IP Library › Granted Patent US 12,703,762

Granted Patent B2

US 12,703,762 · App. 17/309,713 · Granted Aug 11, 2026

Reversal binding agents for anti-factor XI/XIa antibodies and uses thereof

Inventors: Stefan Ewert (Basel, CH); Andrew Green (Basel, CH); Alexander Wolfgang Koch (Cambridge, MA)

Assignee: Novartis AG

C07K16/4241 C07K2317/21 C07K2317/55 C07K2317/76 C07K2317/92

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Quick Facts

Patent No.: US 12,703,762
App. No.: 17/309,713
Granted: Aug 11, 2026
Kind: B2

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Abstract

The present disclosure relates to reversal agents, which specifically bind to anti-Factor XI and/or anti-Factor XIa antibodies (e.g., NOV1401), and reverse one or more anticoagulant effects of the anti-Factor XI and/or anti-Factor XIa antibodies (e.g., NOV1401), as well as to methods of use thereof, such as methods for reversing anticoagulant effects of such anti-Factor XI and/or anti-Factor XIa antibodies (e.g., NOV1401), and to related methods for managing bleeding or bleeding risks.

Claims (59)

1 . An antibody or antigen-binding fragment thereof that specifically binds to an anti-FXI/FXIa antibody wherein the antibody or antigen-binding fragment comprises a heavy chain variable region (VH) comprising complementarity determining regions HCDR1, HCDR2, and HCDR3, and a light chain variable region (VL) comprising complementarity determining regions LCDR1, LCDR2, and LCDR3, wherein:

(a) the HCDR1 comprises an amino acid sequence selected from SEQ ID NO: 51, 54, 55 and 57, the HCDR2 comprises an amino acid sequence selected from SEQ ID NO: 121, 122, and 123, the HCDR3 comprises an amino acid sequence selected from SEQ ID NO: 53 and 59, the LCDR1 comprises an amino acid sequence selected from SEQ ID NO: 64, 67 and 70, the LCDR2 comprises an amino acid sequence selected from SEQ ID NO: 65 and 68, and the LCDR3 comprises an amino acid sequence selected from SEQ ID NO: 125 and 126;

(b) the HCDR1 comprises an amino acid sequence selected from SEQ ID NO: 51, 54, 55 and 57, the HCDR2 comprises an amino acid sequence selected from SEQ ID NO: 105, 106 and 107, the HCDR3 comprises an amino acid sequence selected from SEQ ID NO: 53 and 59, the LCDR1 comprises an amino acid sequence selected from SEQ ID NO: 64, 67 and 70, the LCDR2 comprises an amino acid sequence selected from SEQ ID NO: 65 and 68, and the LCDR3 comprises an amino acid sequence selected from SEQ ID NO: 66 and 69;

(c) the HCDR1 comprises an amino acid sequence selected from SEQ ID NO: 51, 54, 55 and 57, the HCDR2 comprises an amino acid sequence selected from SEQ ID NO: 75, 76 and 77, the HCDR3 comprises an amino acid sequence selected from SEQ ID NO: 53 and 59, the LCDR1 comprises an amino acid sequence selected from SEQ ID NO: 64, 67 and 70, the LCDR2 comprises an amino acid sequence selected from SEQ ID NO: 65 and 68, and the LCDR3 comprises an amino acid sequence selected from SEQ ID NO: 94 and 95;

(d) the HCDR1 comprises an amino acid sequence selected from SEQ ID NO: 51, 54, 55 and 57, the HCDR2 comprises an amino acid sequence selected from SEQ ID NO: 52, 56 and 58, the HCDR3 comprises an amino acid sequence selected from SEQ ID NO: 53 and 59, the LCDR1 comprises an amino acid sequence selected from SEQ ID NO: 64, 67 and 70, the LCDR2 comprises an amino acid sequence selected from SEQ ID NO: 65 and 68, and the LCDR3 comprises an amino acid sequence selected from SEQ ID NO: 94 and 95;

