阅读说明：本技术 抗FXI/FXIa抗体及其用途 (anti-FXI/FXIa antibodies and uses thereof ) 是由 田海军 刘登念 邓俗俊 马克·P·崔西 王成 郑勇 肖亮 薛彤彤 王晶翼 于 2020-04-06 设计创作，主要内容包括：本发明属于治疗性单克隆抗体领域,具体而言提供了抗FXI/FXIa的抗体或其抗原结合片段,编码它们的核酸分子,制备它们的方法。本发明的抗FXI/FXIa抗体或其抗原结合片段对FXI/FXIa具有特异性和高亲和力,能够有效抑制FXI/FXIa的活性。因此,本发明进一步提供了包含所述抗体或其抗原结合片段的药物组合物,以及其在制备药物中的用途,所述药物用于预防和/或治疗与凝血或血栓栓塞相关的疾病或病症。(The present invention is in the field of therapeutic monoclonal antibodies, and specifically provides antibodies or antigen-binding fragments thereof against FXI/FXIa, nucleic acid molecules encoding them, and methods for preparing them. The anti-FXI/FXIa antibody or the antigen-binding fragment thereof has specificity and high affinity to FXI/FXIa and can effectively inhibit the activity of FXI/FXIa. Accordingly, the invention further provides a pharmaceutical composition comprising the antibody or antigen-binding fragment thereof, and the use thereof in the manufacture of a medicament for the prevention and/or treatment of a disease or disorder associated with coagulation or thromboembolism.)

An antibody or antigen-binding fragment thereof that specifically binds FXI and/or FXIa, comprising:

(a) the following three heavy chain Complementarity Determining Regions (CDRs): CDR-H1, CDR-H2 and CDR-H3 contained in the variable region of the heavy chain (VH) as set forth in any one of SEQ ID NOs:1, 15, 16, 17, 29 and 31; and/or

The following three light chain Complementarity Determining Regions (CDRs): CDR-L1, CDR-L2 and CDR-L3 contained in the light chain variable region (VL) shown in any one of SEQ ID NOs:2, 18, 19, 20, 30 and 32;

or the like, or, alternatively,

(b) the three heavy chain CDRs as follows: (a) the CDR-H1 or a variant comprising an amino acid mutation compared thereto of (a), (a) the CDR-H2 or a variant comprising an amino acid mutation compared thereto of (a), (a) the CDR-H3 or a variant comprising an amino acid mutation compared thereto of (a); and/or

The following three light chain CDRs: (a) the CDR-L1 or a variant thereof containing an amino acid mutation as described in (a), (CDR-L2 or a variant thereof containing an amino acid mutation as described in (a), (CDR-L3 or a variant thereof containing an amino acid mutation as described in (a);

wherein at least one of the three heavy chain CDRs and/or the three light chain CDRs of (b) comprises an amino acid mutation compared to the corresponding CDR of (a), said amino acid mutation being a substitution, deletion or addition of one or several amino acids (e.g. a substitution, deletion or addition of 1, 2 or 3 amino acids); preferably, the substitutions are conservative substitutions;

preferably, the CDRs are defined according to the Kabat, IMGT, Chothia or AbM numbering system;

preferably, the antibody or antigen-binding fragment thereof further comprises Framework Regions (FRs) from human or murine immunoglobulins;

preferably, the antibody or antigen-binding fragment thereof binds to human FXI and/or human FXIa.

The antibody or antigen-binding fragment thereof of claim 1, wherein the antibody or antigen-binding fragment thereof comprises:

(1) the following heavy chain variable region (VH) and/or light chain variable region (VL) wherein the CDRs are defined by the IMGT numbering system:

(1a) a heavy chain variable region (VH) comprising 3 CDRs as follows: the sequence is SEQ ID NO: 3, the sequence is SEQ ID NO: 4, the sequence is SEQ ID NO: 5 CDR-H3; and/or the presence of a gas in the gas,

a light chain variable region (VL) comprising the following 3 CDRs: the sequence is SEQ ID NO: 6, the sequence is SEQ ID NO: 7, the sequence of CDR-L2 of SEQ ID NO: 8 CDR-L3;

or

(1b) A heavy chain variable region (VH) comprising 3 CDRs as follows: the sequence is SEQ ID NO: 33, CDR-H1 of SEQ ID NO: 34, CDR-H2 of SEQ ID NO: 35 CDR-H3; and/or the presence of a gas in the gas,

a light chain variable region (VL) comprising the following 3 CDRs: the sequence is SEQ ID NO: 36, the sequence of CDR-L1 of SEQ ID NO: 37, CDR-L2 of SEQ ID NO: 38 CDR-L3;

