanized antibodies, fully human antibodies, biparatopic antibodies, and chimeric antibodies. “Parental antibodies” are antibodies obtained by exposing an immune system to an antigen before modifying the antibodies for an intended use, such as humanizing an antibody for use as a human therapeutic antibody.

[0156] An “antibody” refers, in one embodiment, to a glycoprotein comprising at least two heavy chains (H) and two light chains (L) interconnected by disulfide bonds, or an antigen-binding portion thereof. Each heavy chain comprises a variable heavy chain region (abbreviated herein as Vh) and a constant heavy chain region. In certain naturally occurring IgG, IgD, and IgA antibodies, the constant heavy chain region comprises three domains, CH1, CH2, and CH3. In certain naturally occurring antibodies, each light chain comprises a variable light chain region (abbreviated herein as VL) and a constant light chain region. The constant light chain region comprises one domain, CL. The VH and VL regions may be further subdivided into regions of hypervariability, termed complementarity-determining regions (CDRs), interspersed with regions that are more conserved, Petition 870260051334, dated 05 / 28 / 2026, page 55 / 164 40 / 141 called framework regions (FRs). Each Vh and Vl is composed of three CDRs and four FRs, arranged from the amino-terminal to the carboxy-terminal in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain a binding domain that interacts with an antigen. The constant regions of antibodies can mediate the binding of immunoglobulin to host tissues or factors, including various immune system cells (e.g., effector cells) and the first component (C1q) of the classical complement system.

[0157] In general, the basic structural unit of an antibody comprises a tetramer. Each tetramer includes two identical pairs of polypeptide chains, each pair having a “light” chain (about 25 kDa) and a heavy chain (about 50 to 70 kDa). The amino-terminal portion of each chain includes a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition. The carboxy-terminal portion of the heavy chain may define a constant region primarily responsible for effector function. Typically, human light chains are classified as kappa and lambda light chains. In addition, human heavy chains are typically classified as mu, delta, gamma, alpha, or epsilon, and define the antibody isotype as IgM, IgD, IgG, IgA, and IgE, respectively.Within light and heavy chains, the variable and constant regions are joined by a J region of about 12 or more amino acids, with the heavy chain also including a D region of about 10 more amino acids. See generally, Fundamental Immunology Ch. 7 (Paul, W., ed., 2nd ed. Raven Press, NY (1989).

[0158] The heavy chain of an antibody may or may not contain a terminal lysine (K), or a terminal glycine and lysine (GK). Thus, in particular embodiments of the antibodies here comprising a constant region amino acid sequence of the heavy chain shown here lacking Petition 870260051334, dated 05 / 28 / 2026, p. 56 / 164 41 / 141 a terminal lysine, but terminating with a glycine residue, also include modalities in which the terminal glycine residue is also absent. This is because the terminal lysine, and sometimes glycine and lysine together, are cleaved during antibody expression.

[0159] As used herein, “antigen-binding fragment” refers to antibody fragments, i.e., antibody fragments that retain the ability to bind specifically to the antigen bound by the full-length antibody, for example, fragments that retain one or more CDR regions. Examples of antibody-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 formed from antibody fragments.

[0160] As used herein, a “Fab fragment” is comprised of a light chain and the Ch1 and 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 cleavage of an antibody.

[0161] As used herein, a “Fab' fragment” contains a light chain and a portion or fragment of a heavy chain containing the Vh domain and the Ch1 domain and also the region between the Ch1 and Ch2 domains, such that an interchain disulfide bond can be formed between the two heavy chains of two Fab' fragments to form an F(ab')2 molecule.

[0162] As used herein, an “F(ab')2 fragment” contains two light chains and two heavy chains containing the Vh domain and a portion of the constant region between the Ch1 and Ch2 domains, such that an interchain disulfide bond is formed between the two heavy chains. An F(ab')2 fragment is thus composed of two Fab' fragments that are held together by a bond Petition 870260051334, dated 05 / 28 / 2026, page 57 / 164 42 / 141 disulfide between the two heavy chains. An “F(ab')2 fragment” may be the product of pepsin cleavage of an antibody.

[0163] As used herein, an “Fv region” comprises the variable regions of both heavy and light chains, but lacks the constant regions.

[0164] These and other potential constructs are described in Chan & Carter (2010) Nat. Rev. Immunol. 10:301. These antibody fragments are obtained using conventional techniques known to those skilled in the art, and the fragments are sorted for usefulness in the same manner as intact antibodies. Antigen-binding moieties can be produced by recombinant DNA techniques, or by enzymatic or chemical cleavage of intact immunoglobulins.

[0165] As used herein, an “Fc” region contains two heavy chain fragments comprising the CH1 and CH2 domains of an antibody. The two heavy chain fragments are held together by two or more disulfide bonds and by hydrophobic interactions of the Ch3 domains.

[0166] As used herein, a “diabody” refers to a small antibody fragment with two antigen-binding sites, fragments comprising a variable heavy chain (VH) domain connected to a variable light chain (Vl) domain on the same polypeptide chain (Vh-Vl or Vl-Vh). By 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 the complementarity domains of another chain and create two antigen-binding sites. Diabodies are described more fully in, for example, EP 404097; WO 93 / 11161; and Holliger et al. (1993) Proc. Natl. Acad. Sci. USA 90: 6444-6448. For a review of modified antibody variants, generally see Holliger and Hudson (2005) Nat. Biotechnol. 23:1126 - 1136.

[0167] As used herein, a “bispecific antibody” is an antibody Petition 870260051334, dated 05 / 28 / 2026, page 58 / 164 43 / 141 artificial hybrid having two different heavy / light chain pairs and thus two different binding sites. For example, a bispecific antibody may comprise a first heavy / light chain pair comprising a heavy and a light chain of a first antibody comprising at least the six CDRs of the antibody aFXI-13654p, aFXI-13716p, or aFXI-13716 or embodiments in which one or more of the six CDRs has one, two, or three amino acid substitutions, additions, deletions, or combinations thereof together with a second heavy / light chain pair comprising a heavy and a light chain of a second antibody having specificity for an antigen of interest other than FXI. Bispecific antibodies can be produced by a variety of methods including hybridoma fusion or Fab' fragment ligation. See, for example, Songsivilai, et al., (1990) Clin. Exp. Immunol. 79: 315 - 321, Kostelny, et al., (1992) J Immunol. 148:1547-1553.Furthermore, bispecific antibodies can be formed as diabodies (Holliger, et al., (1993) PNAS USA 90:6444 - 6448) or as Janusins ​​(Traunecker, et al., (1991) EMBO J. 10:3655 - 3659 and Traunecker, et al., (1992) Int. J. Cancer Suppl. 7:51 52).

[0168] As used herein, isolated antibodies or antigen-binding fragments thereof are at least partially free of other biological molecules from the cells or cell cultures in which they are produced. Such biological molecules include nucleic acids, proteins, lipids, carbohydrates, or other material such as cell debris and growth medium. An isolated antibody or antigen-binding fragment may also be at least partially free of components of the expression system such as biological molecules from a host cell or its growth medium. Generally, the term isolated is not intended to refer to a complete absence of such biological molecules or to an absence of water, Petition 870260051334, dated 05 / 28 / 2026, page 59 / 164 44 / 141 buffers, or salts or components of a pharmaceutical formulation that includes antibodies or fragments.

[0169] As used herein, a “monoclonal antibody” refers to a population of substantially homogeneous antibodies, that is, the antibody molecules comprising the population are identical in amino acid sequence except for possible naturally occurring mutations that may be present in minor quantities. In contrast, conventional (polyclonal) antibody preparations typically include a large number of different antibodies having different amino acid sequences in their variable domains that are often specific for different epitopes. The “monoclonal” modifier indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and should not be interpreted as requiring the production of the antibody by any particular method.For example, the monoclonal antibodies to be used according to the present invention can be manufactured by the hybridoma method first described by Kohler et al. (1975) Nature 256: 495, or can be manufactured by recombinant DNA methods (see, for example, U.S. Pat. No. 4,816,567). “Monoclonal antibodies” can also be isolated from phage antibody libraries using the techniques described in Clackson et al. (1991) Nature 352: 624-628 and Marks et al. (1991) J. Mol. Biol. 222: 581-597, for example. See also Presta (2005) J. Allergy Clin. Immunol. 116:731.

[0170] As used herein, a “chimeric antibody” is an antibody having the variable domain of a first antibody and the constant domain of a second antibody wherein (i) the first and second antibodies are of different species (U.S. Pat. No. 4,816,567; and Morrison et al., (1984) Proc. Natl. Acad. Sci. USA 81: 6851-6855) or (ii) the first and second antibodies are of isotypes Petition 870260051334, dated 05 / 28 / 2026, page 60 / 164 45 / 141 different, for example, the variable domain of an IgG1 antibody and the constant domains of an IgG4 antibody, for example aFXI-13465p-IgG4 (S228P). In one aspect, the variable domains are obtained from a human antibody (the “parental antibody”), and the constant domain sequences are obtained from a non-human antibody (e.g., mouse, rat, dog, monkey, gorilla, horse). In another aspect, the variable domains are obtained from a non-human antibody (the “parental antibody”) (e.g., mouse, rat, dog, monkey, gorilla, horse), and the constant domain sequences are obtained from a human antibody. In yet another aspect, the variable domains are obtained from a human IgG1 antibody (the “parental antibody”), and the constant domain sequences are obtained from a human IgG4 antibody.

[0171] As used herein, a “humanized antibody” refers to antibody forms that contain sequences from both human and non-human antibodies (e.g., murine, mouse). In general, the humanized antibody will comprise all of at least one, and typically two, variable domains, wherein the hypervariable loops correspond to those of a non-human immunoglobulin, and all or substantially all of the framework (FR) regions are those of a human immunoglobulin sequence. The humanized antibody may optionally comprise at least a portion of a human immunoglobulin constant region (Fc).

[0172] As used herein, a “fully human antibody” refers to an antibody comprising human immunoglobulin amino acid sequences or variant sequences thereof comprising recombinantly introduced mutations to provide a fully human antibody with modified function or efficacy compared to an antibody lacking said mutations. A fully human antibody Petition 870260051334, dated 05 / 28 / 2026, page 61 / 164 46 / 141 human does not comprise non-human immunoglobulin amino acid sequences, for example, constant domains and variable domains, including CDRs, comprise human sequences apart from those generated from the mutations discussed above. A completely human antibody may include antibody or immunoglobulin amino acid sequences obtained from a completely human antibody library where the diversity in the library is generated in silico (See, for example, U.S. Patent No. 8,877,688 or 8,691,730). A completely human antibody includes such antibodies produced in a non-human organism, for example, a completely human antibody may contain murine carbohydrate chains if produced in a mouse, in a mouse cell, or in a hybridoma derived from a mouse cell. Similarly, “mouse or murine antibody” refers to an antibody comprising mouse or murine immunoglobulin sequences only.Alternatively, a completely human antibody may contain rat carbohydrate chains if produced in a rat, in a rat cell, or in a hybridoma derived from a rat cell. Similarly, "rat antibody" refers to an antibody comprising rat immunoglobulin sequences only.

[0173] As used herein, “non-human amino acid sequences” with respect to antibodies or immunoglobulins refers to an amino acid sequence that is characteristic of the amino acid sequence of a non-human mammal. The term does not include antibody or immunoglobulin amino acid sequences obtained from a completely human antibody library where the diversity in the library is generated in silico (See, for example, U.S. Patent Nos. 8,877,688 or 8,691,730).

[0174] As used herein, “effector functions” refers to those biological activities attributable to the Fc region of an antibody, which vary with the isotype of Petition 870260051334, dated 05 / 28 / 2026, pp. 62 / 164 47 / 141 antibody. Examples of effector functions of antibodies include: C1q binding and complement-dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; downregulation of cell surface receptors (e.g., B cell receptor); and B cell activation.

[0175] The variable regions of each light / heavy chain pair form the antibody binding site. Thus, in general, an intact antibody has two binding sites. Except in bifunctional or bispecific antibodies, the two binding sites are generally the same.

[0176] Typically, the variable domains of both heavy and light chains comprise three hypervariable regions, also called complementarity-determining regions (CDRs), located within relatively conserved scaffold regions (FRs). The CDRs are usually aligned by the scaffold regions, allowing binding to a specific epitope. In general, from N-terminal to C-terminal, variable domains of both light and heavy chains comprise FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The amino acid assignment to each domain is generally in accordance with the definitions of Sequences of Proteins of Immunological Interest, Kabat, et al.; National Institutes of Health, Bethesda, Md.; 5th ed.; NIH Publ. No. 91-3242 (1991); Kabat (1978) Adv. Prot. Chem. 32:1 - 75; Kabat, et al., (1977) J. Biol. Chem. 252:6609 - 6616; Chothia, et al., (1987) J Mol. Biol. 196:901 - 917 or Chothia, et al., (1989) Nature 342:878 - 883.

[0177] As used herein, “hypervariable region” refers to the amino acid residues of an antibody that are responsible for binding to the antigen. The hypervariable region comprises amino acid residues of a “complementarity-determining region” or “CDR” (i.e., CDRL1, CDRL2, and CDRL3 in the variable light chain domain and CDRH1, CDRH2, and CDRH3 in the variable light chain domain). Petition 870260051334, dated 05 / 28 / 2026, pp. 63 / 164 48 / 141 heavy chain variable). See Kabat et al. (1991) Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (defining the CDR regions of an antibody by sequence); see also Chothia and Lesk (1987) J. Mol. Biol. 196: 901 - 917 (defining the CDR regions of an antibody by structure).

[0178] As used herein, framework residues or “FR” refers to those variable domain residues except for hypervariable region residues defined herein as CDR residues.

[0179] As used herein, “conservatively modified variants” or “conservative substitution” refers to amino acid substitutions with other amino acids having similar characteristics (e.g., charge, side chain size, hydrophobicity / hydrophilicity, mainframe conformation and stiffness, etc.), such that changes can often be made without altering the biological activity of the protein. Those skilled in the art recognize that, in general, single amino acid substitutions in non-essential regions of a polypeptide do not substantially alter biological activity (see, for example, Watson et al. (1987) Molecular Biology of the Gene, The Benjamin / Cummings Pub. Co., p. 224 (4th Ed.)). Furthermore, substitutions of structurally or functionally similar amino acids are less likely to disrupt biological activity. Exemplary conservative substitutions are shown in the table below. Original Residue Conservative Substitution Original Residue Conservative Substitution 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 Petition 870260051334, dated 05 / 28 / 2026, pages 64 / 164 49 / 141 Original Residue Conservative Substitution Original Residue Conservative Substitution 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

[0180] As used herein, the term epitope or “antigenic determinant” refers to a site on an antigen (e.g., FXI) to which an immunoglobulin or antibody specifically binds. Epitopes within protein antigens can be formed from either contiguous amino acids (usually a linear epitope) or non-contiguous amino acids juxtaposed by tertiary folding of the protein (usually a conformational epitope). Epitopes formed from contiguous amino acids are typically, but not always, retained upon exposure to denaturing solvents, whereas epitopes formed by tertiary folding are typically lost upon treatment with denaturing solvents. An epitope typically includes at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids in a single spatial conformation.Methods for determining which epitopes are bound by a given antibody (i.e., epitope mapping) are well known in the art and include, for example, immunoblotting and immunoprecipitation assays, in which overlapping or contiguous peptides (e.g., from FXI) are tested for reactivity with a given antibody (e.g., anti-FXI antibody). Methods for determining the spatial conformation of epitopes include techniques in the field and those described herein, for example, X-ray crystallography, two-dimensional nuclear magnetic resonance, and HDX-MS (see, for example, HDX-MS). Petition 870260051334, dated 05 / 28 / 2026, pages 65 / 164 50 / 141 example, Epitope Mapping Protocols in Methods in Molecular Biology, Vol. 66, GE Morris, Ed. (1996)).

[0181] The term “epitope mapping” refers to the process of identifying the molecular determinants in the antigen involved in antibody-antigen recognition.

[0182] The term “binds to the same epitope” with reference to two or more antibodies means that the antibodies bind to the same segment of amino acid residues, as determined by a given method. Techniques for determining whether antibodies bind to the “same epitope in FXI” with the antibodies described herein include, for example, epitope mapping methods, such as X-ray analyses of antigen:antibody complex crystals, which provide atomic resolution of the epitope, and hydrogen / deuterium exchange mass spectrometry (HDX-MS). Other methods monitor antibody binding to antigen fragments (e.g., proteolytic fragments) or to mutated variations of the antigen where loss of binding due to a modification of an amino acid residue within the antigen sequence is often considered an indication of an epitope component (e.g., alanine-scanning mutagenesis - Cunningham & Wells (1985) Science 244:1081).Furthermore, combinatorial computational methods for epitope mapping can also be used. These methods rely on the ability of the antibody of interest to affinity-isolate specific short peptides from combinatorial peptide display libraries.

[0183] Antibodies that “compete with another antibody for binding to a target such as FXI” refer to antibodies that inhibit (partially or completely) the binding of the other antibody to the target. If two antibodies compete with each other for binding to a target, that is, if and to what extent one antibody Petition 870260051334, dated 05 / 28 / 2026, pp. 66 / 164 51 / 141 inhibits the binding of another antibody to a target, which can be determined using known competition experiments. In certain embodiments, one antibody competes with, and inhibits the binding of, another antibody to a target by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%. The level of inhibition or competition may differ depending on which antibody is the “blocking antibody” (i.e., the cold antibody that is incubated first with the target). Competition assays can be conducted as described, for example, in Ed Harlow and David Lane, Cold Spring Harb Protoc; 2006; doi:10.1101 / pdb.prot4277 or in Chapter 11 of “Using Antibodies” by Ed Harlow and David Lane, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, USA 1999. Competing antibodies bind to the same epitope, an overlapping epitope, or adjacent epitopes (e.g., as evidenced by steric hindrance).

[0184] Other competitive binding assays include: direct or indirect solid-phase radioimmunoassay (RIA), direct or indirect solid-phase enzyme immunoassay (EIA), sandwich-type competitive assay (see Stahli et al., Methods in Enzymology 9:242 (1983)); direct solid-phase biotin-avidin EIA (see Kirkland et al., J. Immunol. 137:3614 (1986)); direct solid-phase labeled assay, direct solid-phase labeled sandwich-type assay (see Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Press (1988)); direct solid-phase labeled RIA using label 1-125 (see Morel et al., Mol. Immunol. 25(1):7 (1988)); Direct solid-phase biotin-avidin EIA (Cheung et al., Virology 176:546 (1990)); and direct labeled RIA (Moldenhauer et al., Scand. J. Immunol. 32:77 (1990)).

[0185] As used herein, “specifically binds to” refers, with respect to an antigen or molecule such as FXI, to the preferential association of an antibody or other ligand, in whole or in part, with FXI and not to other Petition 870260051334, dated 05 / 28 / 2026, pp. 67 / 164 52 / 141 molecules, particularly molecules found in human blood or serum. Antibodies typically bind specifically to their cognate antigen with high affinity, reflected by a dissociation constant (Kd) of 10⁻⁷ to 10⁻¹¹ M or less. Any Kd greater than about 10⁻⁶ M is generally considered to indicate nonspecific binding. As used herein, an antibody that “binds specifically to an antigen” refers to an antibody that binds to the antigen and substantially identical antigens with high affinity, meaning having a Kd of 10⁻⁷ M or less, in particular embodiments a Kd of 10⁻⁸ M or less, or 5 x 10⁻⁹ M or less, or between 10⁻⁸ M and 10⁻¹¹ M or less, but does not bind with high affinity to unrelated antigens. The binding kinetics can be determined by Surface Plasma Resonance as described in Example 1 herein.

[0186] An antigen is substantially identical to a given antigen if it exhibits a high degree of amino acid sequence identity to the given antigen, for example, if it exhibits at least 80%, at least 90%, at least 95%, at least 97%, or at least 99% or greater amino acid sequence identity to the amino acid sequence of the given antigen. By way of example, an antibody that specifically binds to human FXI may also cross-react with FXI from certain 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.

[0187] As used herein, isolated nucleic acid molecule means a DNA or RNA molecule of genomic, mRNA, cDNA, or synthetic origin, or some combination thereof, that is not associated with all or a portion of a polynucleotide in which the isolated polynucleotide is found in nature, or is linked to a polynucleotide to which it is not linked in nature. For purposes of the same invention, it should be understood that a nucleic acid molecule Petition 870260051334, dated 05 / 28 / 2026, pp. 68 / 164 53 / 141 nucleic acid comprising a particular nucleotide sequence does not encompass intact chromosomes. Isolated nucleic acid molecules “comprising specific nucleic acid sequences may include, in addition to the specific sequences, coding sequences for up to ten or even up to twenty or more other proteins or portions or fragments thereof, or may include operably linked regulatory sequences that control the expression of the coding region of the reported nucleic acid sequences, and / or may include vector sequences.

[0188] As used herein, “treating” 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 subject or patient having one or more disease symptoms, or being suspected of having a disease, for which the agent has therapeutic or prophylactic activity. Typically, the agent is administered in an amount effective to relieve one or more disease symptoms in the treated subject or population, either by inducing regression of or inhibiting the progression of such symptom(s) to any clinically measurable degree. The amount of a therapeutic agent that is effective in relieving any particular disease symptom may vary according to factors such as the disease state, age, and weight of the patient, and the ability of the drug to evoke a desired response in the subject.Whether a disease symptom has been relieved can be assessed by any clinical measurement typically used by physicians or other qualified healthcare providers to evaluate the severity or progression of that symptom. The term also includes a delay in the development of symptoms associated with a disorder and / or a reduction in the severity of the symptoms of such a disorder. The terms also include improving existing uncontrolled or unwanted symptoms. Petition 870260051334, dated 05 / 28 / 2026, pp. 69 / 164 54 / 141 prevent additional symptoms, and improve or prevent the underlying causes of such symptoms. Thus, the terms denote that a beneficial outcome was conferred on a human or animal subject with a disorder, disease, or symptom, or with the potential to develop such a disorder, disease, or symptom.

[0189] As used herein, treatment, as it applies to a human or veterinary subject, refers to therapeutic treatment as well as diagnostic applications. Treatment as it applies to a human or veterinary subject encompasses the contact of antibodies or antigen-binding fragments of the present invention to a human or animal subject.

[0190] As used herein, therapeutically effective amount refers to an amount of a specific substance sufficient to achieve a desired effect in a subject being treated. For example, this may be the amount required to inhibit FXI activation or the amount required to inhibit coagulation for at least 192 to 288 hours as determined in an aPTT assay. When administered to a subject, a dosage will generally be used that will achieve target tissue concentrations that have been shown to achieve a desired in vitro effect.

[0191] As used herein, thrombosis refers to the formation or presence of a clot (also called a blood clot) within a blood vessel, obstructing blood flow through the circulatory system. Thrombosis is usually caused by abnormalities in blood composition, vessel wall quality, and / or the nature of blood flow. Clot formation is frequently caused by injury to the vessel wall (such as from trauma or infection) and by reduced or stagnant blood flow beyond the point of injury. In some cases, coagulation abnormalities cause thrombosis. Petition 870260051334, dated 05 / 28 / 2026, page 70 / 164 55 / 141

[0192] As used herein, “without compromising hemostasis” means that little or no detectable bleeding is observed in a subject or patient after administration of an antibody or antibody fragment described herein to the subject or patient. In the case of targeting Factor XI, inhibiting the conversion of Factor XI to Factor XIa or activation of Factor IX by Factor Xia inhibits coagulation and associated thrombosis without bleeding. Conversely, inhibiting the conversion or activity of Factor XI inhibits coagulation but also induces bleeding or increases the risk of bleeding. BRIEF DESCRIPTION OF THE DRAWINGS

[0193] Fig. 1A and Fig. 1B show the coagulation cascade, FXI, FXI mAb, and four novel oral anticoagulants (NOACs). Fig. 1A is a diagram depicting FXI in the coagulation cascade (which is composed of intrinsic and extrinsic pathways). An mAb targeting FXI can exert functional neutralization by blocking FXI activation by XIIa and / or thrombin, or FXIa activity in FIX. The antibodies here can exert dual obstruction on FXIa-mediated activation of FIX, and conversion of FXI to FXIa mediated by at least FXIIa. The four NOACs (rivaroxaban, apixaban, edoxaban, dabigatran) targeting FXa or thrombin are shown. Fig. 1B shows the FXI domain structure. FXI is a dimer composed of identical 80 kDa subunits, and each subunit originating from the N-terminus consists of the four apple domains (1, 2, 3, and 4) and a catalytic domain (CAT). The antibodies described here bind to apple domain 3.

[0194] Fig. 2 shows the structure of Factor XI and the Apple 3 domain with peptides protected from deuteration by anti-FXI antibodies of the aFXI18611 and aFXI-18623p families identified. Arginine residue 184, a critical residue in the exocyte for FIX binding, is shown. Peptides in the Apple 3 domain without any deuteration difference are light gray. Peptides where no deuteration has occurred are shown. Petition 870260051334, dated 05 / 28 / 2026, page 71 / 164 56 / 141 data points are available and are dark gray. The catalytic domain is not shown.

[0195] Figs. 3A and 3B show a heat map of deuterium labeling difference of FXI amino acid residues bound by anti-FXI IgG4 HC antibodies from aFXI-18611 (S228P)(E1) (L105) / LC Kappa and IgG4 HC antibodies from aFXI18623p (S228P)(Q1) / LC Kappa, respectively.

[0196] Figs. 4A, 4B, and 4C show the amino acid sequence of the HC and LC domains of antibodies from the aFXI 18611p and aFXI 18611 families. The heavy chain and light chain CDRs are identified as HC-CDR1, HC-CDR2, HC-CDR3, LC-CDR1, LC-CDR2, and LC-CDR3, respectively.

[0197] Figs. 5A and 5B show the amino acid sequence of the HC and LC domains of antibodies from the aFXI 18623p family. The heavy chain and light chain CDRs are identified as HC-CDR1, HC-CDR-2, HC-CDR3, LC-CDR1, LC-CDR2, and LC-CDR3, respectively.

[0198] Fig. 6 shows the results of an activated partial thromboplastin time (aPTT) assay of IgG4 HC of aFXI-18611 (S228P)(E1)(L105) / LC kappa (A) and IgG4 HC of aFXI-18623p (S228P)(Q1) / LC kappa (B) in human plasma, expressed as % increase over the reference value.

[0199] Fig. 7 shows the results of an activated partial thromboplastin time (aPTT) assay of IgG4 HC of aFXI-18611 (S228P)(E1)(L105) / LC kappa (A) and IgG4 HC of aFXI-18623p (S228P)(Q1) / LC kappa (B) in cynomolgus monkey plasma, expressed as % increase over reference value.

[0200] Fig. 8 shows the results of an activated partial thromboplastin time (aPTT) assay of IgG4 HC from aFXI-18611 (S228P)(E1)(L105) / LC kappa (A) and IgG4 HC from aFXI-18623p (S228P)(Q1) / LC Petition 870260051334, dated 05 / 28 / 2026, p. 72 / 164 57 / 141 kappa (B) in rhesus monkey plasma, expressed as a % increase over a reference value.

[0201] Fig. 9 shows a comparison of aPTT results for IgG4 HC of aFXI-18611 (S228P)(E1)(L105) / LC kappa in human plasma, cynomolgus monkey, and rhesus monkey plasma expressed as % increase over reference value.

[0202] Fig. 10 shows a comparison of aPTT results for IgG4 HC of aFXI-18623p (S228P)(Q1) / LC kappa in human plasma, cynomolgus monkey, and rhesus monkey plasma expressed as % increase over reference value.

[0203] Fig. 11 shows BIAcore Sensograms that show the HC binding kinetics of IgG4 aFXI-18623p (S228P)(E1) / LC Kappa to human, cynomolgus, and rhesus monkey FXI and other human and NHP coagulation cascade proteins.

[0204] Fig. 12 shows BIAcore Sensograms that show the HC binding kinetics of IgG4 aFXI-18623p (S228P)(Q1) / LC Kappa to human, cynomolgus and rhesus monkey FXI and other human and NHP coagulation cascade proteins.

[0205] Fig. 13 shows a schematic of the cynomolgus monkey AV bypass test paradigm. Anesthetized monkeys previously instrumented with arterial and femoral venous catheters were administered vehicle or IgG4 aFXI-18623p (S228P)(E1) / LC Kappa (antibody) HC at 0.01 to 1.0 mg / kg by intravenous bolus (Test Article Administration). An AV bypass was inserted as described in the text (AV bypass insertion). Blood flowed through the AV bypass for 40 minutes. Contact between blood and the silk thread suspended inside the tube caused a clot to form. The clots were weighed as described in the text. Blood samples were Petition 870260051334, dated 05 / 28 / 2026, page 73 / 164 58 / 141 obtained to measure circulating antibody levels, aPTT and PT (stars).

[0206] Figs. 14A to 14D show the effects of IgG4 HC of aFXI-18623p (S228P)(E1) / LC Kappa (antibody) on AV-shunt clot formation, aPTT, and PT in the cynomolgus monkey AV-shunt model. In Fig. 14A, clot weight is measured after 2 consecutive AV-shunts in the same animal. Animals were administered vehicle during the first swab (Shunt #1), followed by antibody administration (0.01 to 1.0 mg / kg IV) as shown during the second swab (Shunt #2). Increasing antibody doses resulted in smaller clot formation. The percentage of clot weight inhibition (Fig. 14B) and the percentage change in aPTT (Fig. 14C) increased with increasing plasma antibody concentration. Conversely, PT (Fig. 14D) remained relatively unchanged at all antibody concentrations.