(e) the HCDR1 comprises an amino acid sequence selected from SEQ ID NO: 51, 54, 55 and 57, the HCDR2 comprises an amino acid sequence selected from SEQ ID NO: 105, 106 and 107, the HCDR3 comprises an amino acid sequence selected from SEQ ID NO: 53 and 59, the LCDR1 comprises an amino acid sequence selected from SEQ ID NO: 64, 67 and 70, the LCDR2 comprises an amino acid sequence selected from SEQ ID NO: 65 and 68, and the LCDR3 comprises an amino acid sequence selected from SEQ ID NO: 94 and 95; or

(f) the HCDR1 comprises an amino acid sequence selected from SEQ ID NO: 51, 54, 55 and 57, the HCDR2 comprises an amino acid sequence selected from SEQ ID NO: 75, 76 and 77, the HCDR3 comprises an amino acid sequence selected from SEQ ID NO: 53 and 59, the LCDR1 comprises an amino acid sequence selected from SEQ ID NO: 64, 67 and 70, the LCDR2 comprises an amino acid sequence selected from SEQ ID NO: 65 and 68, and the LCDR3 comprises an amino acid sequence selected from SEQ ID NO: 66 and 69.

2 . The antibody or antigen-binding fragment of claim 1 , wherein:

(a) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 51, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 52 or 75 or 105, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 53, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 64, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 65, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 94; or

(b) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 51, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 75 or 105, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 53, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 64, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 65, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 66.

3 . The antibody or antigen-binding fragment of claim 2 , wherein

(a) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 51, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 52, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 53, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 64, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 65, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 94;

(b) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 51, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 75, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 53, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 64, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 65, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 94;

(c) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 51, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 105, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 53, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 64, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 65, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 94;

(d) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 51, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 75, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 53, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 64, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 65, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 66: or

(e) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 51, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 105, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 53, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 64, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 65, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 66.

4 . The antibody or antigen-binding fragment of claim 3 , wherein:

(a) the HCDR1, HCDR2 and HCDR3 are as set forth in SEQ ID NOs: 51, 52 and 53, respectively, and the LCDR1, LCDR2, and LCDR3 are as set forth in SEQ ID NOs: 64, 65 and 94, respectively;

(b) the HCDR1, HCDR2 and HCDR3 are as set forth in SEQ ID NOs: 51, 75 and 53, respectively, and the LCDR1, LCDR2, and LCDR3 are as set forth in SEQ ID NOs: 64, 65 and 66, respectively;

(c) the HCDR1, HCDR2 and HCDR3 are as set forth in SEQ ID NOs: 51, 105 and 53, respectively, and the LCDR1, LCDR2, and LCDR3 are as set forth in SEQ ID NOS: 64, 65 and 66, respectively;

(d) the HCDR1, HCDR2 and HCDR3 are as set forth in SEQ ID NOs: 51, 75 and 53, respectively, and the LCDR1, LCDR2, and LCDR3 are as set forth in SEQ ID NOs: 64, 65 and 94, respectively; or

(e) the HCDR1, HCDR2 and HCDR3 are as set forth in SEQ ID NOs: 51, 105 and 53, respectively, and the LCDR1, LCDR2, and LCDR3 are as set forth in SEQ ID NOS: 64, 65 and 94, respectively.

5 . The antibody or antigen-binding fragment claim 3 , wherein the antibody or antigen-binding fragment comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein:

(a) the VH comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 124, and the VL comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 127;

(b) the VH comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 78 or 85, and the VL comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 71;

(c) the VH comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 90 or 60, and the VL comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 96;

(d) the VH comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 108 or 112 and the VL comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 71;

(e) the VH comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 112 and the VL comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 96; or

(f) the VH comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 85 and the VL comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 96.