(2) the following heavy chain variable region (VH) and/or light chain variable region (VL), wherein the CDRs are defined by the AbM numbering system:

(2a) a heavy chain variable region (VH) comprising 3 CDRs as follows: the sequence is SEQ ID NO: 9, CDR-H1 of SEQ ID NO: 10, the sequence of CDR-H2 of SEQ ID NO: 11 CDR-H3; and/or the presence of a gas in the gas,

a light chain variable region (VL) comprising the following 3 CDRs: the sequence is SEQ ID NO: 12, CDR-L1 of SEQ ID NO: 13, CDR-L2 of SEQ ID NO: 14 CDR-L3;

or

(2b) A heavy chain variable region (VH) comprising 3 CDRs as follows: the sequence is SEQ ID NO: 39 of SEQ ID NO: 40, the sequence of CDR-H2 of SEQ ID NO: 41 CDR-H3; and/or the presence of a gas in the gas,

a light chain variable region (VL) comprising the following 3 CDRs: the sequence is SEQ ID NO: 42, CDR-L1 of SEQ ID NO: 43, the sequence of CDR-L2 of SEQ ID NO: CDR-L3 of 44;

or

(3) A heavy chain variable region (VH) and/or a light chain variable region (VL) wherein at least one CDR of the heavy chain variable region (VH) and/or the light chain variable region (VL) contains an amino acid mutation which is a substitution, deletion or addition of one or several amino acids or any combination thereof (for example, a substitution, deletion or addition of 1, 2 or 3 amino acids or any combination thereof) as compared with the heavy chain variable region and/or the light chain variable region of any one of (1a), (1b), (2a) or (2 b); preferably, the substitutions are conservative substitutions;

preferably, the antibody or antigen-binding fragment thereof comprises Framework Regions (FRs) from human or murine immunoglobulins in the VH and/or VL;

preferably, the antibody or antigen-binding fragment thereof binds to human FXI and/or human FXIa.

The antibody or antigen-binding fragment thereof of claim 1 or 2, wherein the antibody or antigen-binding fragment thereof comprises:

(a) SEQ ID NOs: 1. 15, 16, 17, and/or, the VH of any one of SEQ ID NOs: 2. 18, 19, 20; or

(b) SEQ ID NOs: 29. 31, and/or, the VH of any one of SEQ ID NOs: 30. 32 VL as shown in any one of;

or, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) that is at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the VH of either group (a) or (b); and/or the antibody or antigen-binding fragment thereof comprises a light chain variable region (VL) that is at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the VL of either of (a) or (b);

alternatively, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) having one or more amino acid substitutions, deletions or additions or any combination thereof (e.g., 1, 2, 3, 4 or 5 amino acid substitutions, deletions or additions or any combination thereof) as compared to the VH of either group (a) or (b); and/or the antibody or antigen-binding fragment thereof comprises a light chain variable region (VL) having one or more amino acid substitutions, deletions or additions or any combination thereof (e.g., 1, 2, 3, 4 or 5 amino acid substitutions, deletions or additions or any combination thereof) as compared to the VL of either group (a) or (b); preferably, the substitutions are conservative substitutions.