[0207] Fig. 15 shows a schematic of the standard bleeding time paradigm in cynomolgus monkeys. Standard bleeding times in the buccal mucosa (inner lip), finger pads, and distal tail were determined in anesthetized cynomolgus monkeys at baseline (before treatment) and after administration of Treatment #1 (vehicle) and Treatment #2 (vehicle or aFXI-18623p (S228P)(E1) / LC Kappa IgG4 HC, 10 mg / kg IV). Blood samples to measure circulating levels of aFXI-18623p (S228P)(E1) / LC Kappa IgG4 HC, aPTT, and PT were collected as shown.

[0208] Figs. 16A to 16F show the effects of IgG4 HC from aFXI-18623p (S228P)(E1) / LC Kappa on standard bleeding times measured in cynomolgus monkeys. Standard bleeding times were measured in the buccal mucosa (Figs. 16A, 16D), finger pads (Figs. 16B, 16E), and distal tail (Figs. 16C, 16F). Treatment effects (IgG4 HC from aFXI-18623p (S228P)(E1) / LC Kappa vs Petition 870260051334, dated 05 / 28 / 2026, page 74 / 164 59 / 141 vehicle) on bleeding times were evaluated by comparing absolute bleeding times (left panels) and percentage change in bleeding times (right panels), with vehicle-vehicle as Treatments #1 and #2 in study session #1, and vehicle-aFXI18623p IgG4 HC (S228P)(E1) / LC Kappa as Treatments #1 and #2 in study session #2, using a one-tailed paired Student's t-test.

[0209] Fig. 17A shows the following concentration-time profiles of IV administration of aFXI-18623p (S228P)(E1) / LC kappa IgG4 HC in Rhesus Monkeys. Plasma concentration-time profiles for aFXI-18623p (S228P)(E1) / LC kappa IgG4 HC in rhesus monkeys are presented. There are 4 animals in each dose group. Each line represents a mean for a particular group.

[0210] Fig. 17B shows the aPTT-time profiles in rhesus monkeys. The aPTT-time profiles for IgG4 HC of aFXI-18623p (S228P)(E1) / LC kappa are presented for each dose group. There were 4 animals in each dose group. Each symbol represents an individual animal aPTT time profile at each point in time. Each line represents an average for a particular group. DETAILED DESCRIPTION OF THE INVENTION

[0211] The present invention provides anti-coagulation 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 thrombosis without compromising hemostasis (antithrombotic indications). For example, anti-FXI antibodies can be used for the treatment and prevention of venous thromboembolism (VTE), prevention of stroke in atrial fibrillation (SPAF), or treatment and prevention of certain thromboembolic disorders related to Petition 870260051334, dated 05 / 28 / 2026, page 75 / 164 60 / 141 medical device (e.g., stents, endovascular stent grafts, catheters (cardiac or venous), continuous flow ventricular assist devices (CF-LVADS), hemodialysis, cardiopulmonary bypass and Extracorporeal Membrane Oxygenation (ECMO), ventricular assist devices (VADS)). Therefore, the anti-FXI antibodies described here are useful in therapies to treat a thromboembolic disorder or disease in a patient or subject in need of such therapies.

[0212] FXI is a homodimeric serine protease having the domain structure shown in Fig. 1B and an integral component of the intrinsic pathway of the coagulation cascade. The FXI zymogen can be cleaved by Factor XIIa to its activated form FXIa. FXIa then activates Factor IX and ultimately triggers thrombin generation and clot formation. The anti-FXI antibodies described herein inhibit the conversion of FXI to FXIa (See Fig. 1A).

[0213] Anti-FXI antibody molecules were obtained from a fully human synthetic IgG1 / kappa library displayed on the surface of modified yeast strains. The library was screened with FXI or FXIa to identify antibodies capable of binding to human FXI at subnanomolar affinity to human and non-human primate (NHP) FXI and having no binding to human and NHP plasma kallikrein (a protein exhibiting 56% amino acid identity to 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: aFXI-18611p and aFXI-18623p. These antibodies are fully human antibodies comprising a human kappa (κ) light chain and a human IgG1 isotype heavy chain (γ1). The antibodies selectively bind to an epitope of the FXI zymogen comprising the SEQ IDs 82 and 83 located in the apple 3 domain of FXI.These antibodies also bind to FXIa with affinity comparable to the zymogen. Petition 870260051334, dated 05 / 28 / 2026, page 76 / 164 61 / 141 of FXI.

[0214] Antibodies of the aFXI-18611p family comprise heavy chain (HC) complementarity-determining regions (CDRs) 1, 2, and 3 having 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 having the amino acid sequences shown in SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7, respectively. The aFXI-18611p family includes antibodies comprising a variable heavy chain (HC) domain comprising the amino acid sequence shown in SEQ ID NO: 21 or 22 and a variable light chain (LC) domain comprising the amino acid sequence in SEQ ID NO: 25.

[0215] Antibodies of the aFXI-18611 family comprise heavy chain (HC) complementarity-determining regions (CDRs) 1, 2, and 3 having 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 having the amino acid sequences shown in SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7, respectively. The aFXI-18611 family includes antibodies comprising a variable heavy chain (HC) domain comprising the amino acid sequence shown in SEQ ID NO: 23 or 24 and a variable light chain (LC) domain comprising the amino acid sequence in SEQ ID NO: 25.

[0216] Antibodies of the aFXI-18623p family comprise HC 1, 2, and 3 CDRs having the amino acid sequences shown in SEQ ID NO: 8, SEQ ID NO: 9, and SEQ ID NO: 10, respectively, and LC 1, 2, and 3 CDRs having the amino acid sequences shown in SEQ ID NO: 11, SEQ ID NO: 12, and SEQ ID NO: 13, respectively. The aFXI-13716p family includes antibodies comprising a variable heavy chain (HC) domain comprising the amino acid sequence shown in SEQ ID NO: 28 or 29 and a variable chain domain. Petition 870260051334, dated 05 / 28 / 2026, page 77 / 164 62 / 141 light (LC) comprising the amino acid sequence in SEQ ID NO: 30. Antibodies from the same family were obtained from a different germline than the previous families.

[0217] The present invention further provides anti-FXI antibodies comprising at least the six CDRs of an anti-FXI antibody of the aFXI-18611p family, aFXI-18611 family, or aFXI-18623p family, or embodiments thereof in which one or more of the six CDRs has one, two, or three amino acid substitutions, additions, deletions, or combinations thereof, and methods of using the antibodies to treat antithrombotic indications, for example SPAF.

[0218] In particular aspects, anti-FXI antibodies comprise at least the variable HC domain of an anti-FXI antibody from the aFXI18611p family, aFXI-18611 family, or aFXI-18623p family or a variant thereof wherein the variable HC domain comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, deletions, or combinations thereof.

[0219] In particular aspects, anti-FXI antibodies comprise at least the variable LC domain of an anti-FXI antibody from the aFXI-18611p family, aFXI-18611 family, or aFXI-18623p family or a variant thereof wherein the variable LC domain comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, deletions, or combinations thereof.

[0220] In particular aspects, anti-FXI antibodies comprise at least the HC variable domain of an anti-FXI antibody from the aFXI18611p family, aFXI-18611 family, or aFXI-18623p family, or a variant thereof, wherein the HC variable domain comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, deletions, or combinations thereof, and the LC variable domain of an anti-FXI antibody from the aFXI-18611p family, aFXI-18611 family, or aFXI-18623 family, or a variant thereof, wherein the domain Petition 870260051334, dated 05 / 28 / 2026, page 78 / 164 63 / 141 variable of LC comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, deletions, or combinations thereof.

[0221] In particular embodiments, the antibodies herein comprise at least the six CDRs of an anti-FXI antibody of the aFXI-18611p family, aFXI-18611 family, or aFXI-18623p family or embodiments thereof in which one or more of the six CDRs has one, two, or three amino acid substitutions, additions, deletions, or combinations thereof and further comprise a heavy chain (HC) that is of the human IgG1, IgG2, IgG3, or IgG4 isotype and the light chain (LC) may be of the kappa or lambda type. In other embodiments, the antibodies comprise at least the six CDRs of an anti-FXI antibody from the aFXI-18611p family, aFXI-18611 family, or aFXI-18623p family, or embodiments thereof in which one or more of the six CDRs has one, two, or three amino acid substitutions, additions, deletions, or combinations thereof, and may also be of the IgM, IgD, IgA, or IgE class.In particular embodiments, the human IgG1, IgG2, IgG3, or IgG4 isotype may include 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, deletions, or combinations thereof.

[0222] In particular embodiments, the antibodies may comprise at least the six CDRs of an anti-FXI antibody of the aFXI-18611p family, aFXI-18611 family, or aFXI-18623p family, or embodiments thereof, in which one or more of the six CDRs has one, two, or three amino acid substitutions, additions, deletions, or combinations thereof, and further comprise a constant HC domain that is of the IgG4 isotype. An IgG4 scaffold provides an antibody with little or no effector function. In another aspect of the invention, the antibodies may comprise at least the six CDRs of an anti-FXI antibody of the aFXI-18611p family, aFXI-18611 family, or aFXI-18623p family, or embodiments thereof, in which one or more of the six CDRs has one, Petition 870260051334, dated 05 / 28 / 2026, p. 79 / 164 64 / 141 two, or three amino acid substitutions, additions, deletions, or combinations thereof, and further comprise a constant HC domain that is of the IgG4 isotype fused to a variable HC domain that is of the IgG1 isotype. In another aspect of the invention, the antibodies may comprise at least the variable HC domain and variable LC domain of an anti-FXI antibody of the aFXI-18611p family, aFXI-18611 family, or aFXI-18623p family or variants thereof, wherein the variable HC and LC domains independently comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, deletions, or combinations thereof, and further comprise a constant HC domain that is of the IgG4 isotype.In another aspect of the invention, the antibodies may comprise at least the variable HC and LC domain of an anti-FXI antibody of the aFXI-18611p family, aFXI-18611 family, or aFXI-18623p family or variants thereof, wherein the HC and LC independently comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, deletions, or combinations thereof, and further comprise a constant HC domain that is of the IgG4 isotype.

[0223] The antibodies of the present invention also 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 chimeric antibodies.

[0224] In general, the amino acid sequence of the heavy chain of an antibody such as IgG1 or IgG4 has a lysine at the C-terminal of the heavy chain constant domain. In some examples, to improve the homogeneity of an antibody product, the antibody can be produced lacking a C-terminal lysine. The anti-FXI antibodies of the present invention include embodiments in which the C-terminal lysine is present and embodiments in which Petition 870260051334, dated 05 / 28 / 2026, p. 80 / 164 65 / 141 that the C-terminal lysine is absent. For example, a constant IgG1 HC domain may have the amino acid sequence shown in SEQ ID NO: 18 or 19 and a constant IgG4 HC domain may have the amino acid sequence shown in SEQ ID NO: 16 or 17.

[0225] In particular embodiments, the N-terminal amino acid of the HC may be a glutamine residue. In particular embodiments, the N-terminal amino acid of the HC may be a glutamic acid residue. In particular aspects, the N-terminal amino acid is modified to be a glutamic acid residue.

[0226] The present invention further provides anti-FXI antigen-binding fragments comprising at least the six CDRs of an anti-FXI antibody from the aFXI-18611p family, aFXI-18611 family, or aFXI-18623p family, or embodiments thereof, in which one or more of the six CDRs has one, two, or three amino acid substitutions, additions, deletions, or combinations thereof.

[0227] The present invention further provides anti-FXI Fab fragments comprising at least the six CDRs of an anti-FXI antibody from the aFXI18611p family, aFXI-18611 family, or aFXI-18623p family, or embodiments thereof, in which one or more of the six CDRs has one, two, or three amino acid substitutions, additions, deletions, or combinations thereof.

[0228] The present invention further provides anti-FXI antibodies comprising at least the six CDRs of an anti-FXI antibody of the aFXI18611p family, aFXI-18611 family, or aFXI-18623p family or embodiments thereof wherein one or more of the six CDRs has one, two, or three amino acid substitutions, additions, deletions, or combinations thereof and antigen-binding fragments thereof comprising an Fc region and methods of using them. Petition 870260051334, dated 05 / 28 / 2026, p. 81 / 164 66 / 141

[0229] The present invention further provides Fab' anti-FXI fragments comprising at least the six CDRs of an anti-FXI antibody from the aFXI18611p family, aFXI-18611 family, or aFXI-18623p family, or embodiments thereof, in which one or more of the six CDRs has one, two, or three amino acid substitutions, additions, deletions, or combinations thereof.

[0230] The present invention further provides F(ab')2 anti-FXI comprising at least the six CDRs of an anti-FXI antibody of the aFXI18611p family, aFXI-18611 family, or aFXI-18623p family, or embodiments thereof, in which one or more of the six CDRs has one, two, or three amino acid substitutions, additions, deletions, or combinations thereof.

[0231] The present invention further provides Fv anti-FXI fragments comprising at least the six CDRs of an anti-FXI antibody from the aFXI18611p family, aFXI-18611 family, or aFXI-18623p family, or embodiments thereof, in which one or more of the six CDRs has one, two, or three amino acid substitutions, additions, deletions, or combinations thereof.

[0232] The present invention further provides anti-FXI scFv fragments comprising at least the six CDRs of an anti-FXI antibody from the aFXI18611p family, aFXI-18611 family, or aFXI-18623p family, or embodiments thereof, in which one or more of the six CDRs has one, two, or three amino acid substitutions, additions, deletions, or combinations thereof.

[0233] The present invention further provides anti-FXI domain antibodies comprising at least three HC CDRs or three LC CDRs of an anti-FXI antibody from the aFXI-18611p family, aFXI-18611 family, or aFXI18623p family, or embodiments thereof, in which one or more of the HC or LC CDRs have one, two, or three amino acid substitutions, additions, deletions, or combinations thereof. In one embodiment of the invention, the antibody domain is a single antibody domain or nanobody. In another embodiment of the Petition 870260051334, dated 05 / 28 / 2026, p. 82 / 164 67 / 141 invention, an antibody domain is a nanobody comprising at least the CDRs of the aFXI-18611p family, aFXI-18611 family, or aFXI-18623p family, or embodiments in which one or more of the CDRs has one, two, or three amino acid substitutions, additions, deletions, or combinations thereof.

[0234] The present invention further provides bivalent anti-FXI antibodies comprising at least the six CDRs of an anti-FXI antibody from the aFXI-18611p family, aFXI-18611 family, or aFXI-18623p family, or embodiments thereof, in which one or more of the six CDRs has one, two, or three amino acid substitutions, additions, deletions, or combinations thereof.

[0235] The present invention further provides bispecific antibodies and antigen-binding fragments having a binding specificity for FXI and another antigen of interest and methods of use thereof.

[0236] Biparatopic antibodies are antibodies having binding specificity for different epitopes on the same antigen. The present invention further provides biparatopic antibodies having a first heavy / light chain pair of a first antibody comprising at least the six CDRs of an anti-FXI antibody of the aFXI-18611p family, aFXI-18611 family, or aFXI-18623p family or embodiments thereof in which one or more of the CDRs has one, two, or three amino acid substitutions, additions, deletions, or combinations thereof and a second heavy / light chain pair of a second antibody having specificity for an FXI epitope that is different from the epitope recognized by the first heavy / light chain pair.

[0237] The present invention further provides anti-FXI antibodies and antigen-binding fragments thereof comprising a first heavy / light chain pair of an antibody comprising at least the six CDRs of an antibody of the aFXI-18611p or aFX-18611 family or embodiments thereof wherein one or more of the CDRs has one, two, or three substitutions, additions, Petition 870260051334, dated 05 / 28 / 2026, p. 83 / 164 68 / 141 amino acid deletions, or combinations thereof, and a second heavy / light chain pair of an antibody comprising at least the six CDRs of an aFXI-18623p antibody family or embodiments thereof, in which one or more of the CDRs has one, two, or three amino acid substitutions, additions, deletions, or combinations thereof.

[0238] The present invention further provides anti-FXI diabodies comprising at least the six CDRs of an anti-FXI antibody of the aFXI18611p family, aFXI-18611 family, or aFXI-18623p family, or embodiments thereof, in which one or more of the six CDRs has one, two, or three amino acid substitutions, additions, deletions, or combinations thereof.

[0239] An antibody comprising at least the six CDRs of an anti-FXI antibody of the aFXI-18611p family, aFXI-18611 family, or aFXI-18623p family, or embodiments thereof, in which one or more of the CDRs have one, two, or three amino acid substitutions, additions, deletions, or combinations thereof that may be modified in such a manner that it retains at least 10% of its FXI-binding activity (when compared to the parent antibody, i.e., an antibody of the respective aFXI-18611p family, aFXI-18611 family, or aFXI-18623p family) when this activity is expressed on a molar basis. Preferably, an antibody or antigen-binding fragment of the invention retains at least 20%, 50%, 70%, 80%, 90%, 95%, or 100% or more of the FXI binding affinity as the parental antibody.It is also intended that an antibody or antigen-binding fragment of the invention may include conservative or non-conservative amino acid substitutions (referred to as "conservative variants" or "variants of conserved function" in the antibody) that do not substantially alter its biological activity.

[0240] The present invention also provides isolated anti-FXI antibodies that Petition 870260051334, dated 05 / 28 / 2026, p. 84 / 164 69 / 141 comprise at least the six CDRs of an anti-FXI antibody of the aFXI18611p family, aFXI-18611 family, or aFXI-18623p family or embodiments thereof in which one or more of the six CDRs has one, two, or three amino acid substitutions, additions, deletions, or combinations thereof and antigen-binding fragments thereof and methods of use thereof as well as isolated immunoglobulin polypeptide chains thereof and isolated polynucleotides encoding such polypeptides and isolated vectors including such polynucleotides.

[0241] The present invention further provides anti-FXI monoclonal antibodies comprising at least the six CDRs of an anti-FXI antibody of the aFXI-18611p family, aFXI-18611 family, or aFXI-18623p family, or embodiments thereof, in which one or more of the six CDRs has one, two, or three amino acid substitutions, additions, deletions, or combinations thereof, and antigen-binding fragments thereof, as well as monoclonal compositions comprising a plurality of isolated monoclonal antibodies.

[0242] The present invention further provides chimeric anti-FXI antibodies comprising at least the six CDRs of an anti-FXI antibody of the aFXI-18611p family, aFXI-18611 family, or aFXI-18623p family, or embodiments thereof, in which one or more of the six CDRs has one, two, or three amino acid substitutions, additions, deletions, or combinations thereof.

[0243] The present invention includes fully human anti-FXI antibodies comprising at least the six CDRs of an anti-FXI antibody of the aFXI-18611p family, aFXI-18611 family, or aFXI-18623p family, or embodiments thereof, in which one or more of the six CDRs has one, two, or three amino acid substitutions, additions, deletions, or combinations thereof, and antigen-binding fragments thereof, and methods of use thereof. In one embodiment of the invention, a fully human anti Petition 870260051334, dated 05 / 28 / 2026, p. 85 / 164 70 / 141 FXI or antigen-binding fragment thereof is the product of isolation from a transgenic animal, for example, a mouse (e.g., a HUMAB mouse, see for example, U.S. Pat. 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 Harding, et al., (1995) Ann. NY Acad. - 23), which has been genetically modified to have completely human immunoglobulin genes; or the product of isolation from a phage or virus expressing the immunoglobulin chains of the completely human anti-FXI antibody or antigen-binding fragment thereof.

[0244] In some embodiments, different constant domains may be attached to the Vl and Vh regions derived from the CDRs provided herein. For example, if a particular intended use of an antibody (or fragment) of the present invention has to call upon altered effector functions, a heavy chain constant domain, except human IgG1, may be used, or the IgG1 / IgG4 hybrid may be used.

[0245] Although human IgG1 antibodies provide long half-life and effector functions, such as complement activation and antibody-dependent cellular cytotoxicity, such activities may not be desirable for all uses of the antibody. In such examples, a human IgG4 constant domain, for example, can be used. The present invention includes anti-FXI antibodies and antigen-binding fragments thereof comprising an IgG4 constant domain, for example, antagonistic human anti-FXI antibodies and fragments, and methods of using them. In one embodiment, the IgG4 constant domain may differ from the native human IgG4 constant domain (Swiss-Prot Accession No. P01861.1) at a position corresponding to position 228 in the EU system and position 241 in the KABAT system, wherein the native serine in Petition 870260051334, dated 05 / 28 / 2026, page 86 / 164 71 / 141 position 108 (Ser108) of the HC constant domain is replaced with proline (Pro), so as to prevent a potential inter-chain disulfide bond between cysteine ​​at position 106 (Cys106) and cysteine ​​at position 109 (Cys109), which correspond to positions Cys226 and Cys229 in the EU system and positions Cys239 and Cys242 in the KABAT system) that could interfere with the formation of the appropriate intra-chain disulfide bond. See Angal et al. Mol. Immunol. 30:105 (1993); see also (Schuurman et al., Mol. Immunol. 38: 1 - 8, (2001); SEQ ID NOs: 14 and 41). In other examples, a modified IgG1 constant domain that has been modified to reduce effector function may be used, for example, the IgG1 isotype may include IgG2 residue substitutions at positions 233 to 236 and IgG4 residues at positions 327, 330 and 331 to greatly reduce ADCC and CDC (Armour et al., Eur J Immunol. 29(8):2613-24 (1999); Shields et al., J Biol Chem.In another embodiment, the IgG HC is genetically modified to lack N-glycosylation of the asparagine (Asn) residue around position 297. The consensus sequence for N-glycosylation is Asn-XaaSer / Thr (where Xaa is any amino acid except Pro); in IgG1 the consensus sequence for N-glycosylation is Asn-Ser-Thr. The modification can be achieved by replacing the codon for Asn at position 297 in the nucleic acid molecule encoding the HC with a codon for another amino acid, for example Gln. Alternatively, the codon for Ser can be replaced with the codon for Pro or the codon for Thr can be replaced with any codon except the codon for Ser. Such modified IgG1 molecules have little or no detectable effector function. Alternatively, all three codons are modified.

[0246] In one embodiment of the invention, anti-FXI antibodies comprising at least the six CDRs of an anti-FXI antibody from the aFXI-18611p family, aFXI-18611 family, or aFXI-18623p family, or embodiments thereof, wherein one or more of the six CDRs has one, two, or three substitutions, Petition 870260051334, dated 05 / 28 / 2026, p. 87 / 164 72 / 141 additions, deletions of amino acids, or combinations thereof comprising a complete tetrameric structure having two light chains and two heavy chains, including constant regions. The variable regions of each light / heavy chain pair form the antibody binding site. Thus, in general, an intact antibody has two binding sites. Except in bispecific antibodies, the two binding sites are generally the same.

[0247] In specific embodiments, the present invention provides the anti-FXI antibodies shown in Table 1. Table 1 Antibody Family SEQ ID NO: Heavy Chain (HC) SEQ ID NO: Light Chain (LC) aFXI-18611p aFXI-18611p IgG4 HC (S228P)(Q1)(M105) / LC kappa 33 26 aFXI-18611p IgG4 HC (S228P)(E1)(M105) / LC kappa 35 26 aFXI-18611p IgG1 HC (Q1)(M105) / LC kappa 45 26 aFXI-18611p IgG1 HC (E1)(M105) / LC kappa 47 26 aFXI-18611p IgG4 HC (S228P)(Q1)(M105)(K-) / LC kappa 57 26 aFXI-18611p IgG4 HC (S228P)(E1)(M105)(K-) / LC kappa 59 26 aFXI-18611p IgG1 HC (Q1)(M105)(K-) / LC kappa 69 26 Petition 870260051334, dated 05 / 28 / 2026, p. 88 / 164 73 / 141 aFXI-18611p IgG1 HC (E1)(M105) (K-) / LC kappa 71 26 aFXI- 18611 aFXI-18611 IgG4 HC (S228P)(Q1)(L105) / LC kappa 37 26 aFXI-18611 IgG4 HC (S228P)(E1)(L105) / LC kappa 39 26 aFXI-18611 IgG1 HC (Q1)(L105) / LC kappa 49 26 aFXI-18611 IgG1 HC (E1)(L105) / LC kappa 51 26 aFXI-18611 IgG4 HC (S228P)(Q1)(L105)(K-) / LC kappa 61 26 HC of IgG4 of aFXI-18611 (S228P)(E1)(L105)(K-) / LC kappa 63 26 aFXI-18611 IgG1 HC (Q1)(L105) (K-) / LC kappa 73 26 aFXI-18611 IgG1 HC (E1)(L105) (K-) / LC kappa 75 26 aFXI- 18623p aFXI-18623p IgG4 HC (S228P)(Q1) / LC kappa 41 31 aFXI-18623p IgG4 HC (S228P)(E1) / LC kappa 43 31 aFXI-18623p IgG1 HC (Q1) / LC kappa 53 31 aFXI-18623p IgG1 HC (E1) / LC kappa 55 31 Petition 870260051334, dated 05 / 28 / 2026, page 89 / 164 74 / 141 aFXI-18623p IgG1 HC (S228P)(Q1)(K-) / LC kappa 65 31 aFXI-18623p IgG4 HC (S228P)(E1)(K-) / LC kappa 67 31 aFXI-18623p IgG1 HC (Q1)(K-) / LC kappa 77 31 aFXI-18623p IgG1 HC (E1)(K-) / LC kappa 79 31

[0248] Epitope mapping by hydrogen / deuterium exchange mass spectrometry (HDX-MS) as described in Example 3 showed that anti-FXI antibodies comprising the HC and LC of previously mentioned CDRs bind to a particular epitope in the apple 3 domain comprising SEQ ID NO: 82 and SEQ ID NO: 83.

[0249] Thus, the antibodies described here bind to the apple 3 domain of FXI and inhibit FXI activation by FXIIa and also behave as competitive, allosteric inhibitors of FIX activation by FXIa. Epitope mapping results suggesting the “footprint” of the aFXI18623p family on Apple 3 overlaps with the FIX-binding exosite on FXIa. Pharmaceutical Compositions and Administration

[0250] To prepare pharmaceutical or sterile compositions of anti-FXI antibodies or binding fragments thereof, the antibody or antigen-binding fragments thereof are mixed with a pharmaceutically acceptable carrier or excipient. See, for example, Remington's Pharmaceutical Sciences and US Pharmacopeia: National Formulary, Mack Publishing Company, Easton, PA (1984) and continuously updated on the Internet by the US Pharmacopeial Convention (USP) 12601 Twinbrook Parkway, Rockville, MD 20852 - 1790, USA. Petition 870260051334, dated 05 / 28 / 2026, pp. 90 / 164 75 / 141

[0251] Formulations of therapeutic and diagnostic agents may be prepared by mixing them with acceptable carriers, excipients, or stabilizers in the form of, for example, lyophilized powders, fluid pastes, solutions, or aqueous suspensions (see, for example, Hardman, et al. (2001) Goodman and Gilman's The Pharmacological Basis of Therapeutics, McGraw-Hill, New York, NY; Gennaro (2000) Remington: The Science and Practice of Pharmacy, Lippincott, Williams, and Wilkins, New York, NY; Avis, et al. (eds.) (1993) Pharmaceutical Dosage Forms: Relative Medications, Marcel Dekker, NY; Lieberman, et al. (eds.) (1990) Pharmaceutical Dosage Forms: Dispersion Systems, Marcel Dekker, NY; Weiner and Kotkoskie (2000) Toxicity and Safety excipient, Marcel Dekker, Inc., New York, NY).

[0252] In another embodiment, a composition comprising an antibody or antibody fragment described herein is administered to a subject in accordance with the Physicians' Desk Reference 2017 (Thomson Healthcare; 75th edition (November 1, 2002)).

[0253] The method of administration may vary. Suitable routes of administration are preferably parenteral or subcutaneous. Other routes of administration may include oral, transmucosal, intradermal, direct intraventricular, intravenous, intranasal, inhalation, insufflation, or intra-arterial.

[0254] In particular embodiments, the anti-FXI antibody or antigen-binding fragment thereof may be administered by an invasive route such as by injection. In further embodiments of the invention, an anti-FXI antibody or antigen-binding fragment thereof, or pharmaceutical composition thereof, may be administered intravenously, subcutaneously, intra-arterially, or by inhalation, aerosol delivery. Administration by non-invasive routes (e.g., orally; for example, Petition 870260051334, dated 05 / 28 / 2026, pp. 91 / 164 76 / 141 in a pill, capsule or tablet) is also within the scope of the present invention.

[0255] Compositions can be administered with medical devices known in the art. For example, a pharmaceutical composition of the invention can be administered by injection with a hypodermic needle, including, for example, a pre-filled syringe or autoinjector.

[0256] The pharmaceutical compositions described herein may also be administered with a needle-free hypodermic injection device; such as the devices described in U.S. Patents 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.

[0257] The pharmaceutical compositions described herein may also be administered by infusion. Examples of well-known implants and modules for administering pharmaceutical compositions include: U.S. Patent No. 4,487,603, which describes an implantable micro-infusion pump for dispensing medication at a controlled rate; U.S. Patent No. 4,447,233, which describes a medication infusion pump for releasing medication at a precise infusion rate; U.S. Patent No. 4,447,224, which describes an implantable variable-flow infusion apparatus for continuous drug delivery; U.S. Patent No. 4,439,196, which describes an osmotic drug delivery system having multi-chamber compartments. Many other such implants, delivery systems, and modules are well known to those skilled in the art.

