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JP-2026076151-A - Factor XI antibody and method of use

JP2026076151AJP 2026076151 AJP2026076151 AJP 2026076151AJP-2026076151-A

Abstract

[Challenge] To provide a safer treatment that offers comparable efficacy to existing treatments but reduces bleeding risk and can reduce thromboembolic complications of AF, such as stroke, systemic embolism, cognitive decline, and mortality. [Solution] The present invention provides a monoclonal antibody that binds to human coagulation factor XI and XIa (activated factor XI) and its antigen-binding fragment, as well as a pharmaceutical composition containing the same, and a treatment method comprising the step of administering the same. [Selection Diagram] None

Inventors

  • エデル，ヨルグ
  • エヴェルト，ステファン
  • ハッシーペン，ウルリッヒ
  • カダー，ヤッサー
  • マイヤー，ローレンツ エム．
  • メルコ，サム
  • シーリング，ニコラウス

Assignees

  • ノバルティス アーゲー

Dates

Publication Date
20260511
Application Date
20251222
Priority Date
20150626

Claims (20)

  1. Isolated anti-FXI antibodies and/or antibodies that bind to the catalytic domain of FXI and/or FXIa. Alternatively, isolated anti-FXIa antibodies or fragments thereof.
  2. An isolated antibody or fragment thereof that binds to one or more epitopes of anti-FXI and/or FXIa, wherein the epitopes are Pro410, Arg413, Leu415 , Cys416, His431, Cys432, Tyr434, Gly435, Glu4 37, Tyr472, Lys473, Met474, Ala475, Glu476, Ty r521, Arg522, Lys523, Leu524, Arg525, Asp526, Lys527, Arg548, His552, Ser575, Ser594, Trp59 5. An isolated antibody or fragment thereof containing two or more amino acid residues from among Gly596, Glu597, Arg602, Glu603, and Arg604.
  3. The aforementioned epitopes are Pro410, Arg413, Leu415, Cys416, Hi s431, Cys432, Tyr434, Gly435, Glu437, Tyr472, Lys473, Met474, Ala475, Glu476, Tyr521, Arg52 2, Lys523, Leu524, Arg525, Asp526, Lys527, Arg 548, His552, Ser575, Ser594, Trp595, Gly596, G The isolated antibody or fragment according to claim 2, comprising four or more amino acid residues selected from lu597, Arg602, Glu603, and Arg604.
  4. The aforementioned epitopes are Pro410, Arg413, Leu415, Cys416, Hi s431, Cys432, Tyr434, Gly435, Glu437, Tyr472, Lys473, Met474, Ala475, Glu476, Tyr521, Arg52 2, Lys523, Leu524, Arg525, Asp526, Lys527, Arg 548, His552, Ser575, Ser594, Trp595, Gly596, G The isolated antibody or fragment according to claim 2, comprising six or more amino acid residues from among lu597, Arg602, Glu603, and Arg604.
  5. The aforementioned epitopes are Pro410, Arg413, Leu415, Cys416, Hi s431, Cys432, Tyr434, Gly435, Glu437, Tyr472, Lys473, Met474, Ala475, Glu476, Tyr521, Arg52 2, Lys523, Leu524, Arg525, Asp526, Lys527, Arg 548, His552, Ser575, Ser594, Trp595, Gly596, G The isolated antibody or fragment according to claim 2, comprising eight or more amino acid residues from among lu597, Arg602, Glu603, and Arg604.
  6. The aforementioned epitopes are Pro410, Arg413, Leu415, Cys416, Hi s431, Cys432, Tyr434, Gly435, Glu437, Tyr472, Lys473, Met474, Ala475, Glu476, Tyr521, Arg52 2, Lys523, Leu524, Arg525, Asp526, Lys527, Arg 548, His552, Ser575, Ser594, Trp595, Gly596, G Claim 2, comprising the residues lu597, Arg602, Glu603, and Arg604. The isolated antibody or fragment described above.
  7. The aforementioned epitope consists of the amino acid residues Pro410, Arg413, and Lys527, and L eu415, Cys416, His431, Cys432, Tyr434, Gly435 , Glu437, Tyr472, Lys473, Met474, Ala475, Glu4 76, Tyr521, Arg522, Lys523, Leu524, Arg525, As p526, Arg548, His552, Ser575, Ser594, Trp595, The isolated antibody or fragment according to claim 2, comprising one or more amino acid residues from Gly596, Glu597, Arg602, Glu603, and Arg604.