The antibody or antigen-binding fragment thereof of any one of claims 1-3, wherein the antibody or antigen-binding fragment thereof comprises:

(a) SEQ ID NO: 1 and the VH and SEQ ID NO:2, VL is a sequence shown in seq id no;

(b) SEQ ID NO: 15 and the VH and SEQ ID NO: 18, VL of the sequence set forth in seq id no;

(c) SEQ ID NO: 15 and the VH and SEQ ID NO: 20, VL of the sequence set forth in seq id no;

(d) SEQ ID NO: 16 and the VH and SEQ ID NO: 18, VL of the sequence set forth in seq id no;

(e) SEQ ID NO: 17 and VH of the sequence shown in SEQ ID NO: 19 VL of the sequence set forth in seq id no;

(f) SEQ ID NO: 17 and VH of the sequence shown in SEQ ID NO: 18, VL of the sequence set forth in seq id no;

(g) SEQ ID NO: 29 and the VH of the sequence shown in SEQ ID NO: 30, VL is a sequence shown as 30; or

(h) SEQ ID NO: 31 and the VH and SEQ ID NO: 32, VL of the sequence set forth in seq id no;

or, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL) that are at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the VH and VL in any one of groups (a) through (h); and/or, a light chain variable region (VL) thereof has at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity;

alternatively, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL) having one or more amino acid substitutions, deletions, or additions or any combination thereof (e.g., 1, 2, 3, 4, or 5 amino acid substitutions, deletions, or additions or any combination thereof) compared to the VH and VL of any one of groups (a) to (h); and/or, a light chain variable region (VL) thereof has one or more amino acid substitutions, deletions or additions or any combination thereof (e.g., 1, 2, 3, 4 or 5 amino acid substitutions, deletions or additions or any combination thereof); preferably, the substitutions are conservative substitutions.

The antibody or antigen-binding fragment thereof of any one of claims 1-4, wherein the antibody or antigen-binding fragment thereof is a murine, chimeric, or humanized antibody.

The antibody or antigen-binding fragment thereof of any one of claims 1-5, wherein the antibody or antigen-binding fragment thereof further comprises:

(a) a heavy chain constant region (CH) of a human immunoglobulin or a variant thereof having one or more amino acid substitutions, deletions or additions, or any combination thereof (e.g., substitutions, deletions or additions of up to 20, up to 15, up to 10, up to 5, 4,3, 2 or 1 amino acids, or any combination thereof), as compared to the wild type sequence from which it is derived; and/or

(b) A light chain constant region (CL) of a human immunoglobulin or a variant thereof having one or more amino acid substitutions, deletions or additions, or any combination thereof (e.g., substitutions, deletions or additions of up to 20, up to 15, up to 10, up to 5, 4,3, 2 or 1 amino acids, or any combination thereof), as compared to the wild-type sequence from which it is derived;

preferably, the heavy chain constant region is an IgG heavy chain constant region, e.g., an IgG1, IgG2, IgG3, or IgG4 heavy chain constant region;

preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region selected from the group consisting of:

(1) human IgG1 heavy chain constant region; or the like, or, alternatively,

(2) human IgG4 heavy chain constant region;

preferably, the antibody or antigen binding fragment thereof comprises an amino acid sequence as set forth in SEQ ID NO:21 or a variant thereof which is identical to SEQ ID NO:21 has conservative substitutions of up to 20 amino acids (e.g., substitutions, deletions or additions of up to 20, up to 15, up to 10, up to 5, 4,3, 2, or 1 amino acids, or any combination thereof);

preferably, the light chain constant region is a kappa light chain constant region;

preferably, the antibody or antigen binding fragment thereof comprises an amino acid sequence as set forth in SEQ ID NO:22 or a variant thereof which is identical to SEQ ID NO:22 with conservative substitutions of up to 20 amino acids (e.g., substitutions, deletions or additions of up to 20, up to 15, up to 10, up to 5, 4,3, 2, or 1 amino acid, or any combination thereof);

more preferably, the antibody or antigen-binding fragment thereof comprises an amino acid sequence as set forth in SEQ ID NO:21 and a heavy chain constant region (CH) as set forth in SEQ ID NO:22 (CL) to the light chain constant region.

