Anti-factor XII/XIIa antibodies and uses thereof
AssigneeRegeneron Pharmaceuticals, Inc.
InventorsDan Chalothorn, Lori C. Morton, Lyndon Mitnaul, KehDih Lai
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Abstract
The present invention provides monoclonal antibodies that bind to the Factor XII (FXII) protein, and methods of use thereof. In various embodiments of the invention, the antibodies are fully human antibodies that bind to FXII and to the activated form of FXII (FXIIa). In some embodiments, the antibodies of the invention are useful for inhibiting or neutralizing FXII activity, thus providing a means of treating or preventing a disease, disorder or condition associated with thrombosis in humans.
Claims31
An antibody, of antigen-binding fragment thereof, that binds specifically to Factor XII (FXII), wherein the antibody, or antigen-binding fragment thereof, has one or more of the following characteristics:
- (a) is a fully human monoclonal antibody;
- (b) binds to activated Factor XII (FXIIa);
- (c) binds to FXII with a dissociation constant (KD) of less than 3.5 nM at 25° C., as measured in a surface plasmon resonance assay;
- (d) binds to FXII with a KD of less than 17 nM at 37° C., as measured in a surface plasmon resonance assay;
- (e) binds to FXIIa with a KD of less than 5 nM, preferably less than 2.5 nM, at 25° C. as measured in a surface plasmon resonance assay;
- (f) binds to FXIIa with a KD of less than 6.5 nM, preferably less than 2.5 nM, at 37° C. as measured in a surface plasmon resonance assay;
- (g) blocks thrombin generation by intrinsic pathway at a concentration of less than 250 nM, as measured by functional plasma assays;
- and
- (h) blocks thrombin generation by intrinsic pathway without blocking thrombin generation by extrinsic pathway, as measured by functional plasma assays.
An antibody, or antigen-binding fragment thereof, that binds to FXII/FXIIa, wherein the antibody, or antigen-binding fragment thereof, comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within a HCVR and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within a LCVR;
- wherein the HCVR comprises:
- (i) an amino acid sequence selected from the group consisting of SEQ ID NOs:
- 2, 18, 34, and 50,
- (ii) an amino acid sequence having at least 90% identity to the amino acid sequence selected from the group consisting of SEQ ID NOs:
- 2, 18, 34, and 50,
- (iii) an amino acid sequence having at least 95% identity to the amino acid sequence selected from the group consisting of SEQ ID NOs:
- 2, 18, 34, and 50;
- or
- (iv) an amino acid sequence selected from the group consisting of SEQ ID NOs:
- 2, 18, 34, and 50 having no more than 12 amino acid substitutions;
- and the LCVR comprises:
- (i) an amino acid sequence selected from the group consisting of SEQ ID NOs:
- 10, 26, 42, and 58,
- (ii) an amino acid sequence having at least 90% identity to the amino acid sequence selected from the group consisting of SEQ ID NOs:
- 10, 26, 42, and 58,
- (iii) an amino acid sequence having at least 95% identity to the amino acid sequence selected from the group consisting of SEQ ID NOs:
- 10, 26, 42, and 58;
- or
- (iv) an amino acid sequence selected from the group consisting of SEQ ID NOs:
- 10, 26, 42, and 58 having no more than 10 amino acid substitutions.
Dependencies are inferred from the claim text.