  8. The aforementioned epitope consists of the amino acid residues Pro410, Arg413, and Lys527, and L eu415, Cys416, His431, Cys432, Tyr434, Gly435 , Glu437, Tyr472, Lys473, Met474, Ala475, Glu4 76, Tyr521, Arg522, Lys523, Leu524, Arg525, As p526, Arg548, His552, Ser575, Ser594, Trp595, The isolated antibody or fragment according to claim 2, comprising four or more amino acid residues selected from Gly596, Glu597, Arg602, Glu603, and Arg604.
  9. The aforementioned epitope consists of the amino acid residues Pro410, Arg413, and Lys527, and L eu415, Cys416, His431, Cys432, Tyr434, Gly435 , Glu437, Tyr472, Lys473, Met474, Ala475, Glu4 76, Tyr521, Arg522, Lys523, Leu524, Arg525, As p526, Arg548, His552, Ser575, Ser594, Trp595, The isolated antibody or fragment according to claim 2, comprising six or more amino acid residues selected from Gly596, Glu597, Arg602, Glu603, and Arg604.
  10. Isolated anti-FXI antibodies and/or antibodies that bind to the catalytic domain of FXI and/or FXIa. Alternatively, isolated anti-FXIa antibodies or fragments thereof, and FXI and/or FXI An isolated antibody or fragment that blocks the binding of a to one or more of factor X, factor XIIa, and thrombin.
  11. Factor IX, Factor XIIa, or thrombin of FXI and/or FXIa, The isolated antibody or fragment according to claim 10, which blocks binding to one or more other components of the coagulation pathway.
  12. The isolated antibody or fragment according to claim 1, which blocks the binding of one or more of FIX, FXI, and FXIa to a platelet receptor.
  13. An isolated antibody or fragment according to claim 1, which prevents activation of the intrinsic coagulation pathway or the common coagulation pathway.
  14. Human FXI protein and/or human FXIa protein are subjected to a titration assay of 34 nM or less, as measured by the BIACORE® assay, or a solution equilibrium titration assay (SET). An isolated antibody or fragment thereof that binds at a KD of 4 pM or less, as measured by ).
  15. The isolated antibody or fragment according to claim 1, comprising at least one complementarity-determining region having at least 90% identity with at least one of the CDRs listed in Table 1.
  16. The isolated antibody or fragment according to claim 1, comprising CDR1, CDR2, and CDR3 of Table 1.
  17. An isolated variant of the antibody or fragment according to claim 1, wherein the antibody or fragment is as shown in Table 1 An isolated mutant comprising CDR1, CDR2, and CDR3, wherein the mutant has at least 1 to 4 amino acid changes in one of CDR1, CDR2, or CDR3.
  18. The isolated antibody or fragment according to claim 1, comprising a heavy chain CDR3 selected from the group consisting of SEQ ID NOs. 5 and 25.
  19. The isolated antibody or fragment according to claim 1, comprising a VH selected from the group consisting of SEQ ID NOs: 9 and 29, or an amino acid sequence having 90% identity thereto; and a VL selected from the group consisting of SEQ ID NOs: 19 and 39, or an amino acid sequence having 90% identity thereto.
  20. The isolated antibody or fragment according to claim 1, comprising a VH selected from the group consisting of SEQ ID NOs: 9 and 29, or an amino acid sequence having 95% identity thereto; and a VL selected from the group consisting of SEQ ID NOs: 19 and 39, or an amino acid sequence having 95% identity thereto.