The antibody or antigen-binding fragment thereof of any one of claims 1-6, wherein the antibody or antigen-binding fragment thereof comprises:

(a) a heavy chain comprising an amino acid sequence selected from the group consisting of:

(i) comprises the amino acid sequence of SEQ ID NO: 15 and the VH and SEQ ID NO:21, the sequence of the heavy chain constant region (CH);

(ii) (ii) a sequence having one or more amino acid substitutions, deletions or additions or any combination thereof (e.g., 1, 2, 3, 4 or 5 amino acid substitutions, deletions or additions or any combination thereof) as compared to the sequence set forth in (i); or

(iii) (ii) a sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to a sequence set forth in (i); and/or

A light chain comprising an amino acid sequence selected from the group consisting of:

(iv) comprises the amino acid sequence of SEQ ID NO: 18 and SEQ ID NO:22, the sequence of a light chain constant region (CL);

(v) (iii) a sequence having one or more amino acid substitutions, deletions or additions or any combination thereof (e.g., 1, 2, 3, 4 or 5 amino acid substitutions, deletions or additions or any combination thereof) as compared to the sequence set forth in (iv); or

(vi) (iii) a sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the sequence set forth in (iv);

or

(b) A heavy chain comprising an amino acid sequence selected from the group consisting of:

(i) comprises the amino acid sequence of SEQ ID NO: 31 and the VH shown in SEQ ID NO:21, the sequence of the heavy chain constant region (CH);

(ii) (ii) a sequence having one or more amino acid substitutions, deletions or additions or any combination thereof (e.g., 1, 2, 3, 4 or 5 amino acid substitutions, deletions or additions or any combination thereof) as compared to the sequence set forth in (i); or

(iii) (ii) a sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to a sequence set forth in (i); and/or

A light chain comprising an amino acid sequence selected from the group consisting of:

(iv) comprises the amino acid sequence of SEQ ID NO: 32 and the VH shown in SEQ ID NO:22, the sequence of a light chain constant region (CL);

(v) (iii) a sequence having one or more amino acid substitutions, deletions or additions or any combination thereof (e.g., 1, 2, 3, 4 or 5 amino acid substitutions, deletions or additions or any combination thereof) as compared to the sequence set forth in (iv); or

(vi) (iii) a sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the sequence set forth in (iv);

preferably, the substitutions described in (ii) or (v) are conservative substitutions.

The antibody or antigen-binding fragment thereof of any one of claims 1-7, wherein the antibody is selected from any one of the group consisting of:

(a) comprises the amino acid sequence of SEQ ID NO: 15 and the VH and SEQ ID NO:21, and a heavy chain comprising the heavy chain constant region (CH) set forth in SEQ ID NO: 18 and SEQ ID NO:22, a light chain of a light chain constant region (CL);

(b) comprises the amino acid sequence of SEQ ID NO: 15 and the VH and SEQ ID NO:21, and a heavy chain comprising the heavy chain constant region (CH) set forth in SEQ ID NO: 20 and SEQ ID NO:22, a light chain of a light chain constant region (CL);

(c) comprises the amino acid sequence of SEQ ID NO: 16 and SEQ ID NO:21, and a heavy chain comprising the heavy chain constant region (CH) set forth in SEQ ID NO: 18 and SEQ ID NO:22, a light chain of a light chain constant region (CL);

(d) comprises the amino acid sequence of SEQ ID NO: 17 and SEQ ID NO:21, and a heavy chain comprising the heavy chain constant region (CH) set forth in SEQ ID NO: 19 and the VL shown in SEQ ID NO:22, a light chain of a light chain constant region (CL);

(e) comprises the amino acid sequence of SEQ ID NO: 17 and SEQ ID NO:21, and a heavy chain comprising the heavy chain constant region (CH) set forth in SEQ ID NO: 18 and SEQ ID NO:22, a light chain of a light chain constant region (CL);

(f) comprises the amino acid sequence of SEQ ID NO: 31 and the VH shown in SEQ ID NO:21, and a heavy chain comprising the heavy chain constant region (CH) set forth in SEQ ID NO: 32 and the VL shown in SEQ ID NO:22, and a light chain of a light chain constant region (CL).

The antibody or antigen-binding fragment thereof of any one of claims 1-8, wherein the antibody or antigen-binding fragment thereof is selected from the group consisting of ScFv, Fab ', (Fab')₂Fv fragments, disulfide-linked Fv (dsfv), and diabodies (diabodies).

The antibody or antigen-binding fragment thereof of any one of claims 1-9, wherein the antibody or antigen-binding fragment thereof is labeled;

preferably, the antibody or antigen-binding fragment thereof carries a detectable label, such as an enzyme (e.g., horseradish peroxidase), a radionuclide, a fluorescent dye, a luminescent substance (e.g., a chemiluminescent substance), or biotin.