[0258] The administration regimen depends on several factors, including the turnover rate of the therapeutic antibody in serum or tissue, the level of symptoms, the immunogenicity of the therapeutic antibody, and the accessibility of target cells in the biological matrix. Preferably, the administration regimen delivers sufficient therapeutic antibody to effect improvement in the patient's condition. Petition 870260051334, dated 05 / 28 / 2026, p. 92 / 164 77 / 141 target disease, while simultaneously minimizing unwanted side effects. Consequently, the amount of biological release depends in part on the particular therapeutic antibody and the severity of the condition being treated. Guidance on selecting appropriate doses of therapeutic antibodies is available (see, for example, Wawrzynczak (1996) Antibody Therapy, Bios Scientific Pub. Ltd, Oxfordshire, UK; Kresina (ed.) (1991) Monoclonal Antibodies, Cytokines and Arthritis, Marcel Dekker, New York, NY; Bach (ed.) (1993) Monoclonal Antibodies and Peptide Therapy in Autoimmune Diseases, Marcel Dekker, New York, NY; Baert, et al. (2003) New Engl. J. Med. 348:601-608; Milgrom et al. (1999) New Engl. J. Med. 341:1966-1973; Slamon et al. (2001) New Engl. J. Med. 344:783-792; Beniaminovitz et al. (2000) New Engl. J Med 342:613-619; Ghosh et al. (2003) New Engl. J Med 348:24-32; Lipsky et al. (2000) New Engl. J. Med. 343:1594-1602).

[0259] Dosage regimens are adjusted to provide the desired optimal response (e.g., a therapeutic response). For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the requirements of the therapeutic situation. It is especially advantageous to formulate parenteral compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form as used herein refers to physically separate units tailored as unit dosages for the subjects to be treated; each unit contains a predetermined amount of active compound calculated to produce the desired therapeutic effect in association with the necessary pharmaceutical carrier.The specification for the unit dosage forms described herein is said to be by and directly dependent on (a) the unique characteristics of the antibody or antibody-binding fragment and the therapeutic effect. Petition 870260051334, dated 05 / 28 / 2026, p. 93 / 164 78 / 141 particular to be obtained, and (b) the inherent limitations in the technique of composing such an active molecule for the treatment of sensitivity in individuals. (see, for example, Yang, et al. (2003) New Engl. J. Med. 349:427-434; Herold, et al. (2002) New Engl. J. Med. 346:1692-1698; Liu, et al. (1999) J. Neurol. Neurosurg. Psych. 67:451-456; Portielji, et al. (2003) Cancer Immunol. Kits

[0260] Kits comprising one or more components including, but not limited to, an anti-FXI antibody or antigen-binding fragment, as discussed herein, in association with one or more additional components including, but not limited to, another therapeutic agent, as discussed herein. The antibody or fragment and / or the therapeutic agent may be formulated as a pure composition or in combination with a pharmaceutically acceptable carrier, in a pharmaceutical composition.

[0261] In one embodiment, the kit includes an anti-FXI antibody or antigen-binding fragment thereof or a pharmaceutical composition thereof in one container (e.g., in a sterile plastic or glass vial) and another therapeutic agent in another container (e.g., in a sterile plastic or glass vial).

[0262] In another embodiment, the kit comprises a combination of the invention, including an anti-FXI antibody or antigen-binding fragment thereof or pharmaceutical composition thereof in combination with one or more therapeutic agents formulated together, optionally, in a pharmaceutical composition, in a single common container.

[0263] If the kit includes a pharmaceutical composition for parenteral administration to a subject, the kit may include a device for performing such administration. Petition 870260051334, dated 05 / 28 / 2026, page 94 / 164 79 / 141 administration. For example, the kit may include one or more hypodermic needles or other injection devices as discussed above. Thus, the present invention includes a kit comprising an injection device and the anti-FXI antibody or antigen-binding fragment thereof, for example, wherein the injection device includes the antibody or fragment or wherein the antibody or fragment is in a separate vessel.

[0264] The kit may include an information leaflet containing information regarding the pharmaceutical compositions and dosage forms in the kit. Generally, such information helps patients and physicians to use the included pharmaceutical compositions and dosage forms effectively and safely. For example, the following information regarding a combination of the invention may be provided in the leaflet: pharmacokinetics, pharmacodynamics, clinical studies, efficacy parameters, indications and use, contraindications, warnings, precautions, adverse reactions, overdose, appropriate dosage and administration as supplied, appropriate storage conditions, references, manufacturer / distributor information, and patent information. Methods of Manufacturing Antibodies and Antigen-Binding Fragments

[0265] The anti-FXI antibodies and fragments thereof described herein can also be produced recombinantly. In this embodiment, nucleic acids encoding antibody molecules can be inserted into a vector (plasmid or viral) and transfected or transformed into a host cell where it can be expressed and secreted from the host cell. There are several methods by which recombinant antibodies are produced that are known in the art.

[0266] Mammalian cell lines available as hosts Petition 870260051334, dated 05 / 28 / 2026, page 95 / 164 80 / 141 for the expression of the antibodies or fragments described herein are well known in the art and include many immortalized cell lines available from the American Type Culture Collection (ATCC). These include, inter alia, Chinese hamster ovary (CHO) cells, NSO cells, SP2 cells, HeLa cells, neonatal hamster kidney (BHK) cells, monkey kidney (COS) cells, human hepatocellular carcinoma cells (e.g., Hep G2), A549 cells, 3T3 cells, human embryonic kidney 293 (HEK-293) cells, and several other cell lines. Cell lines of particular preference are selected by determining which cell lines have high expression levels.Other cell lines that can be used are insect cell lines, such as Sf9 cells, amphibian cells, bacterial cells, plant cells, filamentous fungal cells (e.g., Trichoderma reesei), and yeast cells (e.g., Saccharomyces cerevisiae or Pichia pastoris). In particular, the host cell can be a prokaryotic host cell such as E. coli.

[0267] When recombinant expression vectors comprising a nucleic acid molecule encoding the heavy chain or antigen-binding portion or fragment thereof, the light chain and / or antigen-binding fragment thereof are introduced into host cells, antibodies are produced by culturing the host cells under conditions and for a period of time sufficient to permit antibody expression on the host cells or, more preferably, secretion of the antibody into the culture medium in which the host cells are cultured. The antibodies may be recovered from the culture medium and further purified or processed to produce the antibodies of the invention.

[0268] In particular aspects, host cells are transfected with an expression vector comprising a nucleic acid molecule. Petition 870260051334, dated 05 / 28 / 2026, page 96 / 164 81 / 141 encoding a HC and an LC comprising at least the HC and LC of CDRs of an anti-FXI antibody of the aFXI-18611p family, aFXI-18611 family, or aFXI-18623p family or embodiments thereof wherein one or more of the six CDRs has one, two, or three amino acid substitutions, additions, deletions, or combinations thereof and / or wherein the framework of the variable region of HC and / or LC comprises 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, deletions, or combinations thereof.

[0269] In particular aspects, host cells are transfected with a first expression vector comprising a nucleic acid molecule encoding a HC comprising at least the HC CDRs of an anti-FXI antibody of the aFXI-18611p family, aFXI-18611 family, or aFXI18623p family or embodiments thereof in which one or more of the six CDRs has one, two, or three amino acid substitutions, additions, deletions, or combinations thereof and / or in which the variable region framework of HC and / or LC comprises 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, deletions, or combinations thereof and a second expression vector comprising a nucleic acid molecule encoding a LC comprising at least the LC CDRs of an anti-FXI antibody of the aFXI-18611p family or aFXI18623p family aFXI-18611p, aFXI-18611 family, or aFXI-18623p 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 combinations thereof and / or where the framework of the variable region of HC and / or LC comprises 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, deletions, or combinations thereof.

[0270] In particular embodiments, HC and LC are expressed as a fusion protein in which the N-terminal of HC and LC are fused to a leader sequence to facilitate antibody transport through the secretory pathway. Petition 870260051334, dated 05 / 28 / 2026, p. 97 / 164 82 / 141 Examples of leader sequences that can be used include MSVPTQVLGLLLLWLTDARC (SEQ ID NO: 14) or MEWSWVFLFFLSVTTGVHS (SEQ ID NO: 15).

[0271] The exemplary antibody HC here may be encoded by a nucleic acid molecule having the nucleotide sequence shown in the SEQ ID NOs: 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, or 80.

[0272] The exemplary antibody LC here can be encoded by a nucleic acid molecule having the nucleotide sequence shown in SEQ ID NO: 27 or 32.

[0273] The present invention further provides a plasmid or viral vector comprising a nucleic acid molecule having the amino acid sequences of the following SEQ IDs: 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, or 80. The present invention further provides a plasmid or viral vector comprising a nucleic acid molecule encoding the HC of an anti-FXI antibody of the aFXI-18611p family, aFXI18611 family, or aFXI-18623p family, or embodiments thereof, in which one or more of the six CDRs has one, two, or three amino acid substitutions, additions, deletions, or combinations thereof and / or in that the framework of the variable region of HC and / or LC comprises 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, deletions, or combinations thereof and a nucleic acid molecule encoding the LC of an anti-FXI antibody of the aFXI18611p family, aFXI-18611 family,or the aFXI-18623p family or embodiments thereof in which one or more of the six CDRs has one, two, or three amino acid substitutions, additions, deletions, or combinations thereof and / or in which the framework of the variable region of HC and / or LC comprises 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, deletions, or combinations thereof. Petition 870260051334, dated 05 / 28 / 2026, page 98 / 164 83 / 141

[0274] The present invention further provides a plasmid or viral vector comprising a nucleic acid molecule encoding the HC of an anti-FXI antibody of the aFXI-18611p family, aFXI-18611 family, or aFXI-18623p family and a plasmid or viral vector comprising a nucleic acid molecule encoding the LC of an anti-FXI antibody of the aFXI-18611p family, aFXI-18611 family, or aFXI-18623p family.

[0275] The present invention further provides a host cell comprising one or more plasmids or viral vectors comprising a nucleic acid molecule encoding the HC of an anti-FXI antibody of the aFXI-18611p family, aFXI-18611 family, or aFXI-18623p family, or embodiments thereof, in which one or more of the six CDRs has one, two, or three amino acid substitutions, additions, deletions, or combinations thereof, and / or in which the framework of the variable HC and / or LC region comprises 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, additions, deletions, or combinations thereof, and a nucleic acid molecule encoding the LC of an anti-FXI antibody of the aFXI-18611p family, aFXI-18611 family, or aFXI-18623p family. aFXI-18623p or embodiments thereof in which one or more of the six CDRs has one, two, or three amino acid substitutions, additions, deletions, or combinations thereof and / or in which the framework of the variable region of HC and / or LC comprises 0, 1, 2, 3, 4, 5, 6, 7, 8, 9,or 10 amino acid substitutions, additions, deletions, or combinations thereof. In particular embodiments, the host cell is a CHO or HEK-293 host cell.

[0276] Antibodies can be recovered from the culture medium using standard protein purification methods. Furthermore, the expression of antibodies of the invention (or other portions thereof) from the production of cell lines can be enhanced using various known techniques. For example, the glutamine synthetase gene expression system (the GS system) Petition 870260051334, dated 05 / 28 / 2026, page 99 / 164 84 / 141 is a common method for enhancing expression under certain conditions.

[0277] In general, glycoproteins produced in a particular cell line or transgenic animal will have a glycosylation pattern that is characteristic for glycoproteins produced in that cell line or transgenic animal (See, for example, Croset et al., J. Biotechnol. 161: 336-348 (2012)). Therefore, the particular glycosylation pattern of an antibody will depend on the particular cell line or transgenic 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, comprise the present invention, regardless of the glycosylation pattern that the antibodies may have.

[0278] The following examples are intended to promote a further understanding of the present invention. GENERAL METHODS

[0279] Standard methods in molecular biology are described in Sambrook, Fritsch and Maniatis (1982 & 1989 2nd Edition, 2001 3rd Edition) Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Sambrook and Russell (2001) Molecular Cloning, 3rd ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Wu (1993) Recombinant DNA, Vol. 217, Academic Press, San Diego, CA). Standard methods also appear in Ausbel, et al. (2001) Current Protocols in Molecular Biology, Vols 1 - 4, John Wiley and Sons, Inc. New York, NY, which describes cloning in bacterial cells and DNA mutagenesis (Vol. 1), cloning in mammalian and yeast cells (Vol. 2), glycoconjugates and protein expression (Vol. 3), and bioinformatics (Vol. 4).

[0280] Methods for protein purification including immunoprecipitation, chromatography, electrophoresis, centrifugation, and crystallization are described (Coligan, et al. (2000) Current Protocols in Protein Science, Vol. 1, Petition 870260051334, dated 05 / 28 / 2026, pp. 100 / 164 85 / 141 Chemical analysis, chemical modification, post-translational modification, production of fusion proteins, and protein glycosylation are described (see, for example, Coligan, et al. (2000) Current Protocols in Protein Science, Vol. 2, John Wiley and Sons, Inc., New York; Ausubel, et al. (2001) Current Protocols in Molecular Biology, Vol. 3, John Wiley and Sons, Inc., NY, NY, pages 16.0.5 - 16.22.17; Sigma-Aldrich, Co. (2001) Products for Life Science Research, St. Louis, MO; pages 45 - 89; Amersham Pharmacia Biotech (2001) BioDirectory, Piscataway, NJ, pages 384 - 391). Production, purification, and fragmentation of polyclonal and monoclonal antibodies are described (Coligan, et al. (2001) Current Protocols in Immunology, Vol. 1, John Wiley and Sons, Inc., New York; Harlow and Lane (1999) Using Antibodies, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Harlow and Lane, supra).Standard techniques for characterizing ligand / receptor interactions are available (see, for example, Coligan, et al. (2001) Current Protocols in Immunology, Vol. 4, John Wiley, Inc., New York).

[0281] Monoclonal, polyclonal, and humanized antibodies can be prepared (see, for example, Sheperd and Dean (eds.) (2000) Monoclonal Antibodies, Oxford Univ. Press, New York, NY; Kontermann and Dubel (eds.) (2001) Antibody Engineering, Springer-Verlag, New York; Harlow and Lane (1988) Antibodies A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, páginas 139 - 243; Carpenter, et al. (2000) J. Immunol. 165:6205; He, et al. (1998) J. Immunol. 160:1029; Tang et al. (1999) J. Biol. Chem. 274:27371 - 27378; Baca et al. (1997) J. Biol.

[0282] One alternative for humanization is to use human antibody libraries displayed in phage or human antibody libraries in Petition 870260051334, dated 05 / 28 / 2026, pp. 101 / 164 86 / 141 transgenic mice (Vaughan et al. (1996) Nature Biotechnol. 14:309 314; Barbas (1995) Nature Medicine 1:837 - 839; Mendez et al. (1997) Nature Genetics 15:146 - 156; Hoogenboom and Chames (2000) Immunol. Today 21:371 377; Barbas et al. (2001) Phage Display: A Laboratory Manual, Cold Spring Harbor, New York;

[0283] Antibodies can be conjugated, for example, to small drug molecules, enzymes, liposomes, polyethylene glycol (PEG). Antibodies are useful for therapeutic, diagnostic, kit or other purposes, and include antibodies coupled, for example, to dyes, radioisotopes, enzymes, or metals, for example, colloidal gold (see, for example, Le Doussal et al. (1991) J. Immunol. 146:169-175; Gibellini et al. (1998) J. Immunol. 160:3891-3898; Hsing and Bishop (1999) J. Immunol. 162:2804-2811; Everts et al. (2002) J. Immunol. 168:883-889).

[0284] Methods for flow cytometry, including fluorescence-activated cell separation (FACS), are available (see, for example, Owens, et al. (1994) Flow Cytometry Principles for Clinical Laboratory Practice, John Wiley and Sons, Hoboken, NJ; Givan (2001) Flow Cytometry, 2nd ed.; Wiley-Liss, Hoboken, NJ; Shapiro (2003) Practical Flow Cytometry, John Wiley and Sons, Hoboken, NJ). Suitable fluorescent reagents for modifying nucleic acids, including nucleic acid primers and probes, polypeptides, and antibodies, for use, for example, as diagnostic reagents, are available (Molecular Probes (2003) Catalogue, Molecular Probes, Inc., Eugene, OU; Sigma-Aldrich (2003) Catalogue, St. Louis, MO).

[0285] Standard methods of immune system histology are described (see, for example, Muller-Harmelink (ed.) (1986) Human Thymus: Histopathology and Petition 870260051334, dated 05 / 28 / 2026, pp. 102 / 164 87 / 141 Pathology, Springer Verlag, New York, NY; Hiatt, et al. (2000) Color Atlas of Histology, Lippincott, Williams, and Wilkins, Phila, PA; Louis, et al. (2002) Basic Histology: Text and Atlas, McGraw-Hill, New York, NY).

[0286] Software packages and databases for determining, for example, antigenic fragments, leader sequences, protein folding, functional domains, glycosylation sites, and sequence alignments are available (see, for example, GenBank, Vector NTI® Suite (Informax, Inc., Bethesda, MD); GCG Wisconsin Package (Accelrys, Inc., San Diego, CA); DeCypher® (TimeLogic Corp., Cristal Bay, Nevada); Menne, et al. (2000) Bioinformatics 16: 741-742; Menne, et al. (2000) Bioinformatics Applications Note 16: 741-742; Wren, et al. (2002) Comput. Methods Programs Biomed. 68: 177-181; von Heijne (1983) Eur. J. Biochem. 133: 17- 21; von Heijne (1986) Nucleic Acids Res. 14:4683 - 4690).

[0287] Human FXI and FIX zymogen can be obtained from Haematologic Technologies, Inc., Essex Junction, VT; High Molecular Weight (HMW) kininogen can be obtained from Enzyme Research Laboratories, South Bend, IN; and, Ellagic acid can be obtained from Pacific Hemostasis, ThermoFisher, Waltham, MA. EXAMPLE 1

[0288] In this example, the binding kinetics of the anti-FXI antibodies IgG4 HC of aFXI-18611 (S228P)(E1) (L105) / LC Kappa and IgG4 HC of aFXI-18623p (S228P)(Q1) / LC Kappa and the human FXI zymogen or non-human primate (NHP) FXI zymogen were measured using the following tests. Human FXI / FXIa binding kinetics assay protocol

[0289] The kinetics and binding affinity of the protein-protein interaction between anti-FXI antibodies and human FXI or FXIa zymogen were determined using the ProteOn XPR36 (Bio-Rad), an optical biosensor with Petition 870260051334, dated 05 / 28 / 2026, pp. 103 / 164 88 / 141 based on SPR (surface plasmon resonance) essentially as follows.

[0290] A low-density GLC sensor chip was washed through all vertical and horizontal flow channels with 0.5% sodium dodecyl sulfate, 50 mM sodium hydroxide, and 100 mM hydrochloric acid for 60 seconds at a flow rate of 30 pL / s. The alginate chip surface for all six vertical flow channels (L1-L6) was subsequently activated with 1x EDC / sNHS at a flow rate of 30 pL / s for 150 s. A polyclonal anti-human IgG antibody directed to murine Fc (capture antibody), diluted to 1.25 pg / mL in 10 mM sodium acetate, pH 5.0, was then injected through all six vertical flow channels for 300 s at a flow rate of 25 uL / s to bind approximately 300 response units (RU) of capture antibody to the flow channel-activated chip surface by amine binding to endogenous lysine.Next, 1M ethanolamine HCl was injected through all six vertical flow channels to neutralize any remaining reactive surface amines. Anti-FXI antibodies were then injected at 25 pL / min for 60 seconds each into a distinct vertical flow channel coated with capture antibody (L2, L3, L4, L5, or L6), at a concentration of 5 pg / mL in 10 mM sodium acetate, pH 5.0, to obtain saturation capture levels of approximately 80 RU; vertical flow channel L1 was injected with 10 mM sodium acetate, pH 5.0 (buffer alone), as a reference control.

[0291] After capturing the anti-FXI antibodies, running buffer (1x HBS-N, 5 mM CaCl2, 0.005% P20, pH 7.4) was injected through all horizontal flow channels (A1-A6) for 5 minutes and allowed to dissociate for 20 minutes at 25 pL / min to remove any non-specifically bound anti-FXI antibodies from the chip surface. To measure the association rate (ka) of human FXI or FXa to captured anti-FXI antibodies, a 6-point titration of human FXI or FXIa (diluted to 0, 0.25, 0.5, 1.0, 2.0, 4.0 nM in buffer) was performed. Petition 870260051334, dated 05 / 28 / 2026, pp. 104 / 164 89 / 141 running) was subsequently injected horizontally through all six vertical flow channels for 8 minutes; the bound zymogen was then allowed to dissociate for 60 minutes in running buffer at 25 μL / min to measure the dissociation rate (kd). Kinetics and binding affinity (Kd) were determined using instrument-specific software (Bio-Rad) and are shown in Table 2. Non-human primate FXI / FXIa zymogen binding kinetics assay protocol

[0292] Kinetics and binding affinity of protein-protein interaction between anti-FXI antibodies and FXI or FXIa zymogen from non-human primates (NHP: cynomolgus and rhesus) were determined using the ProteOn XPR36 (Bio-Rad), an optical biosensor based on SPR (surface plasmon resonance).

[0293] A low-density GLC sensor chip was washed through all vertical and horizontal flow channels 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 / s. The alginate chip surface for all six vertical flow channels (L1-L6) was subsequently activated with 1x EDC / sNHS at a flow rate of 30 μL / second for 150 seconds. A polyclonal anti-human IgG antibody directed to murine Fc (capture antibody), diluted to 30 μg / mL in 10 mM sodium acetate, pH 5.0, was then injected through all six vertical flow channels for 150 seconds at a flow rate of 25 μL / s to achieve saturation binding of approximately 4500 response units (RU) of capture antibody to the flow-activated chip surface channel by amine binding to endogenous lysine.Then 1M ethanolamine HCl was injected through all six vertical flow channels to neutralize any remaining reactive surface amines. Anti-FXI antibodies were then injected at 25 μL / min for 60 s, each into a separate flow channel. Petition 870260051334, dated 05 / 28 / 2026, pages 105 / 164 A distinct vertical 90 / 141 channel was coated with capture antibody (L2, L3, L4, L5, or L6) at a concentration of 0.415 μg / mL in running buffer (1x HBS-N, 5 mM CaCl2, 0.005% P20, pH 7.4) to obtain capture levels of approximately 40 RU; vertical flow channel L1 was injected with running buffer alone as a reference control. After capture of anti-FXI antibodies, running buffer was injected through all horizontal flow channels (A1A6) for 5 minutes and allowed to dissociate for 20 minutes at 25 pL / minute to remove non-specifically bound anti-FXI antibodies from the chip surface.To measure the association rate (ka) of NHP FXI to captured anti-FXI antibodies, a 6-point titration of NHP FXI or FXIa (diluted to 0, 0.25, 0.5, 1.0, 2.0, 4.0 nM in running buffer) was subsequently injected horizontally through all six vertical flow channels for 8 minutes; the bound FXI or FXIa zymogen was then allowed to dissociate for 60 minutes in running buffer at 25 μL / min to measure the dissociation rate (kd). Kinetics and binding affinity (Kd) were determined using instrument-specific software (Bio-Rad). The results are shown in Table 2. Table 2: Binding of aFXI-18623P and aFXI-18611 mAbs to FXI / XIa Target N Average affinity Kd for FXI ± SD pM Average affinity Kd for FXIa ± SD pM aFXI-18611 aFXI-18623p aFXI-18611 aFXI-18623P Human 3 100 ± 38 22.6 ± 2.2 55.4 ± 12.2 37.4 ± 10.4 Cynomolgus monkey 3 180 ± 70 13.0 ± 5.7 89.2 ± 10.4 19.5 ± 0.6 Monkey- 3 52.9 ± 9.6 72.2 ± 31.7 175 ± 62.6 149 ± 3.8 Petition 870260051334, dated 05 / 28 / 2026, pp. 106 / 164 91 / 141 rhesus aFXI-18611 = aFXI-18611 IgG4 HC (S228P)(E1) (L105) / LC kappa aFXI-18623p = aFXI-18623p IgG4 HC (S228P)(Q1) / LC kappa EXAMPLE 2 Effect of anti-FXI antibodies on the activation of FXI to FXIa by FXIIa in the presence of kininogen and high molecular weight (HMW) ellagic acid.

[0294] To measure the effects of anti-FXI antibodies HC IgG4 of aFXI18611 (S228P)(E1) (L105) / LC Kappa and HC IgG4 of aFXI-18623p (S228P)(Q1) / LC Kappa on FXI zymogen activation, coupled enzyme assays measuring FXIa-mediated proteolysis of a tripeptide fluorophore (GPRAFC) can be used to determine whether the antibodies inhibit FXI activation per se. For these experiments, anti-FXI antibodies are pre-incubated with FXI zymogen for 1 hour. FXI activation to FXIa is induced by the addition of FXIIa in the presence of HMW kininogen and ellagic acid. The catalytic activity of FXIa on the tripeptide fluorophore substrate is subsequently measured as a readout for zymogen activation. The coupled assay is also conducted in the absence of HMW kininogen as a control.Eleven-point dose titrations of anti-FXI antibodies starting at a concentration of 1 pM with a series of 3-fold dilutions were pre-incubated with human FXI (Haematologic Technologies, Inc., Cat # HCXI-0150, final concentration 30 nM) and HMW kininogen (Enzyme Research Laboratories, Cat # HK, final concentration 280 nM) in 50 mM HEPES, 150 mM NaCl, 5 mM CaCl2, 0.1% PEG-8000, pH 7.4 for two hours at 25 °C in a Corning 3575 non-ligand surface microplate. The activation reaction was then initiated by the addition of APTT-XL Pacific Hemostasis reagent containing ellagic acid (ThermoFisher Scientific, Cat # 100403, stock concentration 100 pM, final concentration 2 pM) and factor XIIa. freshly diluted coagulation (Enzyme Research). Petition 870260051334, dated 05 / 28 / 2026, pp. 107 / 164 92 / 141 Laboratories, Cat # HFXIIa, final concentration of 50 pM). The reaction proceeded at 25 °C for 1 hour when it was stopped by the addition of 1 μM of maize trypsin inhibitor (Haematologic Technologies, Inc., Cat # CTI-01). The enzymatic activity of newly activated FXIa was detected by the substrate cleavage rate of Z-GPR-AFC (Sigma, Cat # C0980-10MG, final concentration of 150 μM) by continuously monitoring the fluorescence at 400 / 505 nm for 10 minutes using a Tecan Infinite M200 plate reader. The % inhibition for each data point was recalculated from the RFU / min data and analyzed using the log(inhibitor) vs. four-parameter response equation with GraphPad Prisma software. The results are shown in Table 3. Activation of FXI to FXIa by FXIIa in the absence of HMW kininogen and ellagic acid.

[0295] Eleven-point dose titrations of anti-FXI antibodies of the same invention, starting at a concentration of 1 μM with a series of 3-fold dilutions, were pre-incubated with human FXI (Haematologic Technologies, Inc., Cat # HCXI-0150, final concentration of 30 nM) in 50 mM HEPES, 150 mM NaCl, 5 mM CaCl2, 0.1% PEG-8000, pH 7.4 for two hours at 25 °C in a Corning 3575 non-bonding surface microplate. The activation reaction was then initiated by the addition of freshly diluted coagulation factor XIIa (Enzyme Research Laboratories, Cat # HFXIIa, final concentration of 15 nM). The reaction proceeded at 25 °C for 1 hour when it was stopped by the addition of 1 μM of maize trypsin inhibitor (Haematologic Technologies, Inc., Cat # CTI-01).The enzymatic activity of newly activated FXIa was detected by the substrate cleavage rate of Z-GPR-AFC (Sigma, Cat # C0980-10MG, final concentration of 150 μM) by continuously monitoring fluorescence at 400 / 505 nm for 10 minutes using a Tecan Infinite M200 plate reader. The % inhibition for each data point was recalculated from the RFU / min data. Petition 870260051334, dated 05 / 28 / 2026, pp. 108 / 164 93 / 141 and analyzed using the log(inhibitor) vs. four-parameter response equation with GraphPad Prisma software. The results are shown in Table 3. Table 3 Effect of aFXI-18623p and aFXI-18611 on FXI Activation by FXIIa Antibody N FXIIa Activation + HK Inhibition (IC50, nM) FXIIa Activation without HK Inhibition (IC50, nM) aFXI-18611 3 7.6 ± 3.5 34 ± 20 aFXI-18623p 3 6.0 ± 1.1 14 ± 9.5 aFXI-18611 = IgG4 HC of aFXI-18611 (S228P)(E1) (L105) / LC kappa aFXI-18623p = IgG4 HC of aFXI-18623p (S228P)(Q1) / LC kappa IC50s are provided as mean ± SD, n = 3

[0296] Together, these mechanistic studies demonstrate that these anti-FXI antibodies functionally neutralize FXI by preventing FXI activation by FXIIa and inhibiting the catalytic activity of FXIa on the native substrate. EXAMPLE 3 Epitope mapping of anti-FXI antibodies by hydrogen / deuterium exchange mass spectrometry

[0297] The HC contact areas of IgG4 from aFXI-18611 (S228P)(E1) (L105) / LC Kappa and aFXI-18623p-IgG4 (S228P) (Q1) / LC Kappa to human FXI were determined using hydrogen / deuterium exchange mass spectrometry (HDX-MS) analysis. HDX-MS measures the incorporation of deuterium into the protein's amide backbone, and changes in incorporation are influenced by hydrogen solvent exposure. A comparison of deuterium exchange levels in antigen-only samples and antibody-bound samples was made to identify antigen regions that may be Petition 870260051334, dated 05 / 28 / 2026, pp. 109 / 164 94 / 141 in contact with the antibody. Human Factor XI has the amino acid sequence shown in SEQ ID NO: 81. Dimeric Factor XI was pre-incubated with the antibodies before incubation in a deuterium buffer. Deuterium incorporation into Factor XI was measured by mass spectrometry.

