Anti-c-Met antibody showing enhanced stability or antigen-binding fragments thereof

1. An anti-c-Met antibody or an antigen-binding fragment comprising:

(a) an immunoglobulin heavy chain variable domain comprising the structure of FRH1-CDRH1-FRH2-CDRH2-FRH3-CDRH3-FRH4; and

(b) an immunoglobulin light chain variable domain comprising the structure of FRL1-CDRL1-FRL2-CDRL2-FRL3-CDRL3-FRL4:

wherein the CDRH1, the CDRH2, and the CDRH3 comprise the amino acid sequences of SEQ ID NOS: 1, 2, and 3, respectively, and the CDRL1, CDRL2, and CDRL3 comprise the amino acid sequences of SEQ ID NOS: 4, 5, and 6, respectively,

wherein (a) and (b) are selected from the following group:

i) immunoglobulin heavy chain variable domain comprising an amino acid sequence of SEQ ID NO: 11 and immunoglobulin light chain variable domain comprising an amino acid sequence of SEQ ID NO: 18;

ii) immunoglobulin heavy chain variable domain comprising an amino acid sequence of SEQ ID NO: 12 and immunoglobulin light chain variable domain comprising an amino acid sequence of SEQ ID NO: 17;

iii) immunoglobulin heavy chain variable domain comprising an amino acid sequence of SEQ ID NO: 12 and immunoglobulin light chain variable domain comprising an amino acid sequence of SEQ ID NO: 18;

iv) immunoglobulin heavy chain variable domain comprising an amino acid sequence of SEQ ID NO: 14 and immunoglobulin light chain variable domain comprising an amino acid sequence of SEQ ID NO: 17;

v) immunoglobulin heavy chain variable domain comprising an amino acid sequence of SEQ ID NO: 14 and immunoglobulin light chain variable domain comprising an amino acid sequence of SEQ ID NO: 18

vi) immunoglobulin heavy chain variable domain comprising an amino acid sequence of SEQ ID NO: 14 and immunoglobulin light chain variable domain comprising an amino acid sequence of SEQ ID NO: 21;

vii) immunoglobulin heavy chain variable domain comprising an amino acid sequence of SEQ ID NO: 15 and immunoglobulin light chain variable domain comprising an amino acid sequence of SEQ ID NO: 17;

viii) immunoglobulin heavy chain variable domain comprising an amino acid sequence of SEQ ID NO: 15 and immunoglobulin light chain variable domain comprising an amino acid sequence of SEQ ID NO: 18;

ix) immunoglobulin heavy chain variable domain comprising an amino acid sequence of SEQ ID NO: 16 and immunoglobulin light chain variable domain comprising an amino acid sequence of SEQ ID NO: 17; and

x) immunoglobulin heavy chain variable domain comprising an amino acid sequence of SEQ ID NO: 16 and immunoglobulin light chain variable domain comprising an amino acid sequence of SEQ ID NO: 18.

2. The anti-c-Met antibody or antigen-binding fragment of claim 1 , comprising

i) immunoglobulin heavy chain comprising an amino acid sequence of SEQ ID NO: 34 and immunoglobulin light chain comprising an amino acid sequence of SEQ ID NO: 42;

ii) immunoglobulin heavy chain comprising an amino acid sequence of SEQ ID NO: 35 and immunoglobulin light chain comprising an amino acid sequence of SEQ ID NO: 41;

iii) immunoglobulin heavy chain comprising an amino acid sequence of SEQ ID NO: 35 and immunoglobulin light chain comprising an amino acid sequence of SEQ ID NO: 42;

iv) immunoglobulin heavy chain comprising an amino acid sequence of SEQ ID NO: 37 and immunoglobulin light chain comprising an amino acid sequence of SEQ ID NO: 41;

v) immunoglobulin heavy chain comprising an amino acid sequence of SEQ ID NO: 37 and immunoglobulin light chain comprising an amino acid sequence of SEQ ID NO: 42;

vi) immunoglobulin heavy chain comprising an amino acid sequence of SEQ ID NO: 37 and immunoglobulin light chain comprising an amino acid sequence of SEQ ID NO: 45;