The antibody or antigen-binding fragment thereof of any one of claims 1-10, wherein the antibody or antigen-binding fragment thereof has at least one of the following properties:

(a) binds FXI and/or FXIa (e.g., human FXI and/or human FXIa) with a KD of less than about 100nM, e.g., less than about 10nM, 1nM, 0.1nM, or lower; preferably, the KD is measured by the biofilm interference technique (BLI);

(b) binds FXI and/or FXIa (e.g., human FXI and/or human FXIa) with an EC50 of less than about 500nM, e.g., less than about 100nM, 10nM, 1nM, 0.9nM, 0.8nM, 0.7nM, 0.6nM, 0.5nM, 0.4nM, 0.3nM, 0.2nM, 0.1nM, or less; preferably, the EC50 is measured by flow cytometry or by cell competition ELISA;

(c) binding of the antibody or antigen-binding fragment thereof to FXI and/or FXIa inhibits or blocks binding of FXI and/or FXIa to a substrate, thereby prolonging coagulation time;

(d) binding of the antibody or antigen-binding fragment thereof to FXI and/or FXIa inhibits or blocks the catalytic effect of FXI and/or FXIa on a substrate;

(e) binding of the antibody or antigen-binding fragment thereof to FXI and/or FXIa does not affect extrinsic coagulation;

(f) the antibody or antigen-binding fragment thereof has reduced ADCC and/or CDC activity;

(g) the antibody or antigen-binding fragment thereof has no ADCC and/or CDC activity;

(h) binding of said antibody or antigen-binding fragment thereof to FXI and/or FXIa inhibits or blocks formation of FXI and/or FXIa respective dimers;

(i) the binding of said antibody or antigen-binding fragment thereof to FXI and/or FXIa inhibits or blocks the formation of complexes of FXI and/or FXIa with high molecular weight kininogen (HK);

(j) said antibody or antigen-binding fragment thereof binds to and/or induces a conformational change in FXI and/or FXIa;

(k) the antibody or antigen-binding fragment thereof inhibits or blocks FXI and/or FXIa binding to platelet receptors; or

(l) Any combination of (a) - (k).

An isolated nucleic acid molecule encoding the antibody or antigen binding fragment thereof of any one of claims 1-11, a heavy chain and/or light chain thereof, or a heavy chain variable region and/or light chain variable region thereof.

The isolated nucleic acid molecule of claim 12, comprising a nucleic acid molecule encoding an antibody heavy chain variable region, and/or a nucleic acid molecule encoding an antibody light chain variable region, wherein,

the nucleic acid molecule encoding the variable region of the antibody heavy chain has a nucleotide sequence selected from the group consisting of:

(a) the nucleotide sequence shown as SEQ ID NO. 23 or 27,

(b) a sequence substantially identical to the nucleotide sequence of (a) (e.g., a sequence having at least about 85%, 90%, 95%, 99% or more identity, or a sequence having one or more nucleotide substitutions, as compared to the nucleotide sequence of (a)), or

(c) A sequence that differs from the nucleotide sequence of (a) by no more than 3, 6, 15, 30 or 45 nucleotides;

and/or the presence of a gas in the gas,

the nucleic acid molecule encoding the variable region of the antibody light chain has a nucleotide sequence selected from the group consisting of:

(d) the nucleotide sequence shown as SEQ ID NO. 24 or 28,

(e) a sequence substantially identical to the nucleotide sequence of (d) (e.g., a sequence having at least about 85%, 90%, 95%, 99% or more identity, or a sequence having one or more nucleotide substitutions, as compared to the nucleotide sequence of (d)), or

(f) A sequence that differs from the nucleotide sequence of (d) by no more than 3, 6, 15, 30 or 45 nucleotides;

preferably, the nucleic acid molecule encoding the variable region of the antibody heavy chain has the nucleotide sequence shown as SEQ ID NO. 23, and/or the nucleic acid molecule encoding the variable region of the antibody light chain has the nucleotide sequence shown as SEQ ID NO. 24;

preferably, the nucleic acid molecule encoding the variable region of the antibody heavy chain has the nucleotide sequence shown as SEQ ID NO. 27, and/or the nucleic acid molecule encoding the variable region of the antibody light chain has the nucleotide sequence shown as SEQ ID NO. 28.

