Humanized PAI-1 Antibodies and Uses Thereof

摘要

The present application relates to compositions of humanized anti-PAI-1 antibodies and antigen-binding fragments thereof which convert PAI-1 to its latent form. One aspect relates to antibodies having one or more modifications in at least one amino acid residue of at least one of the framework regions of the variable heavy chain, the variable light chain or both. Another aspect relates to antibodies which bind and neutralize PAI-1 by converting PAI-1 to its latent form or increasing proteolytic cleavage. Another aspect relates to the use of humanized antibodies which inhibit or neutralize PAI-1 for the detection, diagnosis or treatment of a disease or condition associated with PAI-1 or a combination thereof.

主权项

1. An antibody, or antigen-binding fragment thereof, that binds plasminogen activator inhibitor-1 (PAI-1), comprising a heavy chain variable region having an amino acid sequence set forth as SEQ ID NO: 197 and a light chain variable region having an amino acid sequence set forth as SEQ ID NO: 196,
wherein said heavy chain variable region comprises:
(i) a heavy chain CDR 1 having the amino acid sequence of SEQ ID NO: 52 or the amino acid sequence of SEQ ID NO: 52 except for one or more substitutions selected from the group consisting of:(a) a substitution of asparagine (N) by glycine (G) at position 1;(b) a substitution of glycine (G) by tyrosine (Y) at position 3; and(c) a substitution of asparagine (N) by histidine (H) at position 5 utilizing the Kabat numbering system; (ii) a heavy chain CDR2 having the amino acid sequence of SEQ ID NO: 53 or the amino acid sequence of SEQ ID NO: 53 except for one or more substitutions selected from the group consisting of:
(a) a substitution of threonine (T) by proline (P) at position 4;(b) a substitution of tyrosine (Y) by asparagine (N) at position 5;(c) a substitution of threonine (T) by serine (S) at position 6;(d) a substitution of glutamate (E) by glycine (G) at position 8;(e) a substitution of proline (P) by threonine (T) at position 9;(f) a substitution of threonine (T) by asparagine (N) at position 10;(g) a substitution of threonine (T) by alanine (A) at position 12;(h) a substitution of aspartate (D) by glutamine (Q) at position 13;(i) a substitution of aspartate (D) by lysine (K) at position 14; and(j) a substitution of lysine (K) by glutamine (Q) at position 16 utilizing the Kabat numbering system; and (iii) a heavy chain CDR3 having the amino acid sequence of SEQ ID NO: 54 or the amino acid sequence of SEQ ID NO: 54 except for one or more substitutions selected from the group consisting of:
(a) a substitution of lysine (K) by arginine (R) at position 1;(b) a substitution of valine (V) by tyrosine (Y) at position 7 utilizing the Kabat numbering system; and wherein said light chain variable region comprises: (i) a light chain CDR1 having the amino acid sequence of SEQ ID NO: 10 or the amino acid sequence of SEQ ID NO: 10 except for one or more substitutions selected from the group consisting of:
(a) a substitution of leucine (L) by valine (V) at position 6;(b) a substitution of asparagine (N) by tyrosine (Y) at position 8;(c) a substitution of isoleucine (I) by serine (S) at position 9;(d) a substitution of isoleucine (I) by serine (S) at position 10;(e) a substitution of lysine (K) by asparagine (N) at position 11;(f) a substitution of glutamine (Q) by asparagine (N) at position 12; and(g) a substitution of cysteine (C) by tyrosine (Y) or leucine (L) at position 15 utilizing the Kabat numbering system; (ii) a light chain CDR2 having the amino acid sequence of SEQ ID NO: 12 or the amino acid sequence of SEQ ID NO: 12 except for one or more conservative substitutions; and (iii) a light chain CDR3 having the amino acid sequence of SEQ ID NO: 13 or the amino acid sequence of SEQ ID NO: 13 except for a substitution of tyrosine (Y) by threonine (T) at position 6 utilizing the Kabat numbering system.