[0298] The human Factor XI regions protected from deuteration by antibodies are Epitope-A DIFPNTVF (Factor XI residues 185 to 192; SEQ ID NO: 82) and Epitope-B PSTRIKKSKALSG (Factor XI residues 247 to 259; SEQ ID NO: 83). Figs. 3A and 3B show heatmaps of the difference in deuterium labeling of Factor XI amino acid residues bound by aFXI-18611 (S228P)(E1) (L105) / LC Kappa IgG4 HC antibodies and aFXI-18623p (S228P)(Q1) / LC Kappa IgG4 HC antibodies, respectively. These amino acid sequences are located in the Apple 3 domain of Factor XI (Fig. 2). Significant deuteration changes were not observed in the Apple 1, 2, 4 or catalytic domains, indicating that they are not involved in the binding of aFXI-18623. Thus, the epitope recognized by aFXI-18623p-IgG4 (S228P) / kappa comprises Epitope A and Epitope B. EXAMPLE 4

[0299] FIX is the endogenous protein substrate of FXIa, the zymogen-active protease of FXI. FXIa activates FIX to FIXa, perpetuating the coagulation cascade. Inhibition of FXIa-mediated activation of FIX is a potential mechanism of action (MOA) for FXI mAbs. To investigate this MOA, FXIa enzymatic assays using full-length FIX zymogen were developed. FXIa Protease Activity on a Small Tripeptide Substrate

[0300] Anti-FXI antibodies were pre-incubated with human FXIa (Sekisui Diagnostics, Exton, PA, Cat # 4011A, final concentration of 100 pM) in 50 mM HEPES, 150 mM NaCl, 5 mM CaCl2, 0.1% PEG-8000, pH 7.4 for 2 hours at 25 °C in a Corning 3575 non-bonding surface microplate. The activity Petition 870260051334, dated 05 / 28 / 2026, pp. 110 / 164 The enzymatic activity of FXIa (95 / 141) was determined by measuring the substrate cleavage rate of Z-GPR-AFC (Sigma, Cat # C0980-10MG, final concentration of 100 μM) by continuously monitoring fluorescence at 400 / 505 nm for 10 minutes using a Tecan Infinite M200 plate reader. Final concentrations of the 11-point antibody dose titrations started at 1 μM with a 3-fold dilution series. The % inhibition for each data point was recalculated from the RFU / minute data and analyzed using the log(inhibitor) vs. four-parameter response equation with GraphPad Prisma software. The results are shown in Table 4. FIX activation via FIXa

[0301] FIX is the endogenous protein substrate of FXIa, the zymogen-active protease of FXI. FXIa activates FIX to FIXa, perpetuating the coagulation cascade. Inhibition of FXIa-mediated activation of FIX is a potential MOA for FXI mAbs. To investigate this MOA, enzymatic assays of FXIa using full-length FIX were developed.

[0302] Eleven-point dose titrations of anti-FXI antibodies, starting at a concentration of 1 μM with a series of 3-fold dilutions, were pre-incubated with human FXIa (Sekisui Diagnostics, Cat # 4011A, final concentration 100 pM) in 50 mM HEPES, 150 mM NaCl, 5 mM CaCl2, 0.1% PEG-8000, pH 7.4 for 2 hours at 25 °C in a Corning 3575 non-bonding surface microplate. The activation reaction was then initiated by the addition of FIX (Haematologic Technologies, Inc., Cat # HCIX-0040-C, final concentration 300 nM) and preceded at 25 °C for 1 hour, at which point the reaction was stopped by the addition of 100 nM of an anti-FXI antibody directed to the catalytic site on the FXI light chain. (anti-FXI antibody 076D-M007-H04 described in WO2013167669). The enzymatic activity of newly activated FIXa was detected by the substrate cleavage rate of cyclohexyl-GGR-AFC (CPC Scientific, Cat # 839493, concentration Petition 870260051334, dated 05 / 28 / 2026, pp. 111 / 164 96 / 141 final of 300 μM) continuously monitoring fluorescence at 400 / 505 nm for 10 minutes using a Tecan Infinite M200 plate reader. The % inhibition for each data point was recalculated from the RFU / minute data and analyzed using the log(inhibitor) vs. four-parameter response equation with GraphPad Prisma software. The results are shown in Table 4. Table 4 Effect of aFXI-18623p and aFXI-18611 on the catalytic activity of FXIa Antibody N IC50 of FXIa at nM (tripeptide substrate) IC50 of FXIa at nM (full-length, native substrate) aFXI-18611 3 >1000 1.0 ± 0.3 aFXI-18623p 3 >1000 0.4 ± 0.2 aFXI-18611 = HC of IgG4 of aFXI-18611 (S228P)(E1) (L105) / LC kappa aFXI-18623p = HC of IgG4 of aFXI-18623p (S228P)(Q1) / LC kappa IC50s are given as mean ± SD, n=3

[0303] As shown in Table 4, the antibodies did not inhibit the catalytic activity of FXIa in the enzymatic assay using a synthetic tripeptide fluorophore substrate, but both antibodies were potent inhibitors in the assay using the native full-length substrate. These data are consistent with antibodies behaving as competitive, allosteric inhibitors of FIX activation by FXIa, as well as the epitope mapping results from Example 3, which suggest that the antibody footprint on Apple 3 overlaps with the FIX-binding exosite on FXIa. EXAMPLE 5 Self-activation of FXI to FXIa in dextran sulfate Petition 870260051334, dated 05 / 28 / 2026, pp. 112 / 164 97 / 141

[0304] 11-point dose titrations of anti-FXI antibodies of the same invention starting at a concentration of 1 μM with a series of 3-fold dilutions were pre-incubated with human FXI (Haematologic Technologies, Inc., Cat # HCXI-0150, final concentration of 30 nM) in 50 mM HEPES, 150 mM NaCl, 5 mM CaCl2, 0.1% PEG-8000, pH 7.4 for 2 hours at 25 °C in a Corning 3575 non-bonding surface microplate. The auto-activation reaction was then initiated by the addition of dextran sulfate (ACROS, Cat # 433240250, approximate MW of 800 kDa, final concentration of 1 nM). The reaction was carried out at 25 °C for 1 hour when the enzymatic activity of newly activated FXIa was detected by the substrate cleavage rate of Z-GPR-AFC (Sigma, Cat # C098010MG, final concentration of 150 µM) by continuously monitoring the fluorescence at 400 / 505 nm for 10 minutes using a Tecan Infinite M200 plate reader.The percentage of inhibition for each data point was recalculated from the RFU / minute data and analyzed using the log(inhibitor) vs. four-parameter response equation with GraphPad Prisma software. The results are shown in Table 5. Table 5 Effect of aFXI-18623p and aFXI-18611 on FXI auto-activation N antibody IC50 of FXI auto-activation in nM aFXI-18611 2 3.3 ± 0.4 aFXI-18623p 2 5.5 ± 4.0 aFXI-18611 = IgG4 HC of aFXI-18611 (S228P)(E1) (L105) / LC kappa aFXI-18623p = IgG4 HC of aFXI-18623p (S228P)(Q1) / LC kappa IC50s are given as mean ± SD, n=3 EXAMPLE 6

[0305] The ability of anti-FXI antibodies to block coagulation in vitro was evaluated using the activated Partial Thromboplastin Time assay. Petition 870260051334, dated 05 / 28 / 2026, pp. 113 / 164 98 / 141 (aPTT). Activated partial thromboplastin time (aPTT) is a coagulation test that measures the activity of the intrinsic and common coagulation pathways. Activated partial-time thromboplastin assay (aPTT)

[0306] The test is performed on sodium citrate plasma. Human plasma is obtained by collecting blood from healthy donors of both genders in sodium citrate tubes (Sarstedt coagulation at 9NC / 10 mL). The blood is centrifuged at 1500 x 10⁻⁵ and the plasma is collected. aPTT is checked in each individual donor and those within the normal range (28 to 40 seconds) are mixed, aliquoted, and stored at -80 °C. Plasma from other species is obtained commercially (Innovative Research, Novi, MI). Test samples are prepared by injecting inhibitors or vehicle into the plasma. These injected samples are incubated (60 minutes, RT) then run on a coagulation analyzer (STA-R Evolution, Stago Diagnostica, Parsippany, NJ). In general, the analyzer performs the following steps: FXII is activated by the addition of ellagic acid (Pacific Hemostasis, ThermoFisher Scientific, Waltham, MA), and then the time to clotting is measured after recalcification of the sample.Inhibition of FXI will cause the aPTT clotting time to be prolonged. The results are shown in Table 6. Data are expressed as a percentage increase over vehicle control clotting time, and the concentration that causes a 100% (2X) or 50% (1.5X) increase in clotting time is reported. aPTT results are shown in Figs. 6, 7, 8, 9, and 10. Table 6 Antibody Human Cynomolgus Monkey Rhesus Monkey 2x (nM) 1.5 (nM) 2x (nM) 1.5 (nM) 2x (nM) 1.5 (nM) aFXI-18623p 24 19 21 15 22 15 Petition 870260051334, dated 05 / 28 / 2026, pages 114 / 164 99 / 141 aFXI-18611 37 23 218 42 79 22 aFXI-18611 = IgG4 HC of aFXI-18611 (S228P)(E1) (L105) / LC kappa αFXI-18623p = IgG4 HC of aFXI-18623p (S228P)(Q1) / LC kappa EXAMPLE 7 Surface Plasmonic Resonance Assay for Evaluating Off-Target Binding of Monoclonal Anti-FXI Antibodies to Human Coagulation Cascade Proteins and NHP

[0307] A surface plasmon resonance (SPR) based assay (Biacore T200) was used to determine the potential nonspecific interaction of anti-FXI Factor mAbs, IgG4 HC of aFXI-18611 (S228P)(E1) (L105) / LC Kappa and IgG4 HC of αFXI-18623p (S228P)(Q1) / LC Kappa with other human coagulation cascade proteins and NHP (Table 7). Anti-FXI mAbs were captured on a CM5 sensor chip immobilized with the anti-human IgG (Fc) capture kit (GE Healthcare) at approximately 500RU to minimize potential background co-purifying Igs 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 of plasma-derived proteins.Binding kinetics were measured using an analyte concentration of FXI at 5 nM; all other coagulation cascade proteins were used at an analyte concentration of 500 nM. Single concentration injections (n ​​= 2) were conducted at 30 pL / min, 25 °C, HBS-EP+, pH 7.4. Table 7 Human and recombinant and plasma-derived NHP coagulation cascade proteins. Lot number / Catalog number. Seller. Common name. Source. Petition 870260051334, dated 05 / 28 / 2026, pages 115 / 164 100 / 141 00AJF Merck, Sharp & Dohme Corp., Kenilworth, NJ USA Rhesus monkey plasma kallikrein His-tagged C-terminal recombinant protein. NCBI Reference Sequence: EHH26351 65AJE Merck, Sharp & Dohme Corp., Kenilworth, NJ USA Cynomolgus monkey plasma kallikrein His-tagged C-terminal recombinant protein. NCBI Reference Sequence: XP_005556538,1 97AJY / HPK 1302 Enzyme Research Laboratories Human plasma prekallikrein Isolated from human plasma 98AJY / HPKa 1303 Enzyme Research Laboratories Human plasma kallikrein Isolated from human plasma 42AHG / HCP-0010 Haematologic Technologies Inc. Human factor II (α-thrombin) Isolated from human plasma 50AHK / HCVII-0030 Haematologic Technologies Inc. Human factor VII Isolated from human plasma 51AHK HCVIIA-0031 Haematologic Technologies Inc. Human factor VIIa protease Isolated from human plasma 38AHG / HCIX-0040 Haematologic Technologies Human factor IX Isolated from human plasma Petition 870260051334, dated 05 / 28 / 2026, pages 116 / 164 101 / 141 14AJZ / HFIXa 1080 Enzyme Research Laboratories Human Factor IXa Protease Isolated from human plasma 15AJZ / HFX1010 Enzyme Research Laboratories Human Factor X Isolated from human plasma 18AJZ / HFXa 1011 Enzyme Research Laboratories Human Factor Xa Protease Isolated from human plasma 19AJZ / HFXII 1212 Enzyme Research Laboratories Human Factor XII Isolated from human plasma 20AJZ / HFXII 1212a Enzyme Research Laboratories Human Factor XIIa Protease Isolated from human plasma 23AIR / HCXI-0150-C Haematologic Technologies Inc. Human FXI Isolated from human plasma 41AHG HCP-0010 Haematologic Technologies Inc. Human Factor II (Prothrombin) Isolated from human plasma 82AJK / 2460-SE R&D FXI human - His-tagged recombinant C-terminal protein. Mouse myeloma cell line, derived Petition 870260051334, dated 05 / 28 / 2026, pp. 117 / 164 102 / 141 From NSO. NCBI Reference PO3951. 23AFE Merck, Sharp & Dohme Corp., Kenilworth, NJ USA IgG4 mAb anti-RSV SEQ ID NO: 84 (LC) and SEQ ID NO: 85 (HC)

[0308] The binding kinetics of anti-FXI Factor mAbs, IgG4 HC of aFXI18611 (S228P)(E1) (L105) / LC Kappa and IgG4 HC of aFXI-18623p (S228P)(Q1) / LC Kappa to human, cynomolgus, and rhesus monkey FXI, and other human and NHP coagulation cascade proteins was measured as described above and is shown in Fig. 11 and Fig. 12). The Biacore T200 evaluation software was used to fit the data to a 1:1 binding model to determine the association rate constant, ka (M-1s-1, where M equals molar and s equals seconds) and the dissociation rate constant, kd (s-1). These rate constants were used to calculate the equilibrium dissociation constant, KD (M).

[0309] IgG4 HCs of aFXI-18611 (S228P)(E1) (L105) / LC Kappa and IgG4 HCs of aFXI-18623p (S228P)(Q1) / LC Kappa captured on the chip showed no cross-reactivity against coagulation cascade proteins other than FXI (Fig. 11 and Fig. 12). These monoclonal antibodies showed expected levels of strong binding to human and civet (and Rhesus) FXI proteins. EXAMPLE 8 Cynomolgus monkey femoral arteriovenous (AV) thrombosis shunt model

[0310] The antithrombotic efficacy of the IgG4 HC antibody of aFXI-18623p (S228P)(E1) / LC Kappa was characterized in vivo in a cynomolgus monkey femoral arteriovenous (AV) shunt model developed at Merck, Sharp & Dohme Corp. Research Laboratories, Kenilworth, NJ USA and Palo Alto, CA USA. Petition 870260051334, dated 05 / 28 / 2026, pages 118 / 164 103 / 141

[0311] Study design: These studies used a repeated design where each animal received 2 derivations in 2 consecutive test periods (see Fig. 13 Schematic of study). Monkeys were administered either antibody-free vehicle (20 mM sodium acetate, 9% sucrose, pH 5.5) or aFXI-18623p (S228P)(E1) / LC Kappa IgG4 HC antibody (dose range 0.01 to 1.0 mg / kg) during the first and second test periods, respectively. The difference between clot weight measured during the first (vehicle) and second (antibody) test sections determined the antithrombotic efficacy. That is, a greater decrease in clot weight during exposure to aFXI-18623p (S228P)(E1) / LC Kappa IgG4 HC antibody versus vehicle would indicate a greater antithrombotic effect. The use of the repeated paired design described above takes into account a pre- vs. post-treatment within-animal assessment of antithrombotic efficacy.

[0312] Details of the AV shunt placement procedure: To perform this model, anesthetized cynomolgus monkeys were instrumented with arterial and femoral venous catheters. These catheters allowed for the insertion and removal of an AV shunt. The AV shunts were composed of TYGON tubing with a piece of silk suture running through it and suspended through the opening in the tubing. To place the AV shunt, both arterial and venous catheters were closed to stop blood flow. An AV shunt was then placed between the two catheters. The timing of catheter placement and removal is shown in Fig. 13. Once the shunt was in place, the catheters were opened and blood flowed through the shunt circuit, contacting the silk suture. The action of the blood contacting the suture promoted clot formation. The AV shunt remained in place for 40 minutes.To remove the AV shunt, both arterial and venous catheters were closed to stop blood flow through the AV shunt. Then, a. Petition 870260051334, dated 05 / 28 / 2026, pp. 119 / 164 104 / 141 shunt was removed and the incision opened to evaluate the silk suture and blood clot. The blood clot was weighed. The data are reported as the net clot weight, which is defined as the total clot weight minus the silk suture weight.

[0313] Coagulation biomarkers activated partial thromboplastin time (aPTT) and prothrombin time (PT) as well as circulating plasma levels of aFXI-18623p (S228P)(E1) / LC Kappa IgG4 HC antibody were measured from blood samples collected throughout the experiment as described in Fig. 13. aPTT and PT were measured from thawed / frozen (-80 °C) citrated plasma collected from cynomolgus monkeys using the Sta Compact Max coagulation analyzer (Stago Diagnostic, Inc). The Stago analyzer measures clot formation time using an electromagnetic and mechanical clot detection system. For the aPTT assay, fifty microliters of plasma were mixed with 50 μL of ellagic acid mixture (APTT-XL, Pacific Hemostasis; Fisher Diagnostics cat # 10-0402) at 37 °C for 3 minutes. Fifty microliters of 0.025M calcium chloride (Sta - CaCl2 0.025M, Stago Diagnostic, Inc.) were also added.(cat# 00367) were added to the mixture, and the time to clot formation was measured. For the PT assay, fifty microliters of plasma were incubated at 37 °C for 4 minutes. The time to clot formation was initiated by adding 100 μL of thromboplastin reagent (Neoplastine Cl Plus 10, Stago Diagnostic, Inc., cat# 00667). The plasma was measured as follows. A generic hIgG4 immunoassay based on electrochemiluminescence was used to quantify the antibody in cynomolgus monkey plasma. The assay was set up with biotinylated goat anti-IgG (H+L) from Betil (cat# A80-319B) as the capture reagent, and sulfoTAG-labeled mouse anti-IgG (Fc-specific) from Southern Biotech (cat# 9190-01) as the detection reagent. Petition 870260051334, dated 05 / 28 / 2026, pages 120 / 164 105 / 141 This assay was qualified and the lower limit of quantification of the assay was determined to be 40 ng / mL with a minimum required dilution of 100.

[0314] Figures 14A to 14D summarize the effects of administering the IgG4 HC antibody from aFXI-18623p (S228P)(E1) / LC Kappa on blood clot formation (Fig. 14A, Fig. 14B), aPTT (Fig. 14C), and PT (Fig. 14D). Table 8 summarizes the effect of the IgG4 HC antibody from aFXI-18623p (S228P)(E1) / LC Kappa on clot weight in the Cino AV derivation model. Table 9 summarizes the effect of the IgG4 HC antibody from aFXI-18623p (S228P)(E1) / LC Kappa on aPTT and PT in the Cino AV derivation model. Table 8 Effect of αFXI-18623p (S228P)(E1) / LC Kappa IgG4 HC antibody on clot weight in the AV cinoleic model Antibody Dose (mg / kg) Derivation #1 (Vehicle) Derivation #2 (Antibody) % Clot Weight Antibody Inhibition Conc. (Rg / mL) 1 772.0 1.0 100 % 29.13 0.1 957.0 1.0 100 % 2.42 0.01 974.0 1007.0 -3 % 0.17 0.03 927.0 935.0 -1 % 0.54 0.04 909.0 887.0 2 % 0.79 0.05 607.0 472.0 22 % 0.91 0.05 710.0 147.0 79 % 1.03 0.05 688 66 90 % 0.83 Petition 870260051334, dated 05 / 28 / 2026, pp. 121 / 164 106 / 141 Table 9 Effect of aFXI-18623p (S228P)(E1) / LC Kappa IgG4 HC antibody on aPTT and PT in the AV derivation model of cino Antibody Dose (mg / kg) % Change in aPTT % Change in PT Antibody Conc. (mg / mL) 1 143% 1% 29.13 0.1 93% 1% 2.42 0.01 4% 3% 0.17 0.03 10% 1% 0.54 0.04 5% -2% 0.79 0.05 17% 2% 0.91 0.05 21% 0% 1.03 0.05 42% 3% 0.83

[0315] As shown in Fig. 14A, 14B and Table 8, the IgG4 HC antibody of aFXI-18623p (S228P)(E1) / LC Kappa exhibited a dose- and plasma concentration-dependent decrease in clot weight with complete efficacy (90 to 100% clot reduction) observed at plasma [antibody] greater than 1 pg / mL (approximately 10 nM). As shown in Fig. 14C and Table 9, the antibody exhibited a dose- and plasma concentration-dependent increase in aPTT. A plasma concentration of 2.4 pg / mL (~17 nM) of the aFXI-18623p (S228P)(E1) / LC Kappa IgG4 HC antibody produced a 93% increase in aPTT, while 29 pg / mL (~200 nM) of the aFXI-18623p (S228P)(E1) / LC Kappa IgG4 HC antibody (at the highest dose tested) resulted in a 143% increase in aPTT. Unlike aPTT, as shown in Fig. 14D and Table 9, PT changed less than 10% across the evaluated antibody concentrations. Petition 870260051334, dated 05 / 28 / 2026, pp. 122 / 164 107 / 141 consistent with a selective inhibition effect of FXI on the intrinsic coagulation pathway. EXAMPLE 9 Cynomolgus Monkey Standard Hemorrhage Time Model.

[0316] The bleeding tendency of the anti-FXI HC IgG4 mAb of aFXI18623p (S228P)(E1) / LC Kappa was characterized in vivo in a standard bleeding time model of cynomolgus monkeys developed at Merck, Sharp & Dohme Corp. Research Laboratories, Kenilworth, NJ USA and Palo Alto, CA USA. This model was previously used to demonstrate significant increases in standard bleeding times at multiple anatomical sites with triple antiplatelet therapy (Cai et al., Eur. J. Pharmacol. 758:107-114 (2015)).

[0317] To run this model, standard bleeding times were determined using spring-loaded lancets on the buccal mucosa (inner lip), finger pads, and distal tail at varying time points to induce bleeding.

[0318] Hemorrhage time test: The hemorrhage time test was performed on anesthetized cynomolgus monkeys as follows. •Each test region (buccal mucosa, finger pads, or distal tail) was examined to identify a suitable incision site for inducing bleeding. •To induce bleeding, a spring-loaded lancet was placed firmly against the selected test site and activated to cause a uniform linear incision. The lancet specifications determined the dimensions of the incision. • Blood from the incision site was allowed to flow freely and was monitored until bleeding stopped for 30 continuous seconds. This defined the bleeding time (BT). BT was recorded for each BT site. During BT determinations, the distal tail incision site was superfused with Petition 870260051334, dated 05 / 28 / 2026, pp. 123 / 164 108 / 141 sterile warm lactated Ringer's solution, and the finger pad site was immersed in warm sterile lactated Ringer's solution. Application of lactated Ringer's improved the ability to see blood flow to these sites.

[0319] Study design: Each study comprised three standard 30-minute bleeding time (BT) tests in the three test regions (see Study Scheme in Fig. 15). The first BT determined bleeding as the baseline value. The second BT occurred 70 minutes after a 3-minute IV infusion (4.17 mL / kg) of compound-free vehicle (20 mM sodium acetate, 9% sucrose, pH 5.5) (Treatment #1). The third BT occurred 70 minutes after a 3-minute IV infusion (4.17 mL / kg) of compound-free vehicle or aFXI-18623p (S228P)(E1) / LC Kappa IgG4 HC (10 mg / kg) (Treatment #2). Bleeding was monitored and bleeding time recorded as described above. The time when bleeding stopped was recorded for each site. Periodic blood samples were collected to determine circulating plasma levels of IgG4 HC antibody of aFXI-18623p (S228P)(E1) / LC Kappa, aPTT, and PT.

[0320] Each test animal had two study sessions. In study session #1, the vehicle was administered under Treatment #1 and Treatment #2 consisting of vehicle, respectively. In study session #2, the vehicle was administered under Treatment #1 and Treatment #2 consisting of 10 mg / kg IV of aFXI-18623p (S228P)(E1) / LC Kappa IgG4 HC, respectively.

[0321] The 70-minute time period between the end of the infusion and the start of the bleeding time assessment test article reflected the timing in the AV shunt model for determining blood clot mass (shunt placement 30 min after treatment + 40 min of blood flow through the shunt). The IV test dose of 10 mg / kg of aFXI-18623p (S228P)(E1) / LC IgG4 Kappa was estimated to achieve 10x the Cmax. Petition 870260051334, dated 05 / 28 / 2026, pages 124 / 164 109 / 141 human engineered for IgG4 HC of aFXI-18623p (S228P)(E1) / LC Kappa based on previously described primate PK / PD modeling studies.

[0322] Activated coagulation biomarkers such as partial thromboplastin time (aPTT) and prothrombin time (PT), as well as circulating plasma levels of aFXI-18623p (S228P)(E1) / LC Kappa IgG4 HC, were measured from blood samples collected throughout the experiment as described in Fig. 15. aPTT and PT were measured from thawed / frozen (-80°C) citrated plasma collected from animals using the Sta-R Evolution coagulation analyzer (Stago Diagnostic, Inc). The coagulation analyzer measures the time to clot formation using an electromagnetic and mechanical clot detection system. For the aPTT assay, the analyzer mixes 50 pL of plasma with 50 pL of ellagic acid (APTT-XL, Pacific Hemostasis; Fisher Diagnostics cat # 10-0402) in a cuvette which is then incubated at 37 °C for 3 minutes. 50 pL of 0.025M calcium chloride (Sta-CaCl2 0.025M, Stago Diagnostic, Inc.), cat# 00367) are then added to the mixture to initiate coagulation, and the time for clot formation is measured. For the PT assay, 50 pL of plasma were incubated in a cuvette at 37 °C for 4 minutes; coagulation was initiated by adding 100 pL of solubilized thromboplastin reagent (Triniclot PT Excel, TCoag, Inc., cat# T1106).

[0323] A generic electrochemiluminescence-based hIgG4 immunoassay was used to quantify aFXI-18623p (S228P)(E1) / LC kappa IgG4 HC in rhesus monkey plasma. The assay was established using Betil biotinylated goat antihIgG (H+L) (cat# A80-319B) as the capture reagent, and Southern Biotech sulfoTAG-labeled mouse antihIgG (Fc-specific) (cat# 9190-01) as the detection reagent. This assay was qualified, and the lower limit of quantification was determined to be 41 ng / mL with a minimum required dilution. Petition 870260051334, dated 05 / 28 / 2026, pages 125 / 164 110 / 141 out of 100.

[0324] Figs. 16A to 16F summarize the effects of vehicle and administration of 10 mg / kg IV of aFXI-18623p (S228P)(E1) / LC Kappa IgG4 HC in six cynomolgus monkeys on standard bleeding times from the buccal mucosa (Figs. 16A, 16D), finger pads (Figs. 16B, 16E), and distal tail (Figs. 16C, 16F). The effects on bleeding times were assessed by comparing absolute bleeding times (left panels) and percentage changes in bleeding times (right panels) with vehicle-vehicle as Treatments #1 and #2 in study session #1, and vehicle-aFXI18623p (S228P)(E1) / LC Kappa IgG4 HC as Treatments #1 and #2 in study session #2.Comparisons of both vehicle vs. vehicle-IgG4 HC aFXI-18623p (S228P)(E1) / LC Kappa absolute bleeding times, as well as percentage changes in vehicle-vehicle vs. vehicle-IgG4 HC aFXI-18623p (S228P)(E1) / LC Kappa bleeding times, did not detect a statistically significant change in bleeding times at either test site with administration of IgG4 HC aFXI-18623p (S228P)(E1) / LC Kappa at this test dose.

[0325] The plasma concentration of IgG4 HC of aFXI-18623p (S228P)(E1) / LC Kappa obtained with the test dose of 10 mg / kg IV in the cynomolgus bleeding time study was 290.7±17.2 (mean±SEM) pg / mL (~1938.2 nM). Plasma aPTT values ​​were 31.0±0.5 s at baseline vs 71.3±1.6 s following 10 mg / kg IV of IgG4 HC of aFXI-18623p (S228P)(E1) / LC Kappa (2.3-fold increase). Plasma PT values ​​were 12.7±0.1 s at baseline vs 12.6±0.1 s following 10 mg / kg IV of aFXI-18623p (S228P)(E1) / LC Kappa IgG4 (no notable increase). EXAMPLE 10 Pharmacokinetic (PK) and Pharmacodynamic (PD) Evaluation of IgG4 HC Petition 870260051334, dated 05 / 28 / 2026, pp. 126 / 164 111 / 141 aFXI-18623p (S228P)(E1) / LC kappa Following Multiple Intravenous Administrations in Rhesus Monkeys.

[0326] The PKPD properties of IgG4 HC aFXI-18623p (S228P)(E1) / LC kappa were characterized in vivo in rhesus monkeys. The aim was to evaluate the PK properties and establish a PK / PD ratio after a total of two weekly doses.