The isolated nucleic acid molecule of any one of claims 12-13, comprising a nucleic acid molecule encoding an antibody heavy chain, and/or a nucleic acid molecule encoding an antibody light chain, wherein,

the nucleic acid molecule encoding the heavy chain of the antibody has a nucleotide sequence selected from the group consisting of:

(a) the nucleotide sequence shown as SEQ ID NO. 25,

(b) a sequence substantially identical to the nucleotide sequence of (a) (e.g., a sequence having at least about 85%, 90%, 95%, 99%, or 100% identity, or a sequence having one or more nucleotide substitutions, as compared to the nucleotide sequence of (a)), or

(c) A sequence that differs from the nucleotide sequence of (a) by no more than 3, 6, 15, 30 or 45 nucleotides;

and/or the presence of a gas in the gas,

the nucleic acid molecule encoding the light chain of an antibody has a nucleotide sequence selected from the group consisting of:

(d) 26 as shown in SEQ ID NO,

(e) a sequence substantially identical to the nucleotide sequence of (d) (e.g., a sequence having at least about 85%, 90%, 95%, 99%, or 100% identity, or a sequence having one or more nucleotide substitutions, as compared to the nucleotide sequence of (d)), or

(f) A sequence that differs from the nucleotide sequence of (d) by no more than 3, 6, 15, 30 or 45 nucleotides;

preferably, the nucleic acid molecule encoding the heavy chain of the antibody has the nucleotide sequence shown as SEQ ID NO. 25, and/or the nucleic acid molecule encoding the light chain of the antibody has the nucleotide sequence shown as SEQ ID NO. 26.

A vector comprising the isolated nucleic acid molecule of any one of claims 12-14; preferably, the vector is a cloning vector or an expression vector.

A host cell comprising the isolated nucleic acid molecule of any one of claims 12-14 or the vector of claim 15.

A method of making the antibody or antigen-binding fragment thereof of any one of claims 1-11, comprising culturing the host cell of claim 16 under conditions that allow expression of the antibody or antigen-binding fragment thereof, and recovering the antibody or antigen-binding fragment thereof from the cultured host cell culture.

A multispecific antibody comprising an antibody or antigen-binding fragment thereof, which specifically binds FXI and/or FXIa, as claimed in any one of claims 1 to 11, and a further antibody or antigen-binding fragment thereof, or antibody analog;

preferably, the multispecific antibody is a bispecific antibody or a trispecific antibody or a tetraspecific antibody.

A conjugate comprising an antibody or antigen-binding fragment thereof that specifically binds FXI and/or FXIa according to any of claims 1-11 and a coupling moiety, wherein the coupling moiety is a detectable label such as a radioisotope, fluorescent substance, luminescent substance, colored substance, or enzyme, or the coupling moiety is a therapeutic agent;

optionally, the therapeutic agent is an antiplatelet drug, an anticoagulant drug, or a thrombolytic drug;

optionally, the therapeutic agent binds to an antibody or antigen-binding fragment thereof of any one of claims 1 to 11 that specifically binds FXI and/or FXIa via a linker.

A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof of any one of claims 1-11, the isolated nucleic acid molecule of any one of claims 12-14, the vector of claim 15, the host cell of claim 16, the multispecific antibody of claim 18, or the conjugate of claim 19, and a pharmaceutically acceptable carrier and/or excipient;

preferably, the pharmaceutical composition further comprises an additional pharmaceutically active agent, such as an antiplatelet agent, an anticoagulant agent, or a thrombolytic agent;

more preferably, the additional pharmaceutically active agent is aspirin, clopidogrel, prasugrel, ticagrelor, abciximab, eptifibatide, vorapazamide, heparin, low molecular heparin, warfarin, fondaparinux sodium, edoxaban, betrixaban, rivaroxaban, apixaban, dabigatran etexilate, argatroban, bivalirudin, streptokinase, urokinase, alteplase, prourokinase, or any combination thereof.

