Tissue factor pathway inhibitor antibodies and uses thereof
The invention relates to antibodies, and antigen-binding fragments thereof, that specifically bind TFPI and inhibit an activity thereof. Such antibodies and fragments are useful for treating bleeding disorders and shortening clotting time.
1. An isolated nucleic acid molecule or nucleic acid molecules, comprising a one or more nucleotide sequences encoding an antibody or antigen-binding fragment thereof that specifically binds to an epitope in Kunitz Domain 2 (K2) of Tissue Pathway Factor Inhibitor (TFPI), wherein the antibody or antigen-binding fragment thereof is selected from the group consisting of:
(a) an antibody or antigen-binding fragment thereof comprising a heavy chain variable region (VH) comprising a VH complementarity determining region one (CDR-H1) comprising the amino acid sequence of SEQ ID NO:38, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:39, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:40, and a light chain variable region (VL) comprising a VL complementarity determining region one (CDR-L1) comprising the amino acid sequence of SEQ ID NO:33, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:34, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:35;
(b) an antibody or antigen-binding fragment thereof comprising a VH comprising the amino acid sequence of SEQ ID NO:63 and a VL comprising the amino acid sequence of SEQ ID NO:36;
(c) an antibody or antigen-binding fragment thereof comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:64 and a light chain comprising the amino acid sequence of SEQ ID NO:37;
(d) an antibody or antigen-binding fragment thereof comprising a VH comprising the amino acid sequence of SEQ ID NO:41 and a VL comprising the amino acid sequence of SEQ ID NO: 36; and
(e) an antibody or antigen-binding fragment thereof comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 42 and a light chain comprising the amino acid sequence of SEQ ID NO: 37.
2. The nucleic acid molecule or nucleic acid molecules of claim 1 , wherein the one or more nucleotide sequences encode a VH comprising a CDR-H1 comprising the amino acid sequence of SEQ ID NO:38, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:39, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO:40, and a VL comprising a CDR-L1 comprising the amino acid sequence of SEQ ID NO:33, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:34, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:35.
3. An isolated nucleic acid molecule or nucleic acid molecules, comprising one or more nucleotide sequences encoding an antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:63 and a VL comprising the amino acid sequence of SEQ ID NO:36.
4. An isolated nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of:
(a) the sequence of SEQ ID NO:175;
(b) the sequence of SEQ ID NO:176;
(c) the sequence of SEQ ID NO:177;
(d) the sequence of SEQ ID NO:178;
(e) the sequence of the insert present in the plasmid deposited under ATCC Accession No. PTA-122328; and
(f) the sequence of the insert present in the plasmid deposited under ATCC Accession No. PTA-122329.
5. The nucleic acid molecule of claim 3 , wherein the nucleotide sequence or nucleic acid molecules of claim 1 , wherein the one or more nucleotide sequences encode an antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:64 and a light chain comprising the amino acid sequence of SEQ ID NO:37.
6. The nucleic acid molecule of claim 3 , wherein the nucleotide sequence or nucleic acid molecules of claim 1 , wherein the one or more nucleotide sequences encode an antibody comprising a heavy chain consisting of the amino acid sequence of SEQ ID NO:64 and a light chain consisting of the amino acid sequence of SEQ ID NO:37.
7. The nucleic acid molecule of claim 3 , wherein the antibody is an IgG1 antibody.
8. The nucleic acid molecule of claim 3 , wherein the antibody is a full length IgG1 antibody.