[0327] Study design. Rhesus monkeys (four animals per dose group) were administered (IV) with vehicle without compound (10 mM Sodium Acetate, pH 5.5, 7% Sucrose, 0.02% PS-80) or aFXI18623p (S228P)(E1) / LC kappa IgG4 HC at five dose levels of 0.1, 0.3, 1, 3, and 6 mg / kg. The study duration was 22 days, and 1.5 mL of blood was collected for determination of drug levels and activated partial thromboplastin time (aPTT).

[0328] The coagulation biomarker (aPTT) and circulating plasma levels of IgG4 HC from aFXI-18623p (S228P)(E1) / LC were measured from blood samples collected throughout the experiment as described in Table 10. Table 10 Sample Collection Schedule Collection Type Time PK Day -3; Day 0: pre-dose (- 1 h) and 30 min, 3 h, 6 h, 24 (Day 1), 48 (Day 2), 96 (Day 4) Day 7: pre-dose and 1 h, 6 h, 24 h (Day 8), 48 h (Day 9), 96 h (Day 11), 168 h (Day 14), 264 h (Day 18) and 528 h (Day 22) after the second dose PD (evaluation of Day -3: Day 0: pre-dose (- 1 h) and 30 min, 3 h, 6 h, 24 (Day 1), 48 (Day 2), 96 (Day 4) Petition 870260051334, dated 05 / 28 / 2026, pages 127 / 164 112 / 141 Table 10 Sample Collection Schedule Collection Type Time (aPTT) Day 7: pre-dose and 1 h, 6 h, 24 h (Day 8), 48 h (Day 9), 96 h (Day 11), 168 h (Day 14), 264 h (Day 18) and 528 h (Day 22) after the second dose

[0329] aPTT was measured from thawed / frozen (-80°C) citrated plasma collected from animals using the Sta-R Evolution coagulation analyzer (Stago Diagnostic, Inc.). The coagulation analyzer measures the time to clot formation using an electromagnetic and mechanical clot detection system. For the aPTT assay, the analyzer mixes 50 pL of plasma with 50 pL of ellagic acid (APTT-XL, Pacific Hemostasis; Fisher Diagnostics cat # 10-0402) in a cuvette which is then incubated at 37°C for 3 minutes. 50 pL of 0.025M calcium chloride (Sta - CaCl2 0.025M, Stago Diagnostic, Inc., cat# 00367) is then added to the mixture to initiate coagulation, and the time to clot formation is measured.

[0330] A generic electrochemiluminescence-based hIgG4 immunoassay was used to quantify aFXI-18623p (S228P)(E1) / LC kappa IgG4 HC in rhesus monkey plasma. The assay was established with Betil biotinylated goat antihIgG (H+L) (cat# A80-319B) as capture reagent, and Southern Biotech sulfoTAG-labeled mouse antihIgG (Fc-specific) (cat#9190-01) as detection reagent. This assay was qualified and the lower limit of quantification of the assay was determined to be 41 ng / mL with a minimum required dilution of 100.

[0331] Individual animal plasma concentration-time data for HC of IgG4 from aFXI-18623p (S228P)(E1) / LC kappa were analyzed using non-compartmental methods (NCA) (Gabrielsson and Weiner, 2000). All Petition 870260051334, dated 05 / 28 / 2026, pages 128 / 164 113 / 141 PK parameters were estimated or calculated using Phoenix 32 WinNonlin 6.3 (version 6.3.0.395, Certara LP St. Louis, MO, 2012). Non-compartmental analyses used Model 201 (IV). All concentration data and PK parameters were rounded to 3 significant figures. Samples with concentration values ​​below the lower limit of quantification (< LLOQ) were excluded from PK analysis and mean data calculations. For graphical purposes, values ​​< LLOQ were adjusted to be ½ of the minimum reportable concentration for individual animal concentration-time plots.

[0332] A PK / PD (Pmax / PD) response model was used to characterize the relationship between exposure and aPTT using GraphPad Prisma version 7.00 (GraphPad Software Inc). In the model, the Emax value corresponds to the maximum increase in aPTT obtained from the reference value and the EC50 value corresponds to half the maximum effective concentration. Variability was reported as a 95% confidence interval (CI) for the EC50 value provided by the software.