The pharmaceutical composition of claim 20, wherein the effective amount of the antibody or antigen-binding fragment thereof in the pharmaceutical composition is sufficient to elicit at least one of the following biological activities in a subject:

(a) bind to and/or induce a conformational change in the catalytic domain of FXI and/or FXIa;

(b) inhibiting or blocking binding of FXI and/or FXIa to a substrate;

(c) inhibiting or blocking FXI and/or FXIa binding to platelet receptors;

(d) inhibiting or blocking binding of FXI to factor xiia (fxiia), thereby inhibiting or blocking conversion of FXI to active FXIa;

(e) inhibiting or blocking binding of FXIa and coagulation factor FIX, thereby inhibiting or blocking conversion of FIX to active FIXa;

(f) inhibits or blocks FXI and/or FXIa mediated activation of the endogenous coagulation pathway;

(g) inhibiting or blocking the activity of FXI and/or FXIa in thrombosis;

(h) prolonging FXI and/or FXIa mediated clotting time;

(i) inhibiting thrombosis;

(j) preventing and/or treating FXI and/or FXIa mediated coagulation or thromboembolism related disorders or diseases; or

(k) Any combination of (a) - (j).

The pharmaceutical composition of claim 20 or 21, further comprising a second antibody or a nucleic acid encoding said second antibody, wherein said second antibody is another antibody recognizing a different epitope of FXI or FXIa or an antibody specifically binding a receptor or ligand selected from the group consisting of: thrombin (thrombin), Antiplasmin (Antiplasmin), Factor twelve (Factor XII), Factor eight (Factor VIII), Factor seven (Factor VII), Factor ten (Factor X), Factor IX (Factor IX), Factor II, Tissue Factor (Tissue Factor), P-selectin and its ligands, L-selectin and its ligands, or any combination of the above antibodies.

A kit comprising the antibody or antigen-binding fragment thereof of any one of claims 1-11, or the vector of claim 15, or the host cell of claim 16, or the multispecific antibody of claim 18, the conjugate of claim 19, or the pharmaceutical composition of any one of claims 20-22, and optionally instructions for use.

Use of the antibody or antigen-binding fragment thereof of any one of claims 1-11, or the isolated nucleic acid molecule of any one of claims 12-14, or the vector of claim 15, or the host cell of claim 16, or the multispecific antibody of claim 18, the conjugate of claim 19, or the pharmaceutical composition of any one of claims 20-22 in the manufacture of a medicament for the prevention and/or treatment of a disease or disorder associated with coagulation or thromboembolism.

Use of the antibody or antigen-binding fragment thereof of any one of claims 1-11, or the isolated nucleic acid molecule of any one of claims 12-14, or the vector of claim 15, or the host cell of claim 16, or the multispecific antibody of claim 18, the conjugate of claim 19, or the pharmaceutical composition of any one of claims 20-22, in the manufacture of a medicament for at least one of the following uses:

(a) bind to and/or induce a conformational change in the catalytic domain of FXI and/or FXIa;

(b) inhibiting or blocking binding of FXI and/or FXIa to a substrate;

(c) inhibiting or blocking FXI and/or FXIa binding to platelet receptors;

(d) inhibiting or blocking binding of FXI and factor xiia (fxiia), thereby inhibiting conversion of FXI to active FXIa;

(e) inhibiting or blocking FXIa binding to coagulation factor FIX, thereby inhibiting FIX conversion to active FIXa;

(f) inhibits or blocks FXI and/or FXIa mediated activation of the endogenous coagulation pathway;

(g) inhibiting or blocking the activity of FXI and/or FXIa in thrombosis;

(h) prolonging FXI and/or FXIa mediated clotting time;

(i) inhibiting thrombosis;

(j) preventing and/or treating FXI and/or FXIa mediated diseases or conditions associated with coagulation or thromboembolism; or

(k) Any combination of (a) - (j).