Description

This application is based on 20 of the following, each of which is incorporated herein by reference in whole: U.S. Provisional Application No. 62/184,955, filed on June 26, 2015, and, We assert the benefits of U.S. Provisional Application No. 62/341,568, filed on 25 May 2016. This application was filed electronically in ASCII format and contains a sequence listing which is incorporated herein by reference in its entirety. The aforementioned AS was prepared on 23 June 2016. The CII copy is named "PAT056955-WO-PCT_SL.txt" and is 45,685 bytes in size. Background Thrombosis refers to the formation of blood clots within blood vessels, following a combination of hereditary risk factors known as thrombotic predisposition or hypercoagulation, and acquired risk factors. Damage to the blood vessel wall, congestion, increased platelet reactivity, and activation of coagulation factors are some of the fundamental characteristics of thrombosis. Thrombosis can occur in both venous and arterial circulation and can result in the development of deep vein thrombosis (DVT), pulmonary embolism, and stroke. When a thrombus forms in the arterial system, ischemia occurs downstream, which can lead to acute coronary syndrome (ACS), ischemic stroke, and acute lower extremity ischemia. Thrombosis in the venous system typically results in deep vein thrombosis, pulmonary embolism, and chronic thromboembolic pulmonary hypertension. Blood clots can also form in the left atrial appendage of patients with atrial fibrillation (AF), and dislodged thrombi can result in potentially serious complications, namely thromboembolic stroke and systemic embolism. All currently available antithrombotic drugs, including low molecular weight heparin (LMWH), thrombin inhibitors, and factor Xa (FXa) inhibitors, This is associated with a significant risk of bleeding (Weitz JI (2010) Thromb. Haemost. 103, 62). There is a strong need for the development of antithrombotic agents that do not affect hemostasis and therefore do not result in bleeding complications. Current anticoagulants are administered by injection or orally. Injectable anticoagulant LMWH It is widely used and provides an improved therapeutic profile compared to unfractionated heparin, which was previously used. Over the past few decades, the most commonly used oral anticoagulant has been: It was warfarin. Warfarin has a narrow therapeutic window, which requires frequent monitoring of the clotting state and exhibits various drug interactions. More recently, orally available direct FXa and thrombin inhibitors have entered the anticoagulant market. Its application is increasing. LMWH, FXa inhibitors, and thrombin inhibitors are all effective in preventing postoperative venous thromboembolic disease, managing spontaneous DVT and pulmonary embolism, and preventing stroke in atrial fibrillation. However, these anticoagulants are also associated with bleeding complications generally comparable to those observed with older drugs such as warfarin and unfractionated heparin. In the ADVANCE-2 clinical trial, the FXa inhibitor apixaban ( Apixaban (Eliquis) was compared to enoxaparin, an LMWH (Lesser Molecular Hemolytic Wave) in patients after total knee arthroplasty. Acute apixaban therapy was more effective than enoxaparin in preventing venous thromboembolic disease, but both drugs were associated with a significant risk of bleeding. Clinically relevant bleeding occurred in 4% of patients treated with apixaban and 5% of patients treated with enoxaparin (Lassen, MR, et al. (2009) N. Engl.). J. Med. 361, 594). In the RE-LY trial, dabigatran (Prada), a direct thrombin inhibitor, was used. xa) was compared to warfarin in patients with atrial fibrillation and a risk of stroke (Connolly, SJ, et al. (2009) N. Engl. J. Med. 361, 1139). Chronic dabigatran therapy was associated with a marked reduction in the risk of stroke or systemic embolism. However, complications of massive bleeding occurred in 3.1% of patients receiving 150 mg of dabigatran daily and in 3.4% of patients receiving warfarin (p = 0.31). Atrial fibrillation (AF) remains the most common cardiac arrhythmia in clinical practice, accounting for approximately one-third of hospitalizations due to cardiac arrhythmias. Currently, AF is prevalent in Europe, with 60 It is estimated that over 10,000 people, and approximately 2.3 million in the United States, are affected, and this number continues to grow rapidly due to the increasing proportion of the aging population. While it is estimated that about 5% of the population over 65 and 10% of those over 80 will develop AF, the prevalence of AF is increasing beyond what can be explained by age alone. Risk factors for AF, such as hypertension, congestive heart failure, left ventricular hypertrophy, coronary artery disease, diabetes, and obstructive sleep apnea, are also increasing. The number of individuals with AF is expected to double or triple in the next 30 years among people of European descent (Kannel).