[0333] Results. Individual concentration-time profiles for IgG4 HC of aFXI-18623p (S228P)(E1) / LC kappa are described in Fig. 17A. Non-linearity was observed for all PK parameters. 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 (6 mg / kg). Concentration-time profiles of aPTT are described in Fig. 17B. A dose-dependent increase in aPTT was observed. The relationship between plasma concentrations of IgG4 HC of aFXI-18623p (S228P)(E1) / LC kappa and aPTT best described by the sigmoidal Emax model adequately described this relationship. The estimated EC50 value for HC of IgG4 from aFXI-18623p (S228P)(E1) / LC kappa was approximately 3.6 pg / mL. Sequence Table Petition 870260051334, dated 05 / 28 / 2026, pp. 129 / 164 114 / 141 SEQ ID NO: Description Sequence 1 HC-CDR1 of aFXI-18611p and aFXI-18611 YSISSGYFWG 2 HC-CDR2 of aFXI-18611p and aFXI-18611 SILHSGVTYYNPSLKS 3 HC-CDR3 of aFXI-18611p ARDRTTVSMIEYFQH 4 HC-CDR3 of aFXI-18611 ARDRTTVSLIEYFQH 5 LC-CDR1 of aFXI-18611p and aFXI-18611 QASQDISNYLN 6 LC-CDR2 of aFXI-18611p and aFXI-18611 DASNLET 7 LC-CDR3 of aFXI-18611p and aFXI-18611 QQFHLLPIT 8 aFXI-18623p HC-CDR1 aFXI-18623p AASSLQS LC-CDR2 Petition 870260051334, dated 05 / 28 / 2026, pp. 130 / 164 115 / 141 13 LC-CDR3 of aFXI-18623p QQYHIVPIT 14 LC of Leader Sequence A MSVPTQVLG LLLLWLTDARC 15 HC of Leader Sequence B MEWSWVFLFFLSVTTGVHS 16 Constant domain of human IgG4 HC: (S228P) S at position 108 replaced with P ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALT SGVHTFPAVLQSSGLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKV DKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVT CVITDVSQEDPEVQFNWYFDGVEVHNAKTKPREEQFNSTYRWS VLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYT LPPSQEEMTKNQVSLTCL VKGFYPSDIA VEWESNGQPENNYKTTP PVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHÈÁLHNHYTQKS LSLSLGK 17 Constant domain of human lgG4 HC: (S228P) S at position 108 replaced with P;C-terminal Without K ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALT SGVHTFPAVLQSSGLYSLSSmVPSSSLGTXTYTCN^'DHKPSNTKV DKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVT CmDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSnRWS VLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYT LPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSRLTVDKSRWQEG^FSCSWEALHNHYTQKS LSLSLG 18 Constant domain of human IgG1 HC ASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEP VTVSWNSC TSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSF VDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM TPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYE RWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP QVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPEN. TTPP VLDSDGSFFLYSKL TVDKSRWQQGNVFSCSVMHEALHNi QKSLSLSPGK; Petition 870260051334, dated 05 / 28 / 2026, pages 131 / 164 116 / 141 19 Constant domain of human IgG1 C-terminal HC Without K ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGAL TSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTK VDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISR TPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY RWSVLTVLHQDWLNGKEYKCKVSFÍKALPAPIEKTISKAKGOPREP QVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK TTPPViA)SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPG 20 Constant domain of human kappa LC RTVAAPSVFIFPPSDEQLKSGTAS^CLLNNFYPREAKVQWKVDNA LQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQ GLSSPVTKSFNRGEC 21 Variable region of the HC of aFXI18611p; (Ql) (M105) QVQLQESGPGLVKPSETLSLTCAVSGYSISSGYFWGWIRQPPG KGLEWIGSILHSGVTYYNPSLKSRVTISVDTSKNQFSLKLSSVT AADTAVYYCARDRTTVSMIEYFQHWGOGTLVTVSS 22 Variable region of the HC of aFXI18611p; (El) (M105) EVOLQESGPGLVKPSETLSLTCAVSGYSISSGYFWGWIROPPG KGLEWIGSILHSGVTYYNPSLKSRVTISVDTSKNOFSLKLSSVT AADTAVYYCARDRTTVSMIEYFOHWGOGTLVTVSS 23 Variable region of the HC of aFXI18611;(Ql) (L105) OVOLQESGPGLVKPSETLSLTCAVSGYSISSGYFWGWIROPPG KGLEWIGSILHSGVIYYNPSLKSRVTISVDTSKNQFSLKLSSVT AADTAVYYCAR DRITVSLIEYFQHWGOGTLVTVSS 24 Variable region of the HC of aFXI18611; (El) (L105) EVOLOESGPGLVKPSETLSLTCAVSGYSISSGYFWGWIROPPG KGLEWIGSILHSGVTYYNPSLKSRVTISVDTSKNOFSLKLSSVT AADTAVYYCAR DRTTVSLIEYFOHWGOGTLVTVSS 25 Variable region of the LC of aFXI18611p and aFXI18611 DIQMTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKPGK APKLLIYDASNLETGVPSRFSGSGSGTDFTFTISSLQPEDIATYYC QQFHLLPITFGGGTKVEIK 26 LC of aFXI-; Petition 870260051334, dated 05 / 28 / 2026, pages 132 / 164 117 / 141 18611p e aFXI- 18611 kappa DI0MT0SPSSLSASVGDRVTITC0AS0DISNYLNWY0QKPGKA PKLLIYDASNLETGVPSRFSGSGSGTDFTFTISSLQPEDIATYYC 00FHLLPITFGGGTKVEIKPW^PW^4PW^ LLNNFYPREAKVQWKVDNALOSGNSQESπEQDSKDSπSLSSTLT LSKADYEKHKmCEVTHQGLSSPVTKSFNRGEC 27 DNA encoding LC of aFXI-18611p and aFXI-18611 kappa GACATCCAGATGACCAGCCAGCCAGCCAGCCAGCCAGCC CGTGGGCGACAGAGTGACCATCACCCTGTCAAGCCTCCCAGG ACATCTCCAACTACCTGAACTGGTACCAGCAGAAGCCCGGC AAGGCTCCCAAGCTGCTGATCTACGACGCCTCCAACCTGGA GACCGGCGTGCCTAGCAGATTTAGCGGCAGCGGCTCCGGCA CAGACTTCACCCTCCCAGCCGACCGCC ATTGCCACCTACTACTGCCAGCAGTTTCACCTGCTGCCTATC ACCTTCGGCGGCGGCACCAAGGTGGAGATCAAAAGGACCG TCGCCGCCCCTAGCGTGTTCATTCCCCCCTAGCGACGAGC AGCTCAAGTCCGGCACCGCCAGCGTGGTGTGTGTCTGCTCAAC ACAACGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTGAC AGAACAGGACAGCAAGGATTCCACATACAGCCTGAGCTCC ACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAGG TGTACGCCTGTGAGGTGACACACCAGGGCCTCAGCTCCCCC GTGACCAAGAGCTTCAACAGGAGGACACACCAGGGGCCTCAGCTCCCCC GTGACCAAGAGCTTCAAGGAGGAGGACACACCAG 28 aFXI- 18623p;(Ql) OVOLOESGPGLVKPSOTLSLTCTVSGGSIYSGAYYWSWIROHP GKGLEWIGSIHYSGLTYYNPSLKSRVTISVDTSKNOFSLKLSSV TAADTAVYYCARDVDDSSGDEHYGMDVWGOGTTVTVSS 29 Variable region of the HC of aFXI- 18623p; (El) EVOLQESGPGLVKPSOTLSLTCTVSGGSIYSGAYYWSWIROHP GKGLEWIGSIHYSGLIYYNPSLKSRVTISVDTSKNQFSLKLSSV TAADTAVYYCARDVDDSSGDEHYGMDVWGOGTTVTVSS 30 LC variable region of aFXI18623p DIOMTQSPSSVSASVGDRVTITCRASOGIDSWLAWYOOKPGK APKLLIYAASSLQSGVPSRFSGSGSGTOFTLTISSLOPEDFATYY CQQYHIVPITFGGGTKVEIK 31 LC de aFXI- 18623p kappa DIQMTOSPSSVSASVGDRVTnCRASQGIDSWLAWYOQKPGK APKLLIYAASSLQSGVPSRFSGSGSGTDFTLUSSLQPEDFATYY COQYHIVPITFGGGTKVEIKÃIFWWFPPÓDEWG^Pr CLLNNFYPREAKVQWKVDNALQSGNSQESyTEODSKDSTYSLSSTL TLSKÁDYEKHKnÃCEnHQGLSSPVÜSFNRGEC; Petition 870260051334, dated 05 / 28 / 2026, pages 133 / 164 118 / 141 32 DNA encoding LC of aFXI-18623p kappa GACATCCAGATGACCCAGAGCCCTAGCAGCGTGAGCGCCA GCGTGGGCGATAGGGTGACCATCACCTGCAGAGCCTCCCAG GGCATCGACAGCTGGCTGGCCTGGTACCAGCAGAAGCCCGGCAAGGCCCGCTGCCTAGCCTAGCCTA AGAGCGGCGTGCCTAGCAGGTTCAGCGGAAGCGGCAGCGG CACCGACTTCCACACTGACCATCAGCAGCCTGCAACCTGAGG ACTTCGCCACCTACTACTGCCAGCAGTATCACATCGTGCCC ATCACCTTCGGCGGCGGAACCAAGGTGGAGATTAAGGAGAGGA CCGTGCCGCCGCCGCCGCCGCCGCCGTT AGCAGCTGAAGAGCGGAACCGCCAGGGTGGTGTGCCTGCTG AACAACTTCTACCCCAGAGAGGCCAAGGTGCAGTGGAAGG TGGACAACGCCCTGCAGTCCGGAAACAGCCAGGAGAGCGT GACCGAGCAGGATTCCAAGGATAGCACCTACAGCCTGAGC AGCACCCTGACACCGACCGACCGAGCAGACCGA AGGTGTACGCCTGTGAGGTGACCCATCAGGCCTGAGCAGC CCTGTGACCAAGAGCTTCAACAGGGGCGAGTGCTGA 33 HC of lgG4 of aFXI-18611p (S228P) (Ql) (M105) KGLEWIGSILHSGVTYYNPSLKSRVTISVDTSKNOFSLKLSSVT AADTAVYYCARDRTTVSMIEYFOHWGQGTLVTVSSJY^GP.v DWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPOVYTLPPSQEE MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG SFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK 34 DNA encoding lgG4 HC of aFXI18611p (S228P)(Q1) (M105); xxx = CAG or CAA (Q). Petition 870260051334, dated 05 / 28 / 2026, pages 134 / 164 119 / 141 xxxGTCCAGCTGCAGGAGAGCGGCCCTGGCCTGGTGAAGCCT AGCGAGACACTGTCCCTGACCTGCGCCGTGAGCGGCTACAG CATCTCCAGCGGCTATTTCTGGGGATGGATCAGACAGCCCC CTGGCAAGGGCCTGGAATGGATCGGTTCTATCCTGCACTCC GGCGTGACATACTATAACCCTAGCCTGAAGAGCAGGGTGAC CATCTCCGTGGATACCAGCAAGAATCAGTTCAGCCTGAAGC TCAGCAGCGTGACCGCCGCCGATACCGCTGTGTACTACTGC GCCAGAGACAGGACCACCGTCTCCATGATCGAGTACTTCCA GCACTGGGGCCAAGGCACCCTGGTCACCGTGTCCTCCGCCT CCACCAAGGGCCCTAGCGTGTTTCCTCTGGCCCCCTGCTCCA GATCCACAAGCGAGAGCACCGCTGCCCTGGGCTGTCTGGTC AAGGACTACTTCCCCGAGCCCGTGACAGTGTCCTGGAACAG CGGCGCCCTGACAAGCGGCGTCCATACATTCCCCGCCGTGC TGCAGTCCAGCGGACTGTATAGCCTGAGCTCCGTGGTGACC GTGCCTTCCAGCAGCCTGGGAACCAAGACATATACCTGCAA CGTGGACCATAAGCCCAGCAACACAAAAGTCGACAAGAGG GTGGAGAGCAAGTACGGACCCCCTTGTCCCCCTTGTCCTGC TCCCGAGTTCCTCGGCGGACCTAGCGTGTTCCTGTTTCCTCC CAAGCCCAAGGATACCCTGATGATCAGCAGGACCCCTGAGG TCACCTGCGTGGTGGTCGACGTGTCCCAGGAGGACCCTGAG GTCCAGTTTAACTGGTACGTGGACGGAGTGGAGGTGCACAA CGCCAAGACCAAGCCCAGAGAGGAGCAGTTCAATTCCACCT ACAGGGTGGTGAGCGTCCTGACCGTGCTGCACCAGGACTGGCTGAATGGAAAGGAGTACAAATGCAAGGTCTCCAACAAGG GCCTCCCTAGCAGCATCGAGAAGACCATCTCCAAGGCCAAG GGCCAGCCTAGGGAGCCCCAGGTGTACACCCTGCCTCCTAG CCAGGAGGAAATGACCAAGAACCAGGTGTCCCTGACATGC CTGGAAGGGAGCCTAGGTCGAGGTTGGTTGAGTC GGAGAGCAATGGCCAGCCCGAGAATAACTACAAGACCACC CCCCCTGTGCTCGATAGCGACGGCAGCTCTCTTTCTGTACAGC AGGCTGACCGTGGACAAGAGCAGGTGGCAAGGGGCAACG TGITTAGCTGCTCCGTCATGCACGAGGCCCTGCATAACCACT ACACCCAAATCCAACTCCTAGGCGACTGAGGGAGGGAG35 de lgG4 of aFXI-18611p (S228P) (El) (M105) EVOLOESGPGLVKPSETLSLTCAVSGYSISSGYFWGWIROPPG KGLEWIGSILHSGVTYYNPSLKSRVTISVDTSKNOFSLKLSSVT AADTAVYYCARDRTTYSMIEYFQHWG0GTLVTVSS4CTCm VFPLAPCSRSTSSTAALGCLVKDYFPEPPVTVSWNSGALTSGVHTF PAVLOSSGLYSLSSTVPSTVPSSLGTKnTCNVDHKPSNTKVDKRVES KYGPPCPPPPEWFPFLVFPVFPGFPGCVPGC SQEDPEVQFNWYVDGVEVHNÂKTKPREEQFNSTYRWSVLTVLHQ DWLNGKEYKCKVSNKGLPSIEKTISCAKGQPREPQVYTLPPSQEE MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPLDGSDG SFFLYSRLTPDKSRIVQEGNVFSCSVMHEALHNHYTQKSLSLSLGK 36 DNA encoding HC of lgG4 of aFXI18611p (S228P); (He) Petition 870260051334, dated 05 / 28 / 2026, pp. 135 / 164 120 / 141 (M105) xxx=GAA ou GAG (E) xxxGTCCAGCTGCAGGAGAGCGGCCCTGGCCTGGTGAAGCCT AGCGAGACACTGTCCCTGACCTGCGCCGTGAGCGGCTACAG CATCTCCAGCGGCTATTTCTGGGGATGGATCAGACAGCCCC CTGGCAAGGGCCTGGAATGGATCGGTTCTATCCTGCACTCC GGCGTGACATACTATAACCCTAGCCTGAAGAGCAGGGTGAC CATCTCCGTGGATACCAGCAAGAATCAGTTCAGCCTGAAGC TCAGCAGCGTGACCGCCGCCGATACCGCTGTGTACTACTGC GCCAGAGACAGGACCACCGTCTCCATGATCGAGTACTTCCA GCACTGGGGCCAAGGCACCCTGGTCACCGTGTCCTCCGCCT CCACCAAGGGCCCTAGCGTGTTTCCTCTGGCCCCCTGCTCCA GATCCACAAGCGAGAGCACCGCTGCCCTGGGCTGTCTGGTC AAGGACTACTTCCCCGAGCCCGTGACAGTGTCCTGGAACAG CGGCGCCCTGACAAGCGGCGTCCATACATTCCCCGCCGTGC TGCAGTCCAGCGGACTGTATAGCCTGAGCTCCGTGGTGACC GTGCCTTCCAGCAGCCTGGGAACCAAGACATATACCTGCAA CGTGGACCATAAGCCCAGCAACACAAAAGTCGACAAGAGG GTGGAGAGCAAGTACGGACCCCCTTGTCCCCCTTGTCCTGC TCCCGAGTTCCTCGGCGGACCTAGCGTGTTCCTGTTTCCTCC CAAGCCCAAGGATACCCTGATGATCAGCAGGACCCCTGAGG TCACCTGCGTGGTGGTCGACGTGTCCCAGGAGGACCCTGAG GTCCAGTTTAACTGGTACGTGGACGGAGTGGAGGTGCACAA CGCCAAGACCAAGCCCAGAGAGGAGCAGTTCAATTCCACCT ACAGGGTGGTGAGCGTCCTGACCGTGCTGCACCAGGACTGGCTGAATGGAAAGGAGTACAAATGCAAGGTCTCCAACAAGG GCCTCCCTAGCAGCATCGAGAAGACCATCTCCAAGGCCAAG GGCCAGCCTAGGGGAGCCCCAGGTTACACCCTGCCTCCTAG CCAGGAGGAAATGACCAAGAACCAGGTGTCCCTGACATGC CTGGAAGGGAGCCTAGGTCGAGTT GGAGAGCAATGGCCAGCCCGAGAATAACTACAAGACCACC CCCCCTGTGCTCGATAGCGACGGCAGCTCTTTCTGTACAGC AGGCTGACCGTGGACAAGAGCAGGTGGCAAGGGCAACG TGTTTAGCTGCTCCGTCATGCACGAGGCCCTGCATAACCACT lgG4 of aFXI-18611 (S228P) (Ql) (L105) OVOLQESGPGLVKPSETLSLTCAVSGYSTSSGYFWGWIRQPPG KGLEWIGSILHSGVTYYNPSLKS RVTIS V DTS KNQFSLKLSS VT AADTAVYYCARDRTTVSLlEYFQHWGQGTLVTVSS^^XGPír FPLAPCSRSTSESTAALGCLVKDYFPEPPVTVSWNSGALTSGVHTFP AVLQSSGLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESK YGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVS QEDPEVQFNWYVDGFEVHNACTKPREEQFNSTYRWSVLTVLHQ DWLNGKEYKCKVSNKGLPPSSIEKTISKAKGQPREPO^TLPPSQÊE MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKPIPPFLDSDG SFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK 38 DNA encoding HC of lgG4 of aFXI18611 (S228P); (Ql) (L105) xxx= CAG orCAA (Q) Petition 870260051334, dated 05 / 28 / 2026, pp. 136 / 164 121 / 141 xxxGTCCAGCTGCAGGAGAGCGGCCCTGGACTCGTGAAGCC CTCCGAAACCCTGAGCCTCACATGCGCCGTCTCCGGATACA GCATCAGCAGCGGATACTTCTGGGGCTGGATCAGACAGCCC CCCGGCAAAGGCCTGGAGTGGATCGGTTCTATTCTCCACAG CGGCGTGACATACTACAACCCCTCCCTGAAGAGCAGGGTGA CCATCAGCGTGGACACCTCCAAGAACCAGTTTTCCCTCAAG CTGAGCAGCGTGACCGCCGCTGACACAGCCGTGTATTACTG CGCCAGGGACAGGACCACCGTGTCCCTGATTGAGTACTTCC AGCATTGGGGCCAGGGCACACTGGTGACCGTCAGCAGCGCC AGCACCAAGGGCCCTTCCGTCTTCCCTCTGGCCCCTTGCAGC AGAAGCACCTCCGAGTCCACAGCCGCCCTGGGATGCCTCGT GAAGGATTACTTCCCCGAGCCCGTCACAGTCTCCTGGAACT CCGGCGCTCTGACCAGCGGAGTGCACACCTTCCCCGCCGTG CTGCAAAGCAGCGGCCTGTACAGCCTGTCCAGCGTGGTCAC CGTGCCTTCCTCCAGCCTGGGCACCAAGACCTACACATGCA ACGTGGACCACAAGCCTTCCAACACCAAGGTGGACAAGAG AGTGGAAAGCAAGTACGGCCCCCCCTGCCCCCCTTGTCCTG CCCCCGAGTTTCTGGGAGGACCCTCCGTGTTCCTCTTTCCTC CCAAGCCTAAGGACACCCTGATGATCTCCAGGACCCCCGAA GTGACCTGCGTGGTCGTGGACGTGTCCCAGGAGGACCCTGA GGTGCAGTTTAACTGGTACGTGGACGGCGTGGAGGTGCACA ACGCCAAGACCAAGCCCAGGGAGGAGCAGTTCAATAGCAC CTACAGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAAGAGTACAAGTGCAAAGTCAGCAACAA GGGCCTGCCCTCCTCCATCGAGAAGACCATTAGCAAGGCCA AGGGCCAGCCTAGGGAGGCCTCAGGTTACACCCTGCCCCCC AGCCAGGAGGAGATGACCAAGAACCAGGTGTCCCTGACCCT GCCAGGGTTACCAGTTGACCGGACCG TGGGAGAGCAATGGCCAGCCCGAGAACAACTACAAGACCA CCCCTCCCGTGCTCGATTCCGACGGCAGCTTTTCCTGTACA GCAGGCTGACCGTGGATAAGAGCAGGTGGCAGGAAGGCAA CGTGTTCTCCTGTTCCGTGATGCATGAGGCCCTGCACAACCA HC of lgG4 of aFXI-18611 (S228P) (El) (L105) EVOLOESGPGLVKPSETLSLTCAVSGYSISSGYFWGWIROPPG KGLEWIGSILHSGVIYYYNPSLKSRVTISVDTSKNOFSLKLSSVT AADTAVYYCARDRTTVSLIEYF0HWG0GTLVTVSSA5TgGAV7 FPLAPCSRSTSESTAALGCLVKDYFPEPPVTVSWNSGALTSGVHTFP AVLQSSGLYSLSSVFTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESK YGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVS QEDPEVQFNWYVDGVEVHNACTKPREEQFNSTYRWSVLTVLHQ DWLNGKEYKCKVSNKGLPSIEKTISKAKGQPREPQVYTLPPQEE MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPPVLDSDG SFFLYSRLTVDKSRWQEGNVFSCSVMHEÃLHNHYTQKSLSLSLGK 40 DNA encoding HC of lgG4 of aFXI18611 (S228P) (Q1xL) or xL=5 Petition 870260051334, dated 05 / 28 / 2026, pp. 137 / 164 122 / 141 GAG (E) xxxGTCCAGCTGCAGGAGAGCGGCCCTGGACTCGTGAAGCC CTCCGAAACCCTGAGCCTCACATGCGCCGTCTCCGGATACA GCATCAGCAGCGGATACTTCTGGGGCTGGATCAGACAGCCC CCCGGCAAAGGCCTGGAGTGGATCGGTTCTATTCTCCACAG CGGCGTGACATACTACAACCCCTCCCTGAAGAGCAGGGTGA CCATCAGCGTGGACACCTCCAAGAACCAGTTTTCCCTCAAG CTGAGCAGCGTGACCGCCGCTGACACAGCCGTGTATTACTG CGCCAGGGACAGGACCACCGTGTCCCTGATTGAGTACTTCC AGCATTGGGGCCAGGGCACACTGGTGACCGTCAGCAGCGCC AGCACCAAGGGCCCTTCCGTCTTCCCTCTGGCCCCTTGCAGC AGAAGCACCTCCGAGTCCACAGCCGCCCTGGGATGCCTCGT GAAGGATTACTTCCCCGAGCCCGTCACAGTCTCCTGGAACT CCGGCGCTCTGACCAGCGGAGTGCACACCTTCCCCGCCGTG CTGCAAAGCAGCGGCCTGTACAGCCTGTCCAGCGTGGTCAC CGTGCCTTCCTCCAGCCTGGGCACCAAGACCTACACATGCA ACGTGGACCACAAGCCTTCCAACACCAAGGTGGACAAGAG AGTGGAAAGCAAGTACGGCCCCCCCTGCCCCCCTTGTCCTG CCCCCGAGTTTCTGGGAGGACCCTCCGTGTTCCTCTTTCCTC CCAAGCCTAAGGACACCCTGATGATCTCCAGGACCCCCGAA GTGACCTGCGTGGTCGTGGACGTGTCCCAGGAGGACCCTGA GGTGCAGTTTAACTGGTACGTGGACGGCGTGGAGGTGCACA ACGCCAAGACCAAGCCCAGGGAGGAGCAGTTCAATAGCAC CTACAGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAAGAGTACAAGTGCAAAGTCAGCAACAA GGGCCTGCCCTCCTCCATCGAGAAGACCATTAGCAAGGCCA AGGGCCAGCCTAGGGAGGCCTCAGGTTACACCCTGCCCCCC AGCCAGGAGGAGATGACCAAGAACCAGGTGTCCCTGACCCT GCCAGGGTTACCAGTTGACCGGACCG TGGGAGAGCAATGGCCAGCCCGAGAACAACTACAAGACCA CCCCTCCCGTGCTCGATTCCGACGGCAGCTTTTTTCCTGTACA GCAGGCTGACCGTGGATAAGAGCAGGTGGCAGGAAGGCAA CGTGTTCTCCTGTTCCGTGATGCATGAGGCCCTGCACAACCA HC of lgG4 of aFXI-18623p (S228P) (Ql) QVQLQESGPGLVKPSQTLSLTCTVSGGSIYSGAYYWSWIRQHP GKGLEWIGSIHYSGLTYYNPSLKSRVTISVDTSKNQFSLKLSSV TAADTAVYCARDGDDSSWGGTVGTVGTVGTVGTV KGPSVFPPLAPCSRSTSESTAALGCL VKDYFPEP VTVSWNSGALTSG VHTFPAVLQSSGLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDK RVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLM1SRTPEVTCV WDVSQEDPEWQFNWYVDGVEVHNACTKPREEQFNSTYRWSVLT VLHQD WLNGKÈYKCKVSNKGLPSIEKTISKAKGPREPO VYTLPP SQEEMTKNQ VSLTCL VKGFYPSDIA VEWESNGQPENNYKTTPPVLT DSDGSFFLYSRLTVDKSRWOEGNVFSCSVMHEALHNHYTQKSLSL SLGK 42 DNA encoding HC of lgG4 of aFXI18623p (S228P) (Ql) xxx= CAG or CAA(Q) xxxGTCCAGCTGCAGGAATCCGGACCCGGCCTGGTGAAGCCT AGCCAGACCCTGAGCCTGACCTGTACCGTGTCCGGCGGAAG CATCTATTCCGGCGCCTACTACTGGTCCTGGATTAGGCAGC ACCCCGGCAAGGGCCTGGAATGGATCGGCTCCATCCACTAC AGCGGCCTGACCTATTACAACCCCTCCCTGAAGTCCAGGGT GACCATCAGCGTCGACACAAGCAAGAACCAGTTCTCCCTCA Petition 870260051334, of 28 / 05 / 2026, p. 138 / 164 123 / 141 AGCTGAGCAGCGTGACCGCCGCGACACCGCCGGTGTATTAT TGCGCCAGAGACGTGGACGACTACCTCCGGAGAGGAGCACTA CGGCATGGACGTCTGGGGCCAGGGCACAAACAGTGACAGTG AGCAGCGCCAGCCACAAAGGACCCTCCGTTCCCTCTGGC CCCTTGCTCCCAGGAGCACAACGAAAGCACAGCGCGCGCCTGG GCTGCCTGGTGAAGGACTACTTTCCGAGCCCGTGACCGTGAGCGTG AGCTGGGAATAGCGGGACCCTCACCTCGGAGTCCACACACAT TCCCGCGTCCTGGCCAGAGCCACGGCCTGTACTCCCTGAGCCT CCGTGGTGACGTGCGTTCCTCCCAGCCTGGGCACCAAGACC TACACCTGCAACGTGGACCACAAGCCTAGCAATACCAAGGT GGACAAGAGGTGGAATCCAAGTACCGGCCCCCTTGCCTCTCCCTCTCTCCGTGTCC TGTTCCCTCCCAAGCCCAAGATACCCTGATGATGATCAGCAGG ACCCCCTGAGGTGACCTTGTGGTGGTGGACGTGAGCCAGGAGG GGACCCCGAGGTGCAGTTCAACTGGTACGTGGATGGCGTGG AAGTGCACAATGCCAAGACAAAGCCCAGGGAGGAGCAGTT CAATAGCACCTCAGGGTGGTCAGCGTGCTCACAGTGCTGC ACCAGGACTGGCTGAACGGAAAGGAGTACAAGTGCAAAGT GTCCAACAAGGGCCTGCCCTCTCCATCGAAAAGACCATCT CCAAGGCCAAAGGCCAGCCAGGAGCCCAAGTGTATAC CCTCCCCCCTAGCCAGGAAGGAATGACACAAAACCAGGTCT CCCTGACCTGTCTGGTGAAGGGCTTCTATCCAGCGACATC GCTGTGGAGTGGGAGAGCAACGGCCAACCCGAGAACAACTATAAGACCACACCCCCCGTCCTGGACTCCGATGGCTCCTTCT TCCTGTACAGCAGGCTGACCGTCGACAAGTCCAGGTGGCAG GAAGGAAACGTGTTCTCCTGTAGCGTCATGCACGAGGCCCT GCACAACCACTATACCCAGAAGTCCCTGTCCCTGAGCCTGGGGCAAGTGA lgHC de aFXI-18623p (S228P) (El) EVQLQESGPGLVKPSQTLSLTCTVSGGSIYSGAYYWSWIRQHP GKGLEWIGSIHYSGLTYYNPSLKSRVTISVDTSKNQFSLKLSSV TAADTAVYYCARDVDDSSGDEHYGQGGTVSSTVV' KGPSVFPPLAPCSRSTSESTAALGCL VKDYFPEP VT7SWNSGALTSG VHTFPAVLQSSGLYSLSSWTEPSSSLGTKTYTCNVDHKPSNTKPDK RVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLM1SRTPEVTCV WDVSQEDPEWQFNWYVDGVEVHNACTKPREEQFNSTYRWSVLT VLHQDWLNGKEYKCKVSNKGLPSIEKTISKAKGQPREPQVYTLPP SQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVL DSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSL SLGK 44 DNA encoding HC of lgG4 of aFXI18623p (S228P) (El) xxx=GAA or GAG (E) xxxGTCCAGCTGGAATCCGGACCAGGCCAGGCCGCT AGCCAGACCCTGAGCCTGACCTGTACCGTGTCCGGCGGAAG CATCTATTCCGGCGCCTACTACTGGTCCTGGATTAGGCAGC ACCCCGGCAAGGGCCTGGAATGGATCGGCTCCATCCACTAC AGCGGCCTGACCTATTACAACCCCTCCCTGAAGTCCAGGGTGACCATCAGCGTCGACACAAGCAAGAACCAGTTCTCCCTCA AGCTGAGCAGCGTGACCGCCGCCGACACCGCCGTGTATTAT TGCGCCAGAGACGTGGACGACTCCTCCGGAGACGAGCACTA CGGCATGGACGTCTGGGGCCAGGGCACAACAGTGACAGTG AGCAGCGCCAGCACCAAAGGACCCTCCGTCTTCCCTCTGGC CCCTTGCTCCAGGAGCACAAGCGAAAGCACACGCCGCCCTGG Petition 870260051334, dated 05 / 28 / 2026, pages 139 / 164 124 / 141 GCTGCCTGGTGAAGGACTACTTTCCCGAGCCCGTGACCGTG AGCTGGAATAGCGGAGCCCTCACCTCCGGAGTCCACACATT TCCCGCCGTCCTGCAGAGCAGCGGCCTGTACTCCCTGAGCT CCGTGGTGACCGTGCCTTCCTCCAGCCCTGGGCACCAAGACC TACACCTGCACCGACCAGCCAGGCC GGACAAGAGGGTGGAATCCAAGTACGGCCCCCCTTGCCCTC CTTGTCCTGCCCCCGAATTTCTGGGGCGGCCCTTCCGTGTTCC TGTTCCCTCCCAAGCCCAAGGATACCCTGATGATCAGCAGG ACCCCTGAGGTGACCTGTGGTGGTGGACGTGAGCCAGGA GGACCCCGAGGTGCAGTTCAACTGGTACGTGGGATGGCGTGG AAGTGCACAATGCCAAGACAAAGCCCAGGGAGGAGCAGTT CAATAGCACCTACAGGGTGGTCAGCGTGCTCACAGTGCTGC ACCAGGACTGGCTGAACGGAAAGGAGTCAAGTCAAGTGCAAAGTGCCAACCAACCAACCAACCAACCAACCAACCATCCATCCAGTT CCAAGGCCAAAGGCCAGCCCAGGGAGCCCCAAGTGTATAC CCTCCCCCCTAGCCAGGAGGAAATGACCAAAACCAGGTCT CCCTGACCTGTCTGGTGAAGGGCTTCTATCCCAGCGACATC GCTGTGGAGTGGGAGAGCAACGGCCAACCCGAGAACAACT TCCTGTACAGCAGGCTGACCGTCGACAAGTCCAGGTGGCAG GAAGGAAACGTGTTCTCCTGTAGCGTCATGCACGAGGCCCT GCACAACCACTATACCCAGAAGTCCCTGTCCCTGAGCCTGG GCAAGTGA 45 HC of IgGl of aFXI-18611p (M15)QVQLQESGPGLVKPSETLSLTCAVSGYSISSGYFWGWIRQPPG KGLEWIGSILHSGVTYYNPSLKSRVTISVDTSKNOFSLKLSSVT AADTAVYYCARDRITVSMIEYFOHWGOGTLVTVSSyl^GPS VFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEP KSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCW VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTV LHQD WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VYTLPPS RDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSKLTVDKSRWOOGNVFSCSVMHEALHNHYTQKSLSLSP GK 46 DNA que codifica HC de IgGl de aFXI18611p (Ql) (M105) xxx= CAG ou CAA (Q) xxxGTCCAGCTGCAGGAGAGCGGCCCTGGCCTGGTGAAGCCT AGCGAGACACTGTCCCTGACCTGCGCCGTGAGCGGCTACAG CATCTCCAGCGGCTATTTCTGGGGATGGATCAGACAGCCCC CTGGCAAGGGCCTGGAATGGATCGGTTCTATCCTGCACTCC GGCGTGACATACTATAACCCTAGCCTGAAGAGCAGGGTGAC CATCTCCGTGGATACCAGCAAGAATCAGTTCAGCCTGAAGC TCAGCAGCGTGACCGCCGCCGATACCGCTGTGTACTACTGC GCCAGAGACAGGACCACCGTCTCCATGATCGAGTACTTCCA GCACTGGGGCCAAGGCACCCTGGTCACCGTGTCCTCCGCTA GCACAAAAGGACCAAGCGTGTTTCCACTGGCACCTAGCAGC AAATCCACCAGCGGCGGAACAGCAGCCCTCGGGTGCCTGGTGAAGGATTACTTCCCTGAGCCAGTCACAGTGTCCTGGAACT CCGGAGCCCTGACATCCGGCGTGCACACCTTCCCCGCTGTG CTGCAATCCAGCGGACTGTATAGCCTCAGCTCCGTCGTGAC AGTCCCTTCCAGCAGCCTGGGCACACAGACTTACATTCATTTGCA ACGTGAACCACAACCAACCAAACTGAAGTA Petition 870260051334, of 28 / 05 / 2026, p. 140 / 164 125 / 141 GGTGGAACCCAAATCCTGTGATAAGACCCATACATGCCCAC CTTGTCCCGCTCCTGAGCTGCTGGGGGGACCTTCCGTCTTTC TGTTTCCTCCAAAACCAAAAGACACACTCATGATCAGCCGG ACCCCCGAAGTCACCTGTGGTGGTGGACGTCAGCCACGA AGATCCAGAGGTCAAGTTCAATTGGTACGTGGGATGGAGTGG AAGTCCACAACGCAAAAACCAAACCTAGAGAAGAACAGTA CAATAGCACATAGGGTGGTGTCCGTCCTGACAGTGCTCC ACCAGGACTGGCTCAATGGCAAAGAGTATAAGTGCAAGGT GCAAGGCAAAGGGGCAGCCACGGGAACCCCAGGTGTTAC CCTGCCCCCAAGCCGGATGAACTGACCAAAACCAGGTCA GCCTGACATGCCTGGTGAAAGGGTTTTACCCAAGCGATATT GGCGTCGAGTGGGAGAGCAACGGACAGCCAGAAAACAATT ACAAAACCACCCCGCCGACTGACTGACTGACT TTCCTGTACAGCAAGCTCACAGTGGACAAGTCCAGATGGCA ACAGGGCAACGTGTTTTCCTGCTCCGTGATGCACGAGGCCC TCCACAACCACTATACAAAAGTCCCTCTCCCTCAGCCCA GGAAAGTGA 47 HC of IgGl of aFXI-18611p (M105) EVOLOESGPGLVKPSETLSLTCAVSGYSISSGYFWGWIRQPPG KGLEWIGSILHSGVTYYNPSLKSRVTTSVDTSKNQFSLKLSSVT AADTAVYCARDRTTVSMIEYFQHWGOGTLVTVSSAVm^ VFPLAPSSKSTSGGTAALVGTLVTSGVSTVG VLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCW VDVSHEDPEWKFNWYVDGVEVHNAKTKPREEQ YNSTYRWSVL TV LHQD WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VYTLPPS RDELTKNQCLVSDIGGFYLTA VEWESNGQPENNYKTTPP VLDS DGSFFLYSKLTVDKSRWQQGNVFSCSPMHEALHNHYTQKSLSLSP GK 48 DNA encoding HC of IgGl of aFXI18611p (Ql) (M105) xxx=GAA or GAG (E) xxxGTCCAGCTGCAGGAGAGCGGCCCTGGCCTGGTGAAGCCT AGCGAGACACTGTCCCTGACCTGCGCCGTGAGCGGCTACAG CATCTCCAGCGGCTATTTCTGGGGATGGATCAGACAGCCCC CTGGCAAGGGCCTGGAATGGATCGGTTCTATCCTGCACTCC GGCGTGACATACTATAACCCTAGCCTGAAGAGCAGGGTGAC CATCTCCGTGGATACCAGCAAGAATCAGTTCAGCCTGAAGC TCAGCAGCGTGACCGCCGCCGATACCGCTGTGTTACTGC GCCAGAGACAGGACCACCGTCTCCATGATCGAGTACTTCCA GCACTGGGGCCAGCCAGCCGCCGCCTAGCCTAGCC GCACAAAAGGACCAAGCGTGTTTCCCACTGGCACCTAGCAGC AAATCCACCAGCGGCGGAACAGCAGCCCTCGGGTGCCTGGT GAAGGATTACTTCCCTGAGCCAGTCACAGTGTCCTGGAACT CCGGAGCCCTGACATCCGGCGTGCACACCTTCCCCGCTGCTG CTGCAATCCAGGGACTGAGCCGCCGCCGGT AGTCCCTTCCAGCAGCCTGGGCACACAGACTTACATTTGCA ACGTGAACCACAAAACCTTCCAACACTAAGGTGGACAAAAAGGTGGAACCCAAATCCTGTGATAAGACCCATACATGCCCAC CTTGTCCCGCTCCTGAGCTGCTGGGGGGACCTTCCGTCTTTC TGTTTCCTCCAAAACCAAAAGACACACTCATGATCAGCCGG ACCCCCGAAGTCACCTGTGTGGTGGTGGACGTCAGCCACGA AGATCCAGAGGTCAAGTTCAATTGGTACGTGGATGGAGTGG Petição 870260051334, de 28 / 05 / 2026, pág. 141 / 164 126 / 141 AAGTCCACAACGCAAAAACCAAACCTAGAGAAGAACAGTA CAATAGCACATAGGGTGGTGTCCGTCCTGACAGTGCTCC ACCAGGACTGGCTCAATGGCAAAGAGTATAAGTGCAAGGT GAGCAACAAGGCCCTGCCTGCACCAATTGAAAAACAATTA GCAAGCAAGGGCCAGGGACCAGGGACCATA CCTGCCCCCAAGCCGGGATGAACTGACCAAAAACCAGGTCA GCCTGACATGCCTGGTGAAAGGGTTTTACCCAAGCGATATT GCCGTCGAGTGGGAGAGCAACGGACAGCCAGAAAACAATT ACAAAACCACCCCACCTGTGCTGGACTCCGATGGGAGCTTT TTCCTGTACCAAGCAGCAGCCAGCAGCAGCAATTT ACAGGGCAACGTGTTTTCCTGCTCCGTGATGCACGAGGCCC TCCACAACCACTATACACAAAAGTCCCTCTCCCTCAGCCCA GGAAAGTGA 49 HC of IgGl of aFXI-18611 (Ql)(L105) KGLEW1GSILHSGVTYYNPSLKSRVT1SVDTSKNOFSLKLSSVT AADTAVYYCARDRTTVSLIEYFQHWGOGTLVTVSSd.SYAGm7 FPLAPSSKSTSGGTAALGCL VKDYFPEP VTVSWNSGALTSG VHTFP AVLQSSGLYSLSSWTVPSSSLGTOTYICNVNHKPSNTKVDKKVEPK SCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCWV DVSHEDPEWKFNWYVDGVVHNACTKPREEQYNSTYRWSVLTVL HQDWLNGKEYKCKVSNCALPAPIEKTISKAKGOPREPQVYTLPPS RDELTKNQVSLTCLVKGFFPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP GK 50 DNA encoding HC of IgGl from aFXI18611 (Ql)(L105) xxx= CAG or CAA (Q) xxxGTCCAGCTGCAGGAGAGCGGCCCTGGACTCGTGAAGCC CTCCGAAACCCTGAGCCTCACATGCGCCGTCTCCGGATACA GCATCAGCAGCGGATACTTCTGGGGCTGGATCAGACAGCCC CCCGGCAAAGGCCTGGAGTGGATCGGTTCTATTCTCCACAG CGGCGTGACATACTACAACCCCTCCCTGAAGAGCAGGGTGA CCATCAGCGTGGACACCTCCAAGAACCAGTTTTCCCTCAAG CTGAGCAGCGTGACCGCCGCTGACACAGCCGTGTATTACTG CGCCAGGGACAGGACCACCGTGTCCCTGATTGAGTACTTCC AGCATTGGGGCCAGGGCACACTGGTGACCGTCAGCAGCGCT AGCACAAAAGGACCAAGCGTGTTTCCACTGGCACCTAGCAG CAAATCCACCAGCGGCGGAACAGCAAGCCCTCGGGTGCCTGG TGAAGGATTACTTCCCTGAGCCAGTCACAGTGTCCTGGAAC TCCGGAGCCCTGACATCCGGCGTGCACACCTTCCCCGCTGT GCTGCAATCCAGCGGACTGTATAGCCTCAGCTCCGTCGTGA CAGTCCCTTCCAGCAGCCTGGGCACAGACTTACATTTGC AACGTGAACCACAAACCTTCCAACACTAAGGTGGACAAAA AGGTGGAACCCAAATCCTGTGATAAGACCCATACATGCCCA CCTTGTCCCGCTCCTGAGCTGCTGGGGGGACCTTCCGTCTTT CTGTTTCCTCCAAAACCAAAAGACACACTCATGATCAGCCG GACCCCCGAAGTCACCTGTGTGGTGGTGGACGTCAGCCACGAAGATCCAAGGTCAAGTCAATTGGTACGTGGATGGAGTG GAAGTCCACAACGCAAAAACCAAACCTAGAGAAGAACAGT ACAATAGCACATACAGGGTGGTGTCCGTCCTGACAGTGCTC CACCAGGACTGGCTCAATGGCAAAGAGTATAAGTGCAAGG TGAGCAACAAGGCCCTGCCTGCACCAATTGAGAAAACAATT AGCAAGGCAAAGGGGCAGCCACGGGAACCCCAGGTGTATA Petition 870260051334, dated 05 / 28 / 2026, pages 142 / 164 127 / 141 CCCTGCCCCCAAGCCGGGATGAACTGACCAAAAACCAGGTC AGCCTGACATGCCTGGTGAAAGGGTTTTACCCAAGCGATAT TGCCGTCGAGTGGGAGAGCAACGGACAGCCAGAAAACAT TACAAAACCACCCCACCTGTGCTGGACTCCGATGGGAGCTT AACAGGGCAACGTGTTTTCCTGCTCCGTGATGCACGAGGCC CTCCACAACCACTATACACAAAAGTCCCTCTCCCTCAGCCC AGGAAAGTGA 51 HC of IgGl of aFXI-18611 (El)(L105) KGLEWIGSILHSGVTYYNPSLKSRVTISVDTSKNOFSLKLSSVT AADTAVYYCARDRTTVSLIEYFOHWGOGTLVTVSS / 457XGAST FPLAPSSKSTSGGTAALGCLPKDYFPEPVTVSWNSGALTSGVHTFP AVLQSSGLYSLSSWTVPSSSLGTQniCNVNHKPSNTKVDKKVEPK SCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVW DVSHEDPEWKFNWYVDG VEVHNACTKPREEQYNSTYR WSVLTVL HQDWLNGKEYKCKVSNCALPAPIEKTISKAKGQPREPQVYTLPPS RDELTKNQVSLTCLVKGFYPSDIAVEWESFGQPENNYKTTPPVLDS DGSFFLYSKLTVDKSRWQOGNVFSCSVMHEALHNHYTQKSLSLSP GK 52 codRNA of IgGHCl aFXI18611 (El)(L105) xxx=GAA or GAG (E) xxxGTCCAGCTGCAGGAGAGCGGCCCTGGACTCGTGAAGCC CTCCGAAACCCTGAGCCTCACATGCGCCGTCTCCGGATACAGCATCAGCAGCGGATACTTCTGGGGCTGGATCAGACAGCCC CCCGGCAAAGGCCTGGAGTGGATCGGTTCTATTCTCCACAG CGGCGTGACATACTACAACCCCTCCCTGAAGAGCAGGGTGA CCATCAGCGTGGACACCTCCAAGAACCAGTTTTCCCTCAAG CTGAGCAGCGTGACCGCCGCTGACACAGCCGTGTATTACTG CGCCAGGGACAGGACCACCGTGTCCCTGATTGAGTACTTCC AGCATTGGGGCCAGGGCACACTGGTGACCGTCAGCAGCGCT AGCACAAAAGGACCAAGCGTGTTTCCACTGGCACCTAGCAG CAAATCCACCAGCGGCGGAACAGCAGCCCTCGGGTGCCTGG TGAAGGATTACTTCCCTGAGCCAGTCACAGTGTCCTGGAAC TCCGGAGCCCTGACATCCGGCGTGCACACCTTCCCCGCTGT GCTGCAATCCAGCGGACTGTATAGCCTCAGCTCCGTCGTGA CAGTCCCTTCCAGCAGCCTGGGCACACAGACTTACATTTGC AACGTGAACCACAAACCTTCCAACACTAAGGTGGACAAAA AGGTGGAACCCAAATCCTGTGATAAGACCCATACATGCCCA CCTTGTCCCGCTCCTGAGCTGCTGGGGGGACCTTCCGTCTTT CTGTTTCCTCCAAAACCAAAAGACACACTCATGATCAGCCG GACCCCCGAAGTCACCTGTGTGGTGGTGGACGTCAGCCACG AAGATCCAGAGGTCAAGTTCAATTGGTACGTGGATGGAGTG GAAGTCCACAACGCAAAAACCAAACCTAGAGAAGAACAGT ACAATAGCACATACAGGGTGGTGTCCGTCCTGACAGTGCTC CACCAGGACTGGCTCAATGGCAAAGAGTATAAGTGCAAGG TGAGCAACAAGGCCCTGCCTGCACCAATTGAGAAAACAATTAGCAAGGCAAAGGGGCAGCCACGGGAACCCCAGGTGTATA CCCTGCCCCCAAGCCGGGATGAACTGACCAAAAACCAGGTC AGCCTGACATGCCTGGTGAAAGGGTTTTACCCAAGCGATAT TGCCGTCGAGTGGGAGAGCAACGGACAGCCAGAAAACAAT TACAAAACCACCCCACCTGTGCTGGACTCCGATGGGAGCTT TTTCCTGTACAGCAAGCTCACAGTGGACAAGTCCAGATGGC AACAGGGCAACGTGTTTTCCTGCTCCGTGATGCACGAGGCC CTCCACAACCACTATACACAAAAGTCCCTCTCCCTCAGCCC AGGAAAGTGA Petição 870260051334, de 28 / 05 / 2026, pág. 143 / 164 128 / 141 53 HC of IgGl of aFXI-18623p (1Q) OVOLOESGPGLVKPSOTLSLTCTVSGGSIYSGAYYWSWIROHP GKGLEWIGSIHYSGLTYYNPSLKSRVTISVDTSKNOFSLKLSSV TAADTAVYYCARDVDDSSGDEHGGGSTVGGSTTV KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKFDK KVEPKSCDKTHTCPPCPPAPELLGGPSVFLFPPKPKDTLMISRTPEV 'rCYVVDPSHEDPEVKFNWYYDGVEVHNACTKPREEQYNSTYYS VLTVLHQDWLNGKEYKCKVSNCALPAPIEKTISKAKGQPREPQVY TLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSnGSFFLYSKLTVDKSRWQQGNVFSCRVMHEALHNHYTQKS LSLSPGK 54 DNA encoding HC of IgGl of aFXI18623p (1Q) xxx= CAG or CAA (Q) xxxGTCCAGCTGCAGGAATCCGGACCAGGGCGGCCCT AGCCAGACCCTGAGCCTGACCTGTACCGTGTCCGGCGGAAG CATCTATTCCGGCGCCTACTACTGGTCCTGGATTAGGCAGC ACCCCGGCAAGGGCCTGGAATGGATCGGCTCCATCCACTAC AGCGGCCTGACCTACAACCCCTCCCTGAAGTCCAGGGT GACCATCAGCCAGCCCAGACCTTCAGACCATCAGATCCACTAC AGCTGAGCAGCGTGACCGCCGCCGACACCGCCGTGTATTAT TGCGCCAGAGACGTGGACGACTCCTCCGGAGACGAGCACTA CGGCATGGACGTCTGGGGCCAGGGCACAACAGTGACAGTG AGCAGCGCTAGCACAAAAGGACCAAGCGTGTTTCCCACTGGCACCTAGCAGCAAATCCACCAGCGGCGGAACAGCAGCCCTC GGGTGCCTGGTGAAGGATTACTTCCCTGAGCCAGTCACAGT GTCCTGGAACTCCGGAGCCCTGACATCCGGCGTGCACACCT TCCCCGCTGTGCTGCAATCCAGCGGACTGTATAGCCTCAGC TCCGTCGTGACCGACCCAGCCGCCGCCGCCG TTACATTTGCAACGTGAACCACAAAACCTTCCAACACTAAGG TGGACAAAAAGGTGGAACCCAAATCCTGTGATAAGACCCAT ACATGCCCACCTTGTCCCGCTCCTGAGCTGCTGGGGGGACC TTCCGTCTTTCTGTTTCCTCCAAAACCAAAAGCACACCAT GATCCCACCGACCGACCGGGGGGGGGGGGGACCAT TCAGCCACGAAGATCCAGAGGTCAAGTTCAATTGGTACGTG GATGGAGTGGAAGTCCACAACGCAAAAACCAAACCTAGAG