6 . The antibody or antigen-binding fragment of claim 1 , wherein the antibody or antigen-binding fragment comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein:

(a) the VH comprises the amino acid sequence of SEQ ID NO: 124, and the VL comprises the amino acid sequence of SEQ ID NO: 127;

(b) the VH comprises the amino acid sequence of SEQ ID NO: 78 or 85, and the VL comprises the amino acid sequence of SEQ ID NO: 71;

(c) the VH comprises the amino acid sequence of SEQ ID NO: 90 or 60, and the VL comprises the amino acid sequence of SEQ ID NO: 96;

(d) the VH comprises the amino acid sequence of SEQ ID NO: 108 or 112, and the VL comprises the amino acid sequence of SEQ ID NO: 71;

(e) the VH comprises the amino acid sequence of SEQ ID NO: 112 and the VL comprises the amino acid sequence of SEQ ID NO: 96;

(f) the VH comprises the amino acid sequence of SEQ ID NO: 85 and the VL comprises the amino acid sequence of SEQ ID NO: 96;

(g) the VH comprises the amino acid sequence of SEQ ID NO: 116, and the VL comprises the amino acid sequence of SEQ ID NO: 103;

h) the VH comprises the amino acid sequence of SEQ ID NO: 116, and the VL comprises the amino acid sequence of SEQ ID NO: 73; or

(i) the VH comprises the amino acid sequence of SEQ ID NO: 119, and the VL comprises the amino acid sequence of SEQ ID NO: 103.

7 . The antibody or antigen-binding fragment of claim 1 wherein the antibody or antigen-binding fragment is in a format selected from Fab, Fab′, F(ab′)2, Fv, and scFv.

8 . The antibody or antigen-binding fragment of claim 1 , wherein the antibody is an IgG1, IgG2, IgG3 or IgG4 isotype antibody.

9 . The antibody or antigen-binding fragment of claim 1 , wherein the antibody is an isolated antibody.

10 . The antibody or antigen-binding fragment of claim 1 , wherein the antibody is a monoclonal human antibody.

11 . A polynucleotide comprising one or more nucleotide sequences encoding the antibody or antigen-binding fragment of claim 1 .

12 . A vector comprising the polynucleotide of claim 11 .

13 . A host cell comprising the polynucleotide of claim 11 .

14 . A method of producing a binding agent or an antibody, wherein said method comprises culturing the host cell of claim 13 under suitable conditions for expression of the binding agent or a portion thereof or the antibody, wherein the method optionally comprises purifying the binding agent or the antibody.

15 . A pharmaceutical composition comprising the antibody or antigen-binding fragment of claim 1 .

16 . A method for reversing the anticoagulant effect of an anti-FXI/FXIa antibody in a patient being treated with the anti-FXI/FXIa antibody comprising administering an effective amount of the antibody or antigen-binding fragment of claim 1 to the patient in need thereof.

17 . The method of claim 16 , wherein the anti-FXI/FXIa antibody comprises (i) a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 3 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 7; or (ii) a heavy chain comprising the amino acid sequence of SEQ ID NO: 5 and a light chain comprising the amino acid sequence of SEQ ID NO: 9.

18 . The method of claim 16 , wherein the patient has or is at risk of developing thrombosis.

19 . The method of claim 16 , wherein the patient has

(a) atrial fibrillation;

(b) suspected or confirmed cardiac arrhythmia comprising paroxysmal, persistent or permanent atrial fibrillation or atrial flutter;

(d) valvular heart disease with or without atrial fibrillation;

(e) pulmonary hypertension;

(f) congenital or acquired thrombophilia including but not exclusively factor V Leiden, prothrombin mutation, antithrombin III, protein C and protein S deficiencies, factor XIII mutation, familial dysfibrinogenemia, congenital deficiency of plasminogen, increased levels of factor XI, sickle cell disease, antiphospholipid syndrome, autoimmune disease, chronic bowel disease, nephrotic syndrome, hemolytic uremia, myeloproliferative disease, disseminated intravascular coagulation, paroxysmal nocturnal hemoglobinuria and heparin induced thrombocytopenia; or

(g) chronic kidney disease.