Thrombin-binding antibody molecules and uses thereof

A method for producing an antibody antigen-binding domain for the exosite 1 epitope of thrombin, the method comprising;

• (i) providing, by way of addition, deletion, substitution or insertion of one or more amino acids in the amino acid sequence of a parent VH domain comprising HCDR1, HCDR2 and HCDR3,
• wherein the parent VH domain HCDR1, HCDR2 and HCDR3 have the amino acid sequences of SEQ ID NOS:
• 3, 4 and 5 respectively, a VH domain which is an amino acid sequence variant of the parent VH domain,
• (ii) optionally combining the VH domain thus provided with one or more VL domains to provide one or more VH/VL combinations;
• and
• (iii) testing said VH domain which is an amino acid sequence variant of the parent VH domain or the VH/VL combination or combinations to identify an antibody antigen binding domain for the exosite 1 epitope of thrombin.

A method for producing an antibody molecule that specifically binds to the exosite 1 epitope of thrombin, which method comprises:

• providing starting nucleic acid encoding a VH domain or a starting repertoire of nucleic acids each encoding a VH domain, wherein the VH domain or VH domains either comprise a HCDR1, HCDR2 and/or HCDR3 to be replaced or lack a HCDR1, HCDR2 and/or HCDR3 encoding region;
• combining said starting nucleic acid or starting repertoire with donor nucleic acid or donor nucleic acids encoding or produced by mutation of the amino acid sequence of an HCDR1, HCDR2, and/or HCDR3 having the amino acid sequences of SEQ ID NOS:
• 3, 4 and 5 respectively, such that said donor nucleic acid is or donor nucleic acids are inserted into the CDR1, CDR2 and/or CDR3 region in the starting nucleic acid or starting repertoire, so as to provide a product repertoire of nucleic acids encoding VH domains;
• expressing the nucleic acids of said product repertoire to produce product VH domains;
• optionally combining said product VH domains with one or more VL domains;
• selecting an antibody molecule that binds exosite 1 of thrombin, which antibody molecule comprises a product VH domain and optionally a VL domain;
• and
• recovering said antibody molecule or nucleic acid encoding it.