AAGAACAGTACAATAGCACATAGGGTGGTGTCCGTCCTG ACAGTGCTCCACCAGGACTGGCTCAATGGCAAAGAGTATAA GTCCAAGGAGGAGCAGCCATGACCATGACTGA AAACAATTAGCAAGGCAAAGGGGCAGCCACGGGAACCCCA GGTGTATACCCTGCCCCCAAGCCGGGATGAACTGACCAAAA ACCAGGTCAGCCTGACATGCCTGGTGAAAGGGTTTTACCCA AGCGATATTGCCGTCGAGTGGGAGAGCAACGGACAGCCAG AAAACATTACACCACCACCGACCGGACCTT GGGAGCTTTTTCCTGTACAGCAAGCTCACAGTGGACAAGTC CAGATGGCAACAGGGCAACGTGTTTTCCTGCTCCGTGATGC ACGAGGCCCTCCACAACCACTATACAAAAGTCCCTCTCC CTCAGCCCAGGAAAGTGA 55 HC of IgGlaFXI-18623p (1E) EVOLOESGPGLVKPSOTLSLTCTVSGGSIYSGAYYWSWIRQHP GKGLEWIGSIHYSGLTYYNPSLKSRVTTSVDTSKNQFSLKLSSV Petition 870260051334, dated 05 / 28 / 2026, pages 144 / 164 129 / 141 T AADTAVYYC ARDVDDSSGDEHYGMDVWGQGTTVTV S SXST KGPSVFPLAPSSKSFSGGTAALGCL VKDYFPEP VTVSWNSGALTSG VHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDK KVEPPKSCCDKTHCPFPGFPGCVP TCVWDVSHEDPEWKFNWYVDGVEVHNACTKPREEQYNSTYRWS VLTVLHQDWLNGKEYKCKVSNCALPAPIEKTISKKGPREPQVY TLPPSRDELTKNQ VKGFYPSDIA VEWESNGQPENNYCTTPTP PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTOKS LSLSPGK 56 DNA encoding HC of IgGl of aFXI18623p (1E) xxx=GAA or GAG (E) xxxGTCCAGCTGCAGGAATCCGGACCAGGGCGCCT AGCCAGACCCTGAGCCTGACCTGTACCGTGTCCGGCGGAAG CATCTATTCCGGCGCCTACTACTGGTCCTGGATTAGGCAGC ACCCCGGCAAGGGCCTGGAATGGATCGGCTCCATCCACTAC AGCGGCCTGACCTATACAACCCCTCCCTGAAGTCCAGGGT AGCTGAGCAGCGTGACCGCCGCCGACACCGCCGTGTATTAT TGCGCCAGAGACGTGGACGACTCCTCCGGAGACGAGCACTA CGGCATGGACGTCTGGGGCCAGGGCACAACAGTGACAGTG AGCAGCGCTAGCACAAAAGGACCAAGCGTGTTTCCCACTGGCTACCAGCCAGCCAGCCAGCCAGCCAGCCAGCCAGCCAGCA GGGTGCCTGGTGAAGGATTACTTCCCTGAGCCAGTCACAGT GTCCTGGAACTCCGGAGCCCTGACATCCGGCGTGCACACCTTCCCCGCTGTGCTGCAATCCAGCGGACTGTATAGCCTCAGC TCCGTCGTGACAGTCCCTTCCAGCAGCCTGGGCACACAGAC TTACATTTGCAACGTGAACCACAAAACCTTCCAACACTAAGG TGGACAAAAAGGTGGAACCCAAATCCCTGTGATAAGACCCAT ACATGCCCACCCCGCCGGGGGGGGGCCTT TTCCGTCTTTCTGTTTCCTCCAAAACCAAAAGACACACTCAT GATCAGCCGGACCCCGAAGTCACCTGTGTGGTGGTGGACG TCAGCCACGAAGATCCAGGTCAAGTTCAATTGGTACGTG GATGGAGTGGAAGTCCACAACGCAAAAACCAAACCTAGAG AAGAACAGTACAGCAGAGGTCGAGGTCCT ACAGTGCTCCACCAGGACTGGCTCAATGGCAAAGAGTATAA GTGCAAGGTGAGCAACAAGGCCCTGCCTGCACCAATTGAGA AAACAATTAGCAAGGCAAAGGGGCAGCCACGGGAACCCCA GGTGTATACCCTGCCCCCAAGCCGGGATGAACTGACCAAAA ACCAGGTCAGACCATGAGCCGAGGCCGAGGTTGA AGCGATATTGCCGTCGAGTGGGAGAGCAACGGACAGCCAG AAAACAATTACAAAACCACCCCACCTGTGCTGGACTCCGAT GGGAGCTTTTTCCTGTACAGCAAGCTCACAGTGGACAAGTC CAGATGGCAACAGGGCAACGTTTTCCTGCTCCGTGATGC ACGAGCCCCACCACCTACCACCACCCACT CTCAGCCCAGGAAAGTGA 57 HC of lgG4 of aFXI-18611p (S228P) (Ql) (M105) (C- terminal without K) QVQLQESGPGLVKPSETLSLTCAVSGYSISSGYFWGWTRQPPGKGLEWIGSILHSGVTYYNPSLKSRVTISVDTSKNQFSLKLSSVT AADTAVYYCARDRTTVSMIEYF0HWG0GTLVTVSSX.y7XGJ>5 VFPLAPCSRSTSESTAALGCL VKDYFPEP VTVSWNSGALTSGVHTF PA VLOSSGL YSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVES KYGfpCPPCPAPEFLGGPSVFLFPPKPKDTIMISRTPEVTCVWDV sqfdpevqfnwyvdgvevhnaktkpreeqfnstyrwsvltvlhq DWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQ VYTLPPSQEE MTKNQVSLTCL VKGFYPSDIA VEWESNGQPENNYKTTPPVLDSDG SFFL YSRL TVDKSR WQEGNVFSCSVMHEALHNHYTQKSLSLSLG 58 DNA that Petition 870260051334, dated 05 / 28 / 2026, pages 145 / 164 130 / 141 codifica HC de lgG4 de aFXI18611p (S228P)(Q1) (M105); xxx= CAG ou CAA (Q) (C-terminal sem K) xxxGTCCAGCTGCAGGAGAGCGGCCCTGGCCTGGTGAAGCCT AGCGAGACACTGTCCCTGACCTGCGCCGTGAGCGGCTACAG CATCTCCAGCGGCTATTTCTGGGGATGGATCAGACAGCCCC CTGGCAAGGGCCTGGAATGGATCGGTTCTATCCTGCACTCC GGCGTGACATACTATAACCCTAGCCTGAAGAGCAGGGTGAC CATCTCCGTGGATACCAGCAAGAATCAGTTCAGCCTGAAGC TCAGCAGCGTGACCGCCGCCGATACCGCTGTGTACTACTGC GCCAGAGACAGGACCACCGTCTCCATGATCGAGTACTTCCA GCACTGGGGCCAAGGCACCCTGGTCACCGTGTCCTCCGCCT CCACCAAGGGCCCTAGCGTGTTTCCTCTGGCCCCCTGCTCCA GATCCACAAGCGAGAGCACCGCTGCCCTGGGCTGTCTGGTC AAGGACTACTTCCCCGAGCCCGTGACAGTGTCCTGGAACAG CGGCGCCCTGACAAGCGGCGTCCATACATTCCCCGCCGTGC TGCAGTCCAGCGGACTGTATAGCCTGAGCTCCGTGGTGACC GTGCCTTCCAGCAGCCTGGGAACCAAGACATATACCTGCAA CGTGGACCATAAGCCCAGCAACACAAAAGTCGACAAGAGG GTGGAGAGCAAGTACGGACCCCCTTGTCCCCCTTGTCCTGC TCCCGAGTTCCTCGGCGGACCTAGCGTGTTCCTGTTTCCTCC CAAGCCCAAGGATACCCTGATGATCAGCAGGACCCCTGAGG TCACCTGCGTGGTGGTCGACGTGTCCCAGGAGGACCCTGAG GTCCAGTTTAACTGGTACGTGGACGGAGTGGAGGTGCACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTTCAATTCCCACCT ACAGGGTGGTGAGCGTCCTGACCGTGCTGCACCAGGACTGG CTGAATGGAAAGGAGTACAAATGCAAGGTCTCCAACAAGG GCCTCCCTAGCAGCATCGAGAAGACCATCTCCAAGGCCAAG GGCCAAGCCCCTAGCCCTAGCCTAGCCTAGCCTA CCAGGAGGAAATGACCAAGAACCAGGTGTCCCTGACATGC CTGGTGAAGGGCTTCTATCCTAGCGACATCGCCGTGGAGTG GGAGAGCAATGGCCAGCCCGAGAATAACTACAAGACCACC CCCCCTGTGCTCGATAGCGACGGCAGCTCTCTCTGTACAGC AGGCTGACCAGGAGGAGGAGGAGGAGGAGGGAG TGTTTAGCTGCTCCGTCATGCACGAGGCCCTGCATAACCACT ACACCCAAAAATCCCTGTCCCTGTCCCTGGGC 59 HC of lgG4 of aFXI-18611p (S228P) (El) (M105) (C- terminal sem K) KGLEWIGSILHSGVTYYNPSLKSRVTISVDTSKNOFSLKLSSVT AADTAVYYCARDRTTVSMIEYFQHWGOGTLVTVSSbXTXGPX VFPLAPCRSTSTAALGCL VKDYFPEP VTVSWNSGALTSG VHTF PAVLQSSGLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVES KYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVWDV SQEDPEVQFNWYVDGVEVHNACTKPREEQFNSTYRWSVLTVLHQ DWLNGKÈYKCKVSNKGIFSSIEKTISKAKGQPREPQVYTLPPSQEE MTKNQVSLTCL VKGFYPSDIA VEWESNGQPENNYKTTPPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG 60 DNA encoding HC of lgG4 of aFXI- 18611p (S228P); (El) (M105) xxx=GAA or GAG (E) (C- xxxGTCCAGCTGCAGGAGAGCGGCCCTGGCCTGGTGAAGCCT AGCGAGACACTGTCCCTGACCTGCGCCGTGAGCGGCTACAG CATCTCCAGCGGCTATTTCTGGGGATGGATCAGACAGCCCC CTGGCAAGGGCCTGGAATGGATCGGTTCTATCCTGCACTCC Petition 870260051334, of 28 / 05 / 2026, p. 146 / 164 131 / 141 terminal sem K) GGCGTGACATACTATAACCCTAGCCTGAAGAGCAGGGTGAC CATCTCCGTGGATACCAGCAAGAATCAGTTCAGCCTGAAGC TCAGCAGCGTGACCGCCGCCGATACCGCTGTGTACTACTGC GCCAGAGACAGGACCACCGTCTCCATGATCGAGTACTTCCA GCACTGGGGCCAAGGCACCCTGGTCACCGTGTCCTCCGCCT CCACCAAGGGCCCTAGCGTGTTTCCTCTGGCCCCCTGCTCCA GATCCACAAGCGAGAGCACCGCTGCCCTGGGCTGTCTGGTC AAGGACTACTTCCCCGAGCCCGTGACAGTGTCCTGGAACAG CGGCGCCCTGACAAGCGGCGTCCATACATTCCCCGCCGTGC TGCAGTCCAGCGGACTGTATAGCCTGAGCTCCGTGGTGACC GTGCCTTCCAGCAGCCTGGGAACCAAGACATATACCTGCAA CGTGGACCATAAGCCCAGCAACACAAAAGTCGACAAGAGG GTGGAGAGCAAGTACGGACCCCCTTGTCCCCCTTGTCCTGC TCCCGAGTTCCTCGGCGGACCTAGCGTGTTCCTGTTTCCTCC CAAGCCCAAGGATACCCTGATGATCAGCAGGACCCCTGAGG TCACCTGCGTGGTGGTCGACGTGTCCCAGGAGGACCCTGAG GTCCAGTTTAACTGGTACGTGGACGGAGTGGAGGTGCACAA CGCCAAGACCAAGCCCAGAGAGGAGCAGTTCAATTCCACCT ACAGGGTGGTGAGCGTCCTGACCGTGCTGCACCAGGACTGG CTGAATGGAAAGGAGTACAAATGCAAGGTCTCCAACAAGG GCCTCCCTAGCAGCATCGAGAAGACCATCTCCAAGGCCAAG GGCCAGCCTAGGGAGCCCCAGGTGTACACCCTGCCTCCTAG CCAGGAGGAAATGACCAAGAACCAGGTGTCCCTGACATGCCTGGTGAAGGGCTTCTATCCTAGCGACATCGCCGTGGAGTG GGAGAGCAATGGCCAGCCCGAGAATAACTACAAGACCACC CCCCCTGTGCTCGATAGCGACGGCAGCTCTTTCTGTACAGC AGGCTGACCGTGGACAAGGAGCAGGTGGCAAGGGCAACG ACACCCAAAAATCCCTGTCCCTGTCCCTGGGC 61 HC of lgG4 of aFXI-18611 (S228P) (Ql) (L105) (C- terminal without K) OVOLOESGPGLVKPSETLSLTCAVSGYSISSGYFWGWIRQPPG KGLEWIGSILHSGVTYYNPSLKSRVTISVDTSKNOFSLKLSSVT AADTAVYYCARDRTTVSLIEYF0HWG0GTLVTVSS4.STÃrGP5F FPLAPCSRSTSESTAALGCL VKDYFPEP VTVSWNSGAL TSGVHTFP AVI.QSSGLYSLSSWTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESK YGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVS QEDPEVOFNWYVDGVEVHNACTKPREEQFNSTYRWSVLTVLHQ DWLNGKEYKCKVSNKGLPSIEKTISKAKGQPREPQVYTLPPSQEE MTKNQ VSLTCL VKGFYPSDIA VEWESNGQPENNYKTTPPVLDSDG SFFLYSRL TVDKSR WQEGNVFSCSVMHEALHNHYTQKSLG 62 DNA queSLG HClG de lgGifica aFXI18611 (S228P); (Ql) (L105) XXX— CAG or CAA (Q) (C-terminal without K) xxxGTCCAGCTGCAGGAGAGCGGCCCTGGACTCGTGAAGCC CTCCGAAACCCTGAGCCTCACATGCGCCGTCTCCGGATACAGCATCAGCAGCGGATACTTCTGGGGCTGGATCAGACAGCCC CCCGGCAAAGGCCTGGAGTGGATCGGTTCTATTCTCCACAG CGGGCGTGACATACTACAACCCCTCCCCTGAAGAGCAGGGTGA CCATCAGCGTGGACACCTCCAAGAACCAGTTTTCCCTCAAG CTGAGCAGCGTGACCGCCGCTGACACAGCCGTGTATTACTG CGCCAGGGACAGGACCACCGTGTCCCTGATTGAGTACTTCC AGCATTGGGGCCAGGGCACACTGGTGACCGTCAGCAGCGCC AGCACCAAGGGCCCTTCCGTCTTCCCTCTGGCCCCTTGCAGC AGAAGCACCTCCGAGTCCACAGCCGCCCTGGGATGCCTCGT Petition 870260051334, dated 05 / 28 / 2026, pages 147 / 164 132 / 141 GAAGGATTACTTCCCCGAGCCCGTCACAGTCTCCTGGAACT CCGGCGCTCTGACCAGCGGAGTGCACACCTTCCCCGCCGTG CTGCAAAGCAGCGGCCTGTACAGCCTGTCCAGCGGTGGTCAC CGTGCCTTCCTCCAGCCCTGGGCACCAAGACCTACCATC AGTGGAAAGCAAGTACGGCCCCCCCTGCCCCCCTTGTCCTG CCCCCGAGTTTCTGGGAGGACCCTCCGTGTTCCTCTTTCCTC CCAAGCCTAAGGACACCCTGATCTCCAGGACCCCCGAA ACGCCAAGACCAAGCCCAGGGAGGAGCAGTTCAATAGCAC CTACAGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACT GGCTGAACGGCAAAGAGTACAAGTGCAAAGTCAGCAACAA GGGCCTGCCCTCCTCCATCGAGAAGACCATTAGCAAGGCCA AGGCCCTAGGCCCTAGGCCCCTAGGCCTAGCCTA AGCCAGGAGGAGATGACCAAGAACAGGTGTCCCTGACCT GCCTGGTCAAGGGATTTTACCCCAGCGACATCGCTGTGGAA TGGGAGAGCAATGGCCAGCCCGAGAACAACTACAAGACCA CCCCTCCCGTGCTCGATTCCGACGGCAGCTTTTCCTGTACA CGTGTTCTCCTGTTCCGTGATGCATGAGGCCCTGCACAACCA CTACACACAGAAGAGCCTGTCCCTGTCCCTGGGC 63 HC of lgG4 of aFXI-18611 (S228P) (El) (L105) (C-terminal without K)EVQLQESGPGLVKPSETLSLTCAVSGYSISSGYFWGWIRQPPG KGLEWIGSILHSGVTYYNPSLKSRVTISVDTSKNOFSLKLSSVT AADTAVYCARDRTTVSLIEYFQHWGOGTLVTVSSAS^^ FPLAPCSRSTSTAALGWGTLVTVSCG FLQSSGLYSLSSVFJVPSSSLGTKTYTCNFDHKPSNTKVD VESK YGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCWVD VS OEDPEVOFNWYVDGVEVHNACTKPREEQFNSTYRWSVLTVLHQ D WLNGKEYKCKVSNKGLPSIEKTISKAKGQPREPQVYTLPPSQEE MTKNQ VSLTCL VKGFYPSDLA VEWESNGQPENNYKTTPPVLDSDG SFFLYSRL TVDKSRWQEGNVFSCSVMHEALHNHYTQKSLG 64 DNA queSLG 64 DNA codification deHQ1186 (S228P) (Ql) (L105) xxx=GAA or GAG (E) (C- terminal sem K) xxxGTCCAGCTGCAGGAGAGCGGCCCTGGACTGGTGAAGCC CTCCGAAACCCTGAGCCTCACATGCGCCGTCTCCGGATACA GCATCAGCAGCGG CCCGGCAAAGGCCTGGAGTGGATCGGTTCTATTCTCCACAG CGGCGTGACATACTACAACCCCTCCCTGAAGAGCAGGGTGA CCATCAGCGTGGACACCTCCAAGAACCAGTTCCCTCAAG CTGAGCAGCGTGACCGCCGCTGACAGCCGTGTTACTG AGCATTGGGGCCAGGGCACACTGGTGACCGTCAGCAGCGCC AGCACCAAGGGCCCTTCCGTCTTCCCTCTGGCCCCTTGCAGCAGAAGCACCTCCGAGTCCACAGCCGCCCTGGGATGCCTCGT GAAGGATTACTTCCCCGAGCCCGTCACAGTCTCCTGGAACT CCGGCGCTCTGACCAGCGGAGTGCACACCTTCCCCGCCGTG CTGCAAAGCAGCGGCCTGTACAGCCTGTCCAGCGTGGTCAC CGTGCCTTCCTCCAGCCTGGGCACCAAGACCTACACATGCA ACGTGGACCACAAGCCTTCCAACACCAAGGTGGACAAGAG AGTGGAAAGCAAGTACGGCCCCCCCTGCCCCCCTTGTCCTG CCCCCGAGTTTCTGGGAGGACCCTCCGTGTTCCTCTTTCCTC Petição 870260051334, de 28 / 05 / 2026, pág. 148 / 164 133 / 141 CCAAGCCTAAGGACACCCTGATGATCTCCAGGACCCCCGAA GTGACCTGCGTGGTCGTGGACGTGTCCCAGGAGGACCCTGA GGTGCAGTTTAACTGGTACGTGGACGGCGTGGAGGTGCACA ACGCCAAGACCAAGCCCAGGGAGGAGCAGTTCAATAGCAC GGCTGAACGGCAAAGAGTACAAGTGCAAAGTCAGCAACAA GGGCCTGCCCTCCTCCATCGAGAAGACCATTAGCAAGGCCA AGGGCCAGCCTAGGGAGGCCTCAGGTTACACCCTGCCCCCC AGCCAGGAGGAGATGACCAAGAACCAGGTGTCCCTGACCCT GCCAGGGTTACCAGTTGACCGGACCG TGGGAGAGCAATGGCCAGCCCGAGAACAACTACAAGACCA CCCCTCCCGTGCTCGATTCCGACGGCAGCTTTTTTCCTGTACA GCAGGCTGACCGTGGATAAGAGCAGGTGGCAGGAAGGCAA CGTGTTCTCCTGTTCCGTGATGATGAGGCCCTGCACAACCA CTACACACGAGACCTAGCCCTGCCCT5 lgG4 of aFXI-18623p (S228P) (Ql) (Cterminal sem K) QVQLQESGPGLVKPSQTLSLTCTVSGGSIYSGAYYWSWIRQHP GKGLEWIGSIHYSGLTYYNPSLKSRVTISVDTSKNQFSLKLSSV TAADTAVYYCARDVDDSSGDEHYGMDVWGQGTTVTVSSA67' KGPSVFPLAPCSRSSTAALGCLVKDYFPEPPV1VSWNSGALTSG PHlFPAPLQSSGLYSLSSFFirPSSSSLGTKlYTCNFDHKPSNTKFDK RVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLM1SRTPEVTCV WDVSQEDPEVQENWYVDGVEVHNA KTKPREEQFNSTYR WSVL TVLHQDWLNGKEYKCKVSNKGLPSSIEK11SKAKGQPREPQVYTLPP SQEEMTKNQySLTCL VKGFYPSD1A VEWESNGQPENNYKFiPPVL DSDGSFFL YSRL TVDKSR WOEGNVFSCSVMHEALHNHYTOKSLSL SL6 DNA de lGG66 de lGG ifica otFXI18623p (S228P) (Ql) xxx= CAG or CAA (Q) (Cterminal sem K) xxxGTCCAGCTGCAGGAATCCGGACCCGGCCTGGTGAAGCCCT AGCCAGACCCTGAGCCTGACCTGTACCGTGTCCGGCGGAAG CATCTATTCCGGCCCTGGCCTT ACCCCGGCAAGGGCCTGGAATGGATCGGCTCCATCCACTAC AGCGGCCTGACCTATTACAACCCCTCCCTGAAGTCCAGGGT GACCATCAGCGTCGACACAAGCAAGAACCAGTTCTCCCTCA AGCTGAGCAGCGTGACCGCGCGACACCGCCGTGTATT CGGCATGGACGTCTGGGGCCAGGGCACAACAGTGACAGTG AGCAGCGCCAGCACCAAAGGACCCTCCGTCTTCCCTCTGGC CCCTTGCTCCAGGAGCACAAGCGAAAGCACAGCCGCCCTGG GCTGCCTGGTGAAGGACTACTTTCCCGAGCCCGTGACCGTG AGCTGGACCCCTAGCCTTGGCCTT TCCCGCCGTCCTGCAGAGCAGCGGCCTGTACTCCCTGAGCT CCGTGGTGACCGTGCCTTCCTCCAGCCCTGGGCACCAAGACC TACACCTGCAACGTGGACCACAAGCCTAGCAATACCAAGGT GGACAAGAGGGTGGAATCCAAGTACGGCCCCCCTTGCCCTCCTTGTCCTGCCCCCGAATTTCTGGGCGGCCCTTCCGTGTTCC TGTTCCCTCCCAAGCCCAAGGATACCCTGATGATCAGCAGG ACCCCTGAGGTGACCTGTGTGGTGGTGGACGTGAGCCAGGA GGACCCCGAGGTGCAGTTCAACTGGTACGTGGATGGCGTGG AAGTGCACAATGCCAAGACAAAGCCCAGGGAGGAGCAGTT CAATAGCACCTACAGGGTGGTCAGCGTGCTCACAGTGCTGC ACCAGGACTGGCTGAACGGAAAGGAGTACAAGTGCAAAGT Petição 870260051334, de 28 / 05 / 2026, pág. 149 / 164 134 / 141 GTCCAACAAGGGCCTGCCCTCCTCCATCGAAAAGACCATCT CCAAGGCCAAAGGCCAGCCCAGGGAGCCCCAAGTGTATAC CCTCCCCCCTAGCCAGGAGGAAATGACCAAAAACCAGGTCT CCCTGACCTGTCTGGTGAAGGGCTTATCCCAGCGACATC GCTGTGGAGTGAAGGACCGACCGACCGACCGACCAACT ATAAGACCACACCCCCCGTCCTGGACTCCGATGGCTCCTTCT TCCTGTACAGCAGGCTGACCGTCGACAAGTCCAGGTGGCAG GAAGGAAACGTGTTCTCCTGTAGCGTCATGCACGAGGCCCT GCACAACCACTATACCCAGAAGTCCCTGTCCCTGAGCCTGGG GC 67 lHCG-18XF32 de (S228P) (El) (Cterminal sem K) EVQLQESGPGLVKPSQTLSLTCTVSGGS1YSGAYYWSWIRQHP GKGLEWIGSIHYSGLTYYNPSLKSRVTISVDTSKNQFSLKLSSV TAADTAVYYCARDVDDSGDEHYGMDVWSSGTVGTTVGTTTV KGPSVFPIAPCSRSTCESTAALGCEVKDYFPEPPVTVSWNSGALTSG VHTFPA VLQSSGL YSISSWTVPSSSI.GTKTYTCNVDHKPSNTKVDK RVESKYGPPCPPCPAPEFLGGPSVFLFPPKDTLMISRTPEVTCV WD VSQEDPEVQFNEVSTGWPREVKWNKVNA WSVL T VLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPP SOEEMTKNQVSLTCL VKGFYPSDIA VEWESNGQPENNYKTTPPVL DSDGSFFLYSRLTVDKSRWOEGNVFSCSVMHEALHNHYTQKSLG68 de SLG48 de SLG SLG de SLG aFXI18623p (S228P((E1) xxx=GAA or GAG (E) (Cterminal without K)xxxGTCCAGCTGCAGGAATCCGGACCCGGCCTGGTGAAGCCT AGCCAGACCCTGAGCCTGACCTGTACCGTGTCCGGCGGAAG CATCTATTCCGGCGGCCTACTACTGGTCCTGGATTAGGCAGC ACCCCGGCAAGGGCCTGGAATGGATCGGCTCCATCCACTAC AGCGGCCTGACCTATTACAACCCCTCCCTGAAGTCCAGGGT GACCATCAGCGTCGACACAAGAAGACAGTTCTCCCTCA AGCTGAGCAGCGGTGACCGCCCGACACCGCCGTGTATTAT TGCGCCAGAGACGTGGACGACTCCTCCGGAGACGAGCACTA CGGCATGGACGTCTGGGGCCAGGGCACAACAGTGACAGTG AGCAGCGCCAGCACCAAAGGACCCTCGTCTTCCCTCTGGC CCCTTGCTCCAGGAGCACAAGCGAAAGCACAGCCGCCCTGG GCTGCCTGGTGAAGACTACTTTCCCGAGCCCGTGACCGTG AGCTGGAATAGCGGAGCCCTCACCTCCGGAGTCCACACATT TCCCGCCGTCCTGCAGAGCGCGCCTGTACTCCCTGAGCT CCGTGGTGACCGTGCCTTCCTCCAGCCTGGGCACCAAGACC TACACCTGCAACGTGGACCACAAGCCTAGCAATACCAAGGT GGACAAGAGGGTGGAATCCAAGTACGGCCCCCTTGCCCT CTTGTCCTGCCCCCGAATTTCTGGGCGGCCCTTCCGTGTTCC TGTTCCCTCCCAAGCCCAAGGATACCCTGATGATGATCAGCAGG ACCCCTGAGGTGACCTGTGTGGTGGTGGACGTGAGCCAGGA GGACCCCGAGGTGCAGTTCCAACTGGTACGTGGATGGCGTGG AAGTGCACAATGCCAAAGCCCAGGGAGGAGCAGTT CAATAGCACCTACAGGGTGGTCAGCGTGCTCACAGTGCTGCACCAGGACTGGCTGAACGGAAAGGAGTACAAGTGCAAAGT GTCCAACAAGGGCCTGCCCTCCTCCATCGAAAAGACCATCT CCAAGGCCAAAGGCCAGCCCAGGGAGCCCCAAGTGTATAC CCTCCCCCCTAGCCAGGAGGAAATGACCAAAAACCAGGTCT CCCTGACCTGTCTGGTGAAGGGCTTCTATCCCAGCGACATC GCTGTGGAGTGGGAGAGCAACGGCCAACCCGAGAACAACT Petição 870260051334, de 28 / 05 / 2026, pág. 150 / 164 135 / 141 ATAAGACCACACCCCCCGTCCTGGACTCCGATGGCTCCTTCT TCCTGTACAGCAGGCTGACCGTCGACAAGTCCAGGTGGCAG GAAGGAAACGTGTTCTCCTGTAGCGTCATGCACGAGGCCCT GCACAACCACTATACCCAGAAGTCCCTGTCCCTGAGCCTGGG GC 69 IgHCF18161 de (Ql) (M105) (Cterminal sem K) QVQLQESGPGLVKPSETLSLTCAVSGYSISSGYFWGWIRQPPG KGLEWIGSILHSGVTYYNPSLKSRVTISVDTSKNQFSLKLSSVT AADTAVYYYCARDRTrVSMIEYFQHSSVGGTVXTVXTVGTLV' VFPLAPSSKSTSGGTAALGCLVKDYFPEPPVTVSWNSGALTSGVHTF PAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEP KSCDKTHTCPPCPAPELLGGPSVFLFPPKDTLMISRTPEVTCW VDVSHEDPEWKFNWYVDGVEVHNACTKPREEQYNSTYRWSVLTV LHOD WLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VYTLPPS RDEL TKNO VSL TCL VKGFYPSDIA VEWESNGQPENNYKTTPP VLDS DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP G 70 DNA encoding HC of IgGl of aFXI18611p (Ql) (M105) xxx= CAG or CAA (Q) (C-terminal without K) AGCGAGACACTGTCCCTGACCTGCGCCGTGAGCGGCTACAG CATCTCCAGCGGCTATTTCTGGGGATGGATCAGACAGCCCC CTGGCAAGGGCCTGGAATGGATCGGTTCTATCCTGCACTCCGGCGTGACATACTATAACCCTAGCCTGAAGAGCAGGGTGAC CATCTCCGTGGATACCAGCAAGAATCAGTTCAGCCTGAAGC TCAGCAGCGTGACCGCCGCCGATACCGCTGTGTACTACTGC GCCAGAGACAGGACCACCGTCTCCATGATCGAGTACTTCCA GCACTGGGGCCAAGGCACCCTGGTCACCGTGTCCTCCGCTA GCACAAAAGGACCAAGCGTGTTTCCACTGGCACCTAGCAGC AAATCCACCAGCGGCGGAACAGCAGCCCTCGGGTGCCTGGT GAAGGATTACTTCCCTGAGCCAGTCACAGTGTCCTGGAACT CCGGAGCCCTGACATCCGGCGTGCACACCTTCCCCGCTGTG CTGCAATCCAGCGGACTGTATAGCCTCAGCTCCGTCGTGAC AGTCCCTTCCAGCAGCCTGGGCACACAGACTTACATTTGCA ACGTGAACCACAAACCTTCCAACACTAAGGTGGACAAAAA GGTGGAACCCAAATCCTGTGATAAGACCCATACATGCCCAC CTTGTCCCGCTCCTGAGCTGCTGGGGGGACCTTCCGTCTTTC TGTTTCCTCCAAAACCAAAAGACACACTCATGATCAGCCGG ACCCCCGAAGTCACCTGTGTGGTGGTGGACGTCAGCCACGA AGATCCAGAGGTCAAGTTCAATTGGTACGTGGATGGAGTGG AAGTCCACAACGCAAAAACCAAACCTAGAGAAGAACAGTA CAATAGCACATACAGGGTGGTGTCCGTCCTGACAGTGCTCC ACCAGGACTGGCTCAATGGCAAAGAGTATAAGTGCAAGGT GAGCAACAAGGCCCTGCCTGCACCAATTGAGAAAACAATTA GCAAGGCAAAGGGGCAGCCACGGGAACCCCAGGTGTATAC CCTGCCCCCAAGCCGGGATGAACTGACCAAAAACCAGGTCAGCCTGACATGCCTGGTGAAAGGGTTTTACCCAAGCGATATT GCCGTCGAGTGGGAGAGCAACGGACAGCCAGAAAACAATT ACAAAACCACCCCACCTGTGCTGGACTCCGATGGGAGCTTT TTCCTGTACAGCAAGCTCACAGTGGACAAGTCAGATGGCA GGCA TCCACAACCACTATACACAAAAGTCCCTCTCCCTCAGCCCA GGA 71 HC of IgGl of aFXI-18611p (El) (M105) (C- Petition 870260051334, of 28 / 05 / 2026, p. 151 / 164 136 / 141 terminal sem K) EVOLOESGPGLVKPSETLSLTCAVSGYSISSGYFWGWIRQPPG KGLEWIGSTLHSGVTYYNPSLKSRVTISVDTSKNQFSLKLSSVT AADTAVYCARDRTTVSMIEYFQHWGQGTLVSSAXZ^GAS' VFPLAPSSKSTSGGTAALGCLVKDYFPEPTVSWNSGALTSGVHTE' PAVLQSSGLYSLSSSVVTVPSSSSLGTQTYICNVNHKPSNTKVDKKVEP KSCDKTHTCPPCPPAPELLGGPSVFLFPPKDTLMISRTPEVTCW VDVSHEDPEWKFNWYVDGVEVHNACTKPREEQYNSTYRWSVLTV LHQD WLNGKEYKCKVSNCALPAPIECTICAKGQPREPQ VYTLPPS RdIlLTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPLDS DGSFFLYSKLTVDKSRWOQGNVFSCSVMHEALHNHYTOKSLSLSP G 72 DNA encoding HC of IgGl of aFXI18611p (Ql) (M105) xxx=GAA or GAG (E) (Cterminal without K) xxxGTCCAGCTGAGGAGGAGGGCCGGGCCCT AGCGAGACACTGTCCCTGACCTGCGCCGTGAGCGGCTACAG CATCTCCAGCGGCTATTTCTGGGGATGGATCAGACAGCCCC CTGGCAAGGGCCTGGAATGGATCGGTTCTATCCTGCACTCC GGCGTGACATACTATAACCCTAGCCTGAAGGCAGGGTGAC TCAGCAGCGTGACCGCCGCCGATACCGCTGTGTACTACTGC GCCAGAGACAGGACCACCGTCTCCATGATCGAGTACTTCCA GCACTGGGGCCAAGGCACCCTGGTCACCGTGTCCTCCGCTA GCACAAAAGGACCAAGCGTTTTCCACTGGCACCTAGCAGCAAATCCACCAGCGGCGGAACAGCAGCCCTCGGGTGCCTGGT GAAGGATTACTTCCCTGAGCCAGTCAGTGTCCTGGAACT CCGGAGCCCTGACATCCGGCGTGCACACCTTCCCCGCTGTG CTGCAATCCAGCGGACTGTAGCCTCAGCTCCGTCAGCCATGACCATCAGCTCACTTGTAGCCTCAGCTCCGTCAGCCATGACCATCAGCCAGTGACT ACGTGAACCACAAAACCTTCCAACTAAGGTGGACAAAAA GGTGGAACCCAAATCCTGTGATAAGCCATACATGCCCAC CTTGTCCCGCTCCTGAGCTGCTGGGGGACCTTCCTTCCTTCTTC TGTTTCCTCCAAAACCAAAAGACACTCATGATCAGCCGGTGACCGAGTCGAAGTCAT AGATCCAGGTCAAGTTCAATGGTACGTGGATGGAGTGG AAGTCCACAACGCAAAAACCAAACCTAGAGAGAACAGTA CAATAGCACACACACAGGTGGTGTCCGTCCTGACAGTGCTCC ACCAGGACTGGCTCAATGGCAAAGTAAGTGGACTAAAGGTCCCATTCATTGAGCAACA GCAAGGCAAAGGGGGCAGCCCACGGGAACCCCAGGTGTATAC CCTGCCCCCAAGCCGGATGACTGACCAAAACCAGGTCA GCCTGACATGCCTGGTGAAAGGGTTTTACCCAAGCGATATT GCCGTCGAGTGGAGAGAGCAACGGAGCCAGACTAATTACCCCTGAGACCAATT ACAAACCAG TTCCTGTACAGCAAGCTCACAGTGGACAAGTCCAGATGGCA ACAGGGCAACGTTTTCCTGCTCCGTGATGCACGAGGCCC TCCACAACCACTATACACAAAAGTCCCTCCCTCAGCCCA GGA 73 HC de IgGl de aFXI-18611(Ql)(L105) (C- terminal without K) QVQLQESGPGLVKPSETLSLTCAVSGYSISSGYFWGWIRQPPG KGLEWIGSILHSGVTYYNPSLKSRVTIS VDTS KNQF SLKLSS VT AADTAVYYCARDRTTVSLIEYFQHWGOGTLVTVSS^XT^GPXF FPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPK Petition 870260051334, dated 05 / 28 / 2026, pages 152 / 164 137 / 141 SCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVW DySHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTyL HQDWLNGKEYKCKVSNKALPAP1EKTISKAKGQPREPQVYTLPPS RDELTKNQ VSLTCL VKGFYPSDIA VEWESNGQPENNYKTTPP VLDS DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP 74 DNA encoding HC of IgGl of aFXI18611 (Ql)(L105) XXX— CAG or CAA (Q) (C-terminal without K); xxxGTCCAGCTGCAGGAGAGCGGCCCTGGACTCGTGAAGCC CTCCGAAACCCTGAGCCTCACATGCGCCGTCTCCGGATACA GCATCAGCAGCGGATACTTCTGGGGCTGGATCAGACAGCCC CCCGGCAAAGGCCTGGAGTGGATCGGTTCTATTCTCCACAG CGGCGTGACATACTACAACCCCTCCCTGAAGAGCAGGGTGA CCATCAGCGTGGACACCTCCAAGAACCAGTTTTCCCTCAAG CTGAGCAGCGTGACCGCCGCTGACACAGCCGTGTATTACTG CGCCAGGGACAGGACCACCGTGTCCCTGATTGAGTACTTCC AGCATTGGGGCCAGGGCACACTGGTGACCGTCAGCAGCGCT AGCACAAAAGGACCAAGCGTGTTTCCACTGGCACCTAGCAG CAA ATCC ACC AGCGGCGGA AC AGC AGCCCTC GGGTGCCTGG TGAAGGATTACTTCCCTGAGCCAGTCACAGTGTCCTGGAAC TCCGGAGCCCTGACATCCGGCGTGCACACCTTCCCCGCTGT GCTGCAATCCAGCGGACTGTATAGCCTCAGCTCCGTCGTGA CAGTCCCTTCCAGCAGCCTGGGCACACAGACTTACATTTGCAACGTGAACCACAAACCTTCCAACACTAAGGTGGACAAAAA AGGTGGAACCCAAATCCTGTGATAAGACCCATACATGCCCA CCTTGTCCCGCTCCTGAGCTGCTGGGGGGACCTTCCTTCCTT CTGTTTCCTCCAAAACCAAAAGACACACTCATGATCAGCCG GACCCCCGAGTCGAGTTGCGGGGGGGTCTT AAGATCCAGAGGTCAAGTTCAATTGGTACGTGGGATGGAGTG GAAGTCCACAACGCAAAAACCAAACCTAGAGAAACAGT ACAATAGCACATAGGGTGGTCCGTCCTGAGTGCTC CACCAGGACTGGCTCAATGGCAAAGAGTATAAGTGCAAGTC AGCAAGGCAAAGGGCAGCCACGGGAACCCCAGGTGTATA CCCTGCCCCCAAGCCGGGATGAACTGAACCAAAAACCAGGTC AGCCTGACATGCCTGGTGAAAGGGTTTTACCCAAGCGATAT TGCCGTCGAGTGGGAGAGCAACGGACAGCCAGAAACCAAT TTTCCTGTACAGCAAGCTCACAGTGGACAAGTCCAGATGGC AACAGGGCAACGTGTTTTCCTGCTCCGTGATGCACGAGGCC CTCCACAACCACTATACAAAAGTCCCTCTCCCTCAGCCC AGGA 75 HC of IgGl of aFXI-18611 (E1)(L1) terminal (C-K) EVOLQESGPGLVKPSETLSLTCAVSGYSISSGYFWGWIROPPG KGLEWIGSILHSGVTYYNPSLKSRVTISVDTSKNOFSLKLSSVT AADTAVYCARDRTTVSLIEYFQHWGOGTLVTVSSzíóT^GP.Sy FPLAPSSKSTGGGGFPKDYFPK VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPK SCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVW DVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVL HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGOPREPQVYTLPPS RDEL TKNQ VSL TCL VKGFYPSDIA VEWESNGQPENNYKTTPPVIDS DGSFFL YSKL TVDKSR WQQGNVFSCSVMHEALHNHYTQKSLSLSP G 76 DNA encoding HC of Petition 870260051334, dated 05 / 28 / 2026, pages 153 / 164 138 / 141 IgGl of aFXI18611 (El)(L105) xxx=GAA or GAG (E) (C- terminal sem K) xxxGTCCAGCTGCAGGAGAGCGGCCCTGGACTCGTGAAGCC CTCCGAAACCCTGAGCCTCACATGCGCCGTCTCCGGATACA GCATCAGCAGCGGATACTTCTGGGGCTGGATCAGACAGCCC CCCGGCAAAGGCCTGGAGTGGATCGGTTCTATTCTCCACAG CGGCGTGACATACTACAACCCCTCCCTGAAGAGCAGGGTGA CCATCAGCGTGGACACCTCCAAGAACCAGTTTTCCCTCAAG CTGAGCAGCGTGACCGCCGCTGACACAGCCGTGTATTACTG CGCCAGGGACAGGACCACCGTGTCCCTGATTGAGTACTTCC AGCATTGGGGCCAGGGCACACTGGTGACCGTCAGCAGCGCT AGCACAAAAGGACCAAGCGTGTTTCCACTGGCACCTAGCAG CAAATCCACCAGCGGCGGAACAGCAGCCCTCGGGTGCCTGG TGAAGGATTACTTCCCTGAGCCAGTCACAGTGTCCTGGAAC TCCGGAGCCCTGACATCCGGCGTGCACACCTTCCCCGCTGT GCTGCAATCCAGCGGACTGTATAGCCTCAGCTCCGTCGTGA CAGTCCCTTCCAGCAGCCTGGGCACACAGACTTACATTTGC AACGTGAACCACAAACCTTCCAACACTAAGGTGGACAAAA AGGTGGAACCCAAATCCTGTGATAAGACCCATACATGCCCA CCTTGTCCCGCTCCTGAGCTGCTGGGGGGACCTTCCGTCTTT CTGTTTCCTCCAAAACCAAAAGACACACTCATGATCAGCCG GACCCCCGAAGTCACCTGTGTGGTGGTGGACGTCAGCCACG AAGATCCAGAGGTCAAGTTCAATTGGTACGTGGATGGAGTG GAAGTCCACAACGCAAAAACCAAACCTAGAAGAACAGTACAATAGCACATACAGGGTGGTGTCCGTCCTGACAGTGCTC CACCAGGACTGGCTCAATGGCAAAGAGTATAAGTGCAAAGG TGAGCAACAAGGCCCTGCCTGCACCAATTGAGAAAACAATT AGCAAGGCAAAGGGGCAGCCACGGGAACCCAGGTGTTA CCCTCCCCGAGACCAGGACCAACCAACCAGGACCAGGACCAGGTT AGCCTGACATGCCTGGTGAAAGGGTTTTACCCAAGCGATAT TGCCGTCGAGTGGGAGAGCAACGGACAGCCAGAAAACAT TACAAAACCACCCCACCTGTGCTGGACTCCGATGGGAGCTT TTTCCTGTACAGCAAGCTCACAGTGGACAAGTCCAGATGGCAGGGCAGCCGTTGGCCTT CTCCACAACCACTATACACAAAGTCCCTCTCCCTCAGCCC AGGA 77 HC of IgGl of aFXI-18623p (IQ) (C- terminal without K) OV0LQESGPGLVKPSQTLSLTCTVSGGS1YSGAYYWSWIRQHP GKGLEWIGSIHYSGLTKSLKSWIRQHPY TAADTAVYYCARDVDDSSGDEHYGMDVWGOGTTVTVSSAST KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDK KVEPKSCDKTHPPPPPPPPPPEPFLGFP TCVWDVSHEDPEWKFNWYVDGVEVHNACTKPREEQYNSTYRWS VLTVLHQDWLNGKEYKCKVSNCALPAPIECTISKAKGQPREPOVY TLPPSRDELTKN(2VSLTCLVKGFYPSDlAVEWESNGQPENNYKTrPP PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTOKS LSLSPG 78 DNA encodingHC of IgGl of aFXI18623p (IQ) xxx= CAG or CAA (Q) (Cterminal without K) xxxGTCCAGCTGCAGGAATCCGGACCCGGCCTGGTGAAGCCCT AGCCAGACCCTGAGCCTGACCTGTACCGTGTCCGGCGGAAG CATCTATTCCGGGCCTTGGCCTT ACCCCGGCAAGGGCCTGGAATGGATCGGCTCCATCCACTAC Petition 870260051334, of 28 / 05 / 2026, p. 154 / 164 139 / 141 AGCGGCCTGACCTATTACAACCCCTCCCTGAAGTCCAGGGT GACCATCAGCGTCGACACAAGCAAGAACCAGTTCTCCCTCA AGCTGAGCAGCGTGACCGCCGCCGACACCGCCGTGTATTAT TGCGCCAGAGACGTGGACGACTCCTCCGGAGACGAGCACTA CGGCATGGACGTCTGGGGCCAGGGCACAACAGTGACAGTG AGCAGCGCTAGCACAAAAGGACCAAGCGTGTTTCCACTGGC ACCTAGCAGCAAATCCACCAGCGGCGGAACAGCAGCCCTC GGGTGCCTGGTGAAGGATTACTTCCCTGAGCCAGTCACAGT GTCCTGGAACTCCGGAGCCCTGACATCCGGCGTGCACACCT TCCCCGCTGTGCTGCAATCCAGCGGACTGTATAGCCTCAGC TCCGTCGTGACAGTCCCTTCCAGCAGCCTGGGCACACAGAC TTACATTTGCAACGTGAACCACAAACCTTCCAACACTAAGG TGGACAAAAAGGTGGAACCCAAATCCTGTGATAAGACCCAT ACATGCCCACCTTGTCCCGCTCCTGAGCTGCTGGGGGGACC TTCCGTCTTTCTGTTTCCTCCAAAACCAAAAGACACACTCAT GATCAGCCGGACCCCCGAAGTCACCTGTGTGGTGGTGGACG TCAGCCACGAAGATCCAGAGGTCAAGTTCAATTGGTACGTG GATGGAGTGGAAGTCCACAACGCAAAAACCAAACCTAGAG AAGAACAGTACAATAGCACATACAGGGTGGTGTCCGTCCTG ACAGTGCTCCACCAGGACTGGCTCAATGGCAAAGAGTATAA GTGCAAGGTGAGCAACAAGGCCCTGCCTGCACCAATTGAGA AAACAATTAGCAAGGCAAAGGGGCAGCCACGGGAACCCCA GGTGTATACCCTGCCCCCAAGCCGGGATGAACTGACCAAAAACCAGGTCAGCCTGACATGCCTGGTGAAAGGGTTTTACCCA AGCGATATTGCCGTCGAGTGGGAGAGCAACGGACAGCCAG AAAACAATTACAAAACCACCCCACCTGTGCTGGACTCCGAT GGGAGCTTTTTCCTGTACAGCAAGCTCAGTGGACAAGTC CAGATGGCAACAGGCTGTTGTT ACGAGGCCCTCCACAACCACTATACACAAAGTCCCTCTCC CTCAGCCCAGGA 79 HC of IgGl of aFXI-18623p (1E) (C-terminal without K) EVQLQESGPGLVKPSQTLSLTCTVSGGSIYSGAYYWSWIRQHP GKGLEWIGSTHYSGLTYYNPSLKSRVTISVDTSKNQFSLKLSSV TAADTAVYYCARDVDDSSGDEHYGMDVWGOGTTVSSáXr KGPSVFPIAPSSKSTSGGTAALGCL VKD YFPEP VTVSWNSGALTSG VHTFPA VLQSSGL YSLSSWTFPSSSI.GTQTYICNVNHKPSNTKVDK KVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTIMISRTPKV TCWVDVSHEDPEWKFNWYVDGVEVHNACTKPREEQYNSTYRWS VLTVLHQDWLNGKKKKKKKKKPQQPQQY TLPPSRDELTKNQ VSL TCL VKGFYPSDIA VEWESNGOPENNYKTTP P VLDSDGSFFLYSKLTVDKSR WQOGNVFSCSVMHEALHNHYTQKS LSLSPG 80 DNA encoding HC of IgGl of aFXI18623p (1EA) (1E) or terminal K-E (GxA) (GxA) xxxGTCCAGCTGCAGGAATCCGGACCCGGCCTGGTGAAGCCT AGCCAGCCCTGAGCCTGACCTGTACCGTGTCCGGCGGAAGCATCTATTCCGGCGCCTACTACTGGTCCTGGATTAGGCAGC ACCCCGGCAAGGGCCTGGAATGGATCGGCTCCATCCACTAC AGCGGCCTGACCTATTACAACCCCTCCCCTGAAGTCCAGGGT GACCATCAGCGTCGACACAAGCAAGAACCAGTTCTCCCTCA AGCTGAGCAGCGTGACCGCCGCCGACACCGCCGTGTATTAT TGCGCCAGAGACGTGGACGACTCCTCCGGAGACGAGCACTA CGGCATGGACGTCTGGGGCCAGGGCACAACAGTGACAGTG Petition 870260051334, dated 05 / 28 / 2026, pages 155 / 164 140 / 141 AGCAGCGCTAGCACAAAAGGACCAAGCGTGTTTCCACTGGC ACCTAGCAGCAAATCCACCAGCGGCGGAACAGCAGCCCTC GGGTGCCTGGTGAAGGATTACTTCCCTGAGCCAGTCACAGT GTCCTGGAACTCCGGAGCCCTGACATCCGGCGTGCACACCT TCCCCGCTGTGCTGCAATCCAGCGGACTGTATAGCCTCAGC TCCGTCGTGACAGTCCCTTCCAGCAGCCTGGGCACACAGAC TTACATTTGCAACGTGAACCACAAACCTTCCAACACTAAGG TGGACAAAAAGGTGGAACCCAAATCCTGTGATAAGACCCAT ACATGCCCACCTTGTCCCGCTCCTGAGCTGCTGGGGGGACC TTCCGTCTTTCTGTTTCCTCCAAAACCAAAAGACACACTCAT GATCAGCCGGACCCCCGAAGTCACCTGTGTGGTGGTGGACG TCAGCCACGAAGATCCAGAGGTCAAGTTCAATTGGTACGTG GATGGAGTGGAAGTCCACAACGCAAAAACCAAACCTAGAG AAGAACAGTACAATAGCACATACAGGGTGGTGTCCGTCCTG ACAGTGCTCCACCAGGACTGGCTCAATGGCAAAGAGTATAA GTGCAAGGTGAGCAACAAGGCCCTGCCTGCACCAATTGAGA AAACAATTAGCAAGGCAAAGGGGCAGCCACGGGAACCCCA GGTGTATACCCTGCCCCCAAGCCGGGATGAACTGACCAAAA ACCAGGTCAGCCTGACATGCCTGGTGAAAGGGTTTTACCCA AGCGATATTGCCGTCGAGTGGGAGAGCAACGGACAGCCAG AAAACAATTACAAAACCACCCCACCTGTGCTGGACTCCGAT GGGAGCTTTTTCCTGTACAGCAAGCTCACAGTGGACAAGTC CAGATGGCAACAGGGCAACGTGTTTTCCTGCTCCGTGATGCACGAGGCCCTCCACAACCACTATACACAAAAGTCCCTCTCC CTCAGCCCAGGA 81 FXI humano ECVTQLLKDTCFEGGDITTVFTPSAKYCQVVCTYHPRCLLFTFT AESPSEDPTRWFTCVLKDSVTETLPRVNRTAAISGYSFKQCSH QISACNKDIYVDLDMKGINYNSSVAKSAQECQERCTDDVHCH FFTYATRQFPSLEHRNICLLKHTQTGTPTRITKLDKVVSGFSLK SCALSNLACIRDTFPNTVFADSNIDSVMAPDAFVCGRICTHHPG CLFFTFFSQEWPKESQRNLCLLKTSESGLPSTRIKKSKALSGFSL QSCRHSIPVFCHSSFYHDTDFLGEELDIVAAKSHEACQKLCTNA VRCQFFTYTPAQASCNEGKGKCYLKLSSNGSPTKILHGRGGIS GYTLRLCKMDNECTTKTKPRIVGGTASVRGEWPWQVTLHTTS PTQRHLCGGSIIGNQWILTAAHCFYGVESPKILRVYSGILNQSEI KEDTSFFGVQEIIIHDQYKMAESGYDIALLKLETTVNYTDSQRP ICLPSKGDRNVIYTDCWVTGWGYRKLRDMQNTLQKAKJPLVT NEECQKRYRGHKITHKMICAGYREGGKDACKGDSGGPLSCKH NEVWHLVGITSWGEGCAQRERPGVYTNVVEYVDWILEKTQA V 82 Epítopo A DIFPNTVF 83 Epítopo B PSTRIKKSKALSG 84 Cadeia leve de kappa anti-RSV MAPVQLLGLLVLFLPAMRCDIQMTQSPSTLSSASVGDRVTITCKCQLS VGYMHWYQQKPGKAPKLLJYDTSKLASGVPSRFSGSGSGTEFTLTIS SLQPDDFATYYCFQGSGYPFTFGGGTKLEIKRTl^P^TTEPraDO, KSGTASWCLLNNFYPREAKVOWKVDNALQSGNSQESyTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHOGLSSPVTKSFNRGEC 85 HC lgG4 anti-RSV S228P MAVVQLLGLLVLFLPAMRCQVTLRESGPALVKPTQTLTLTCTFSGFS LSTSGMSVGWIRQPPGKALEWLADIWWDDKKDYNPSLKSRLTISKD TSKNQVVLKVTNMDPADTATYYCARSMITNWYFDVWGAGTTVTV Petition 870260051334, dated 05 / 28 / 2026, pages 156 / 164 141 / 141 FHTFPA FLOSSGLYSLSSYVTVPSSSLGTKTYTCNVDHKPSNTKVDKR VF.S KYGPPCPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSOED PEVQFNWYVDGVEVHNAKTKPREEOFNSTYRWSVLTVLHODWLNGKE YKCKVSNKGLPSSIEKriSKAKGOPREPO VYTLPPSOEENfrKNQVSLTCL V KGFYPSDIAVEWESNGOPENNYKnPPVLDSDGSFFLYSRLTVDKSRWQE GN VFSCSVMHEALHNHY'1 OKSLSLSLGK Constant regions are shown in italics. Underlined amino acid sequences are CDRs.