vii) immunoglobulin heavy chain comprising an amino acid sequence of SEQ ID NO: 38 and immunoglobulin light chain comprising an amino acid sequence of SEQ ID NO: 41;

viii) immunoglobulin heavy chain comprising an amino acid sequence of SEQ ID NO: 38 and immunoglobulin light chain comprising an amino acid sequence of SEQ ID NO: 42;

ix) immunoglobulin heavy chain comprising an amino acid sequence of SEQ ID NO: 39 and immunoglobulin light chain comprising an amino acid sequence of SEQ ID NO: 41 and

x) immunoglobulin heavy chain comprising an amino acid sequence of SEQ ID NO: 39 and immunoglobulin light chain comprising an amino acid sequence of SEQ ID NO: 42.

3. The anti-c-Met antibody or antigen-binding fragment of claim 1 , wherein the antigen-binding fragment is Fab, Fab′, F(ab′) 2 , Fv, scFv or chemically linked F(ab′) 2 .

4. An anti-c-Met antibody or antigen-binding fragment, comprising:

(a) a heavy chain variable domain comprising CDRH1 (complementarity determining region 1 of heavy chain) of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, and CDRH3 of SEQ ID NO: 3;

(b) an immunoglobulin heavy chain constant domain comprising CH1 (constant domain 1 of heavy chain) of SEQ ID NO: 7;

(c) an immunoglobulin light chain variable domain comprising CDRL1 (complementarity determining region 1 of light chain) of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and CDRL3 of SEQ ID NO: 6; and

(d) an immunoglobulin light chain constant domain comprising Ck (kappa-constant domain) of SEQ ID NO: 8,

wherein at least one of the amino acid residue at position 97 in CH1 of SEQ ID NO: 7 and the amino acid residue at position 2 in Ck of SEQ ID NO: 8 is mutated by substitution with arginine or threonine,

wherein (a) and (b) are selected from the following group:

i) immunoglobulin heavy chain variable domain comprising an amino acid sequence of SEQ ID NO: 11 and immunoglobulin light chain variable domain comprising an amino acid sequence of SEQ ID NO: 18;

ii) immunoglobulin heavy chain variable domain comprising an amino acid sequence of SEQ ID NO: 12 and immunoglobulin light chain variable domain comprising an amino acid sequence of SEQ ID NO: 17;

iii) immunoglobulin heavy chain variable domain comprising an amino acid sequence of SEQ ID NO: 12 and immunoglobulin light chain variable domain comprising an amino acid sequence of SEQ ID NO: 18;

iv) immunoglobulin heavy chain variable domain comprising an amino acid sequence of SEQ ID NO: 14 and immunoglobulin light chain variable domain comprising an amino acid sequence of SEQ ID NO: 17;

v) immunoglobulin heavy chain variable domain comprising an amino acid sequence of SEQ ID NO: 14 and immunoglobulin light chain variable domain comprising an amino acid sequence of SEQ ID NO: 18 vi) immunoglobulin heavy chain variable domain comprising an amino acid sequence of SEQ ID NO: 14 and immunoglobulin light chain variable domain comprising an amino acid sequence of SEQ ID NO: 21;

vii) immunoglobulin heavy chain variable domain comprising an amino acid sequence of SEQ ID NO: 15 and immunoglobulin light chain variable domain comprising an amino acid sequence of SEQ ID NO: 17;

viii) immunoglobulin heavy chain variable domain comprising an amino acid sequence of SEQ ID NO: 15 and immunoglobulin light chain variable domain comprising an amino acid sequence of SEQ ID NO: 18;

ix) immunoglobulin heavy chain variable domain comprising an amino acid sequence of SEQ ID NO: 16 and immunoglobulin light chain variable domain comprising an amino acid sequence of SEQ ID NO: 17; and

x) immunoglobulin heavy chain variable domain comprising an amino acid sequence of SEQ ID NO: 16 and immunoglobulin light chain variable domain comprising an amino acid sequence of SEQ ID NO: 18.

5. The anti-c-Met antibody or antigen-binding fragment of claim 4 , wherein the amino acid residue at position 97 in CH1 of SEQ ID NO: 7 and the amino acid residue at position 2 in Ck of SEQ ID NO: 8 are mutated by substitution with arginine and threonine, respectively.