The use according to claim 24 or 25, wherein the disease or condition associated with coagulation or thromboembolism is selected from the group consisting of: thrombosis, thrombotic stroke, atrial fibrillation, stroke prophylaxis associated with atrial fibrillation (SPAF), deep vein thrombosis, venous thromboembolism, Acute Coronary Syndrome (ACS), ischemic stroke, acute limb ischemia, chronic thromboembolic pulmonary hypertension, systemic embolism, Myocardial Infarction (MI), Acute Myocardial Infarction (AMI), stable angina, unstable angina, reocclusion and restenosis following coronary intervention, Peripheral Arterial Occlusive Disease (PAOD), renal venous thrombosis, Transient Ischemic Attack (TIA), pulmonary thromboembolism, disseminated intravascular coagulation, thromboembolic disorders induced by medical devices (e.g., catheters), severe systemic inflammatory response syndrome, metastatic cancer, infectious disease, organ failure (e.g., renal failure), toxicity resulting from in vivo administration of therapeutic proteins, and the like, Multiple trauma, ischemia reperfusion injury, localized fibrin deposition, adult alveolar proteinosis, thromboembolic events (VTE) before and after joint replacement (TKA) surgery, coronary heart disease, post-myocardial thromboembolism, stroke in patients with non-valvular atrial fibrillation, thrombosis and thromboembolism in chronic kidney disease, thrombosis and thromboembolism in patients undergoing hemodialysis and in patients undergoing oxidation of the outer membrane, Deep Vein Thrombosis (DVT), or Pulmonary Embolism (PE).

A method for preventing and/or treating, and/or delaying the onset, and/or reducing or inhibiting the recurrence of, a disease or disorder associated with coagulation or thromboembolism in a subject, said subject being a mammal, comprising administering to a subject in need thereof an effective amount of the antibody or antigen-binding fragment thereof of any one of claims 1-11, or the isolated nucleic acid molecule of any one of claims 12-14, or the vector of claim 15, or the host cell of claim 16, or the multispecific antibody of claim 18, the conjugate of claim 19, or the pharmaceutical composition of any one of claims 20-22; preferably, the subject is a human.

The method of claim 27, further comprising administering to the subject a second therapy comprising administering a second drug selected from one or more of an antiplatelet drug, an anticoagulant drug, a thrombolytic drug;

preferably, the second drug is selected from aspirin, clopidogrel, prasugrel, ticagrelor, abciximab, eptifibatide, verapamil, heparin, low molecular heparin, warfarin, fondaparinux sodium, edoxaban, betrixaban, rivaroxaban, apixaban, dabigatran etexilate, argatroban, bivalirudin, streptokinase, urokinase, alteplase, prourokinase, or any combination thereof.

The method of claim 27 or 28, wherein the disease or disorder associated with blood coagulation or thromboembolism is selected from the group consisting of thrombosis, thrombotic stroke, atrial fibrillation, stroke prevention associated with atrial fibrillation (SPAF), deep vein thrombosis, venous thromboembolism, Acute Coronary Syndrome (ACS), ischemic stroke, acute limb ischemia, chronic thromboembolic pulmonary hypertension, systemic embolism, Myocardial Infarction (MI), Acute Myocardial Infarction (AMI), stable angina, unstable angina, reocclusion and restenosis following coronary intervention, Peripheral Arterial Occlusive Disease (PAOD), renal venous thrombosis, Transient Ischemic Attack (TIA), pulmonary thromboembolism, disseminated intravascular coagulation, thromboembolic disorders induced by medical devices such as catheters, severe systemic inflammatory response syndrome, Metastatic cancer, infectious diseases, organ failure (e.g., renal failure), toxicity from in vivo administration of therapeutic proteins, multiple trauma, ischemia reperfusion injury, localized fibrin deposition, adult alveolar proteinosis, thromboembolic events (VTE) prior to and after joint replacement (TKA) surgery, coronary heart disease, post-myocardial thromboembolism, stroke in patients with non-valvular atrial fibrillation, thrombosis and thromboembolism in chronic kidney disease, thrombosis and thromboembolism in patients undergoing hemodialysis and in patients undergoing extracorporeal membrane oxidation, Deep Vein Thrombosis (DVT), or Pulmonary Embolism (PE).

A method of detecting the presence or level of FXI and/or FXIa in a sample comprising contacting the sample with an antibody or antigen-binding fragment thereof according to any one of claims 1 to 11, or a conjugate according to claim 19, under conditions that allow the formation of a complex between the antibody or antigen-binding fragment thereof and FXI and/or FXIa, and detecting the formation of the complex.