[0334] Although the present invention is described herein with reference to the embodiments illustrated, it should be understood that the invention is not limited to these. Those skilled in the art and having access to the teachings herein will recognize additional modifications and embodiments within the scope thereof. Therefore, the present invention is limited only by the claims appended hereto.

Claims

CLAIMS 1. Antibody or antigen-binding fragment, characterized in that it comprises: (a) a heavy chain (HC) having a constant domain and a variable domain (VH), wherein the VH comprises a HC complementarity-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; and (b) a light chain (LC) having a constant domain and a variable domain (VL), wherein the VL comprises a complementarity-determining region of LC (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.

2. Antibody or antigen-binding fragment according to claim 1, characterized in that the antibody comprises a constant HC domain comprising the amino acid sequence shown in SEQ ID NO: 16, 17, 18 or 19.

3. Antibody or antigen-binding fragment according to claim 1 or 2, characterized in that the antibody comprises a constant LC domain comprising the amino acid sequence shown in SEQ ID NO:

20.

4. Antibody or antigen-binding fragment according to claim 1, characterized in that the antibody or antibody fragment comprises: (a) a VH having the amino acid sequence shown in SEQ ID NO: 28 and a VL having the amino acid sequence shown in SEQ ID NO: 30; or Petition 870260051334, dated 05 / 28 / 2026, page 158 / 164 2 / 5 (b) a VH having the amino acid sequence shown in SEQ ID NO: 29 and a VL having the amino acid sequence shown in SEQ ID NO:

30.

5. Antibody or antigen-binding fragment according to claim 4, characterized in that the antibody further comprises a constant HC domain comprising the amino acid sequence shown in SEQ ID NO: 16, 17, 18 or 19.

6. Antibody or antigen-binding fragment according to claim 4, characterized in that the antibody further comprises a constant LC domain comprising the amino acid sequence shown in SEQ ID NO:

20.

7. Antibody or antigen-binding fragment according to any one of claims 1 to 6, characterized in that the antibody or antigen-binding fragment binds to the apple 3 domain of coagulation factor XI (FXI) and inhibits FXI activation and / or factor XIa-mediated activation of factor IX.

8. Antibody or antigen-binding fragment according to any one of claims 1 to 7, characterized in that the antibody comprises: a HC having the amino acid sequence shown in SEQ ID NO: 41, 43, 53, 55, 65, 67, 77 or 79; and an LC having the amino acid sequence shown in SEQ ID NO:

31.

9. Antibody or antigen-binding fragment according to claim 1, characterized in that the antibody comprises a HC comprising the amino acid sequence shown in SEQ ID NO: 65 and an LC comprising the amino acid sequence shown in SEQ ID NO: 31, wherein it further comprises a constant domain of LC comprising the amino acid sequence shown in SEQ ID NO:

20. Petition 870260051334, dated 05 / 28 / 2026, pp. 159 / 164 3 / 5 10. Antibody or antigen-binding fragment according to claim 1, characterized in that the antibody comprises a HC comprising the amino acid sequence shown in SEQ ID NO: 67 and an LC comprising the amino acid sequence shown in SEQ ID NO:

31.

11. Antibody or antigen-binding fragment according to claim 1, characterized in that the antibody comprises a HC comprising the amino acid sequence shown in SEQ ID NO: 41 and an LC comprising the amino acid sequence shown in SEQ ID NO:

31.

12. Antibody or antigen-binding fragment according to claim 1, characterized in that the antibody comprises a HC comprising the amino acid sequence shown in SEQ ID NO: 43 and an LC comprising the amino acid sequence shown in SEQ ID NO:

31.

13. Antibody or antigen-binding fragment according to claim 1, characterized in that the antibody comprises a HC comprising the amino acid sequence shown in SEQ ID NO: 53 and an LC comprising the amino acid sequence shown in SEQ ID NO:

31.

14. Antibody or antigen-binding fragment according to claim 1, characterized in that the antibody comprises a HC comprising the amino acid sequence shown in SEQ ID NO: 55 and an LC comprising the amino acid sequence shown in SEQ ID NO:

31.

15. Antibody or antigen-binding fragment according to claim 1, characterized in that the antibody comprises a HC comprising the amino acid sequence shown in SEQ ID NO: 77 and an LC comprising the amino acid sequence shown in SEQ ID NO:

31.

16. Antibody or antigen-binding fragment according to claim 1, characterized in that the antibody comprises a HC comprising the amino acid sequence shown in SEQ ID NO: 79 and a Petition 870260051334, dated 05 / 28 / 2026, page 160 / 164 4 / 5 LC comprising the amino acid sequence shown in SEQ ID NO:

31.

17. Composition, characterized in that it comprises an antibody defined in any one of claims 1 to 16 or an antigen-binding fragment defined in claim 1 or 4 and a pharmaceutically acceptable carrier or diluent.

18. Use of an antibody defined in any one of claims 1 to 16 or of the antigen-binding fragment defined in claim 1 or 4, characterized in that it is for the manufacture of a medicament to treat a thromboembolic disorder or disease.

19. Antibody according to any one of claims 1 to 16 or antigen-binding fragment according to claim 1 or 4, characterized in that it is for the treatment or prevention of a thromboembolic disorder or disease.

20. Antibody according to claim 19, characterized in that the thromboembolic disorder or disease is stroke in atrial fibrillation (SPAF).

21. Antibody according to claim 19, characterized in that the thromboembolic disorder or disease is venous thromboembolism (VTE).

22. Antibody according to claim 19, characterized in that the thromboembolic disorder or disease is a medical device-related thromboembolic disorder.

23. Antibody according to claim 22, characterized in that the medical device is a stent, endovascular stent graft, cardiac or venous catheter, continuous flow ventricular assist device (CFLVADS), hemodialysis, cardiopulmonary bypass and extracorporeal membrane oxygenation (ECMO) or ventricular assist device (VAD). Petition 870260051334, dated 05 / 28 / 2026, pp. 161 / 164 5 / 5 24. Antibody according to any one of claims 1 to 16 or antigen-binding fragment according to claim 1 or 4, characterized in that it is for the treatment or prevention of a thromboembolic disorder in severe or end-stage renal disease (ESRD).

25. Method for producing an antibody or antigen-binding fragment, characterized in that it comprises: (a) providing a host cell comprising a nucleic acid molecule encoding the heavy chain (HC) of an antibody defined in any one of claims 1 to 16 and a nucleic acid molecule encoding the light chain (LC) of an antibody defined in any one of claims 1 to 16; and culturing the host cell under conditions and for a time sufficient to produce the antibody; or (b) providing a host cell comprising a nucleic acid molecule encoding a VH defined in claim 1 or 4 and a nucleic acid molecule encoding a VL defined in claim 1 or 4; and culturing the host cell under conditions and for a time sufficient to produce the antigen-binding fragment.

26. Method according to claim 25, characterized in that the host cell is a Chinese hamster ovary cell or a human embryonic kidney cell.

27. Method according to claim 25, characterized in that the host cell is a yeast cell or filamentous fungus.

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