Humanized anti-C5 antibodies and uses thereof

1. An anti-human C5 antibody or antigen-binding fragment thereof that specifically binds human C5, wherein the anti-human C5 antibody or antigen-binding fragment thereof comprises:

a) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 47, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 57, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 49, a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 23, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 10;

b) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 3, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 4, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 5, a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 8, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 11;

c) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 3, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 4, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 5, a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 14, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 10;

d) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 17, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 4, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 5, a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 8, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 10;

e) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 20, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 4, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 5, a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 23, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 10;

f) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 3, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 5, a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 8, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 29;

g) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 3, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 34, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 5, a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 8, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 10;

h) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 37, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 38, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 39, a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 23, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 10;

i) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 42, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 43, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 44, a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 23, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 10;

j) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 47, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 48, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 49, a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 23, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 10;

k) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 52, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 53, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 54, a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 23, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 10;

l) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 37, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 62, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 39, a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 23, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 10;

m) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 42, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 65, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 44, a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 23, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 10; or

n) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 52, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 68, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 54, a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 23, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 10.

2. The anti-human C5 antibody or antigen-binding fragment thereof of claim 1 , wherein the anti-human C5 antibody or antigen-binding fragment thereof comprises:

a) a VH comprising the amino acid residues 20-144 of SEQ ID NO: 59, or a variant thereof comprising at least about 85% sequence identity to the amino acid residues 20-144 of SEQ ID NO: 59; and a VL comprising the amino acid residues 21-127 of SEQ ID NO: 25, or a variant thereof comprising at least about 85% sequence identity to the amino acid residues 21-127 of SEQ ID NO: 25;

b) a VH comprising the amino acid residues 20-144 of SEQ ID NO: 2, or a variant thereof comprising at least about 85% sequence identity to the amino acid residues 20-144 of SEQ ID NO: 2; and a VL comprising the amino acid residues 21-127 of SEQ ID NO: 13, or a variant thereof comprising at least about 85% identity to amino acid residues 21-127 of SEQ ID NO: 13;

c) a VH comprising the amino acid residues 20-144 of SEQ ID NO: 2, or a variant thereof comprising at least about 85% sequence identity to the amino acid residues 20-144 of SEQ ID NO: 2; and a VL comprising the amino acid residues 21-127 of SEQ ID NO: 16 or a variant thereof comprising at least about 85% identity to residues 21-127 of SEQ ID NO: 16;

d) a VH comprising the amino acid residues 20-144 of SEQ ID NO: 19, or a variant thereof comprising at least about 85% identity to amino acid residues 20-144 of SEQ ID NO: 19; and a VL comprising the amino acid residues 21-127 of SEQ ID NO: 7, or a variant thereof comprising at least about 85% identity to residues 21-127 of SEQ ID NO: 7;

e) a VH comprising the amino acid residues 20-144 of SEQ ID NO: 22, or a variant thereof comprising at least about 85% identity to amino acid residues 20-144 of SEQ ID NO: 22; and a VL comprising the amino acid residues 21-127 of SEQ ID NO: 25, or a variant thereof comprising at least about 85% identity to residues 21-127 of SEQ ID NO: 25;

f) a VH comprising the amino acid residues 20-144 of SEQ ID NO: 28, or a variant thereof comprising at least about 85% identity to amino acid residues 20-144 of SEQ ID NO: 28; and a VL comprising the amino acid residues 21-127 of SEQ ID NO: 31, or a variant thereof comprising at least about 85% identity to residues 21-127 of SEQ ID NO: 31;

g) a VH comprising the amino acid residues 20-144 of SEQ ID NO: 36, or a variant thereof comprising at least about 85% identity to amino acid residues 20-144 of SEQ ID NO: 36; and a VL comprising the amino acid residues 21-127 of SEQ ID NO: 7, or a variant thereof comprising at least about 85% identity to residues 21-127 of SEQ ID NO: 7;

h) a VH comprising the amino acid residues 20-144 of SEQ ID NO: 41, or a variant thereof comprising at least about 85% identity to amino acid residues 20-144 of SEQ ID NO: 41; and a VL comprising the amino acid residues 21-127 of SEQ ID NO: 25, or a variant thereof comprising at least about 85% identity to residues 21-127 of SEQ ID NO: 25;

i) a VH comprising the amino acid residues 20-144 of SEQ ID NO: 46, or a variant thereof comprising at least about 85% identity to amino acid residues 20-144 of SEQ ID NO: 46; and a VL comprising the amino acid residues 21-127 of SEQ ID NO: 25, or a variant thereof comprising at least about 85% identity to residues 21-127 of SEQ ID NO: 25;

j) a VH comprising the amino acid residues 20-144 of SEQ ID NO: 51, or a variant thereof comprising at least about 85% identity to amino acid residues 20-144 of SEQ ID NO: 51; and a VL comprising the amino acid residues 21-127 of SEQ ID NO: 25 or a variant thereof comprising at least about 85% identity to residues 21-127 of SEQ ID NO: 25;

k) a VH comprising the amino acid residues 20-144 of SEQ ID NO: 56, or a variant thereof comprising at least about 85% identity to amino acid residues 20-144 of SEQ ID NO: 56; and a VL comprising the amino acid residues 21-127 of SEQ ID NO: 25, or a variant thereof comprising at least about 85% identity to residues 21-127 of SEQ ID NO: 25;

l) a VH comprising the amino acid residues 20-144 of SEQ ID NO: 64, or a variant thereof comprising at least about 85% identity to amino acid residues 20-144 of SEQ ID NO: 64; and a VL comprising the amino acid residues 21-127 of SEQ ID NO: 25, or a variant thereof comprising at least about 85% identity to residues 21-127 of SEQ ID NO: 25;

m) a VH comprising the amino acid residues 20-144 of SEQ ID NO: 67, or a variant thereof comprising at least about 85% identity to amino acid residues 20-144 of SEQ ID NO: 67; and a VL comprising the amino acid residues 21-127 of SEQ ID NO: 25, or a variant thereof comprising at least about 85% identity to residues 21-127 of SEQ ID NO: 25; or

n) a VH comprising the amino acid residues 20-144 of SEQ ID NO: 70, or a variant thereof comprising at least about 85% identity to amino acid residues 20-144 of SEQ ID NO: 70; and a VL comprising the amino acid residues 21-127 of SEQ ID NO: 25, or a variant thereof comprising at least about 85% identity to residues 21-127 of SEQ ID NO: 25.

3. The anti-human C5 antibody or antigen-binding fragment thereof of claim 2 , wherein the anti-human C5 antibody or antigen-binding fragment thereof comprises:

a) a VH comprising the amino acid residues 20-144 of SEQ ID NO: 59, and a VL comprising the amino acid residues 21-127 of SEQ ID NO: 25;

b) a VH comprising the amino acid residues 20-144 of SEQ ID NO: 2, and a VL comprising the amino acid residues 21-127 of SEQ ID NO: 13;

c) a VH comprising the amino acid residues 20-144 of SEQ ID NO: 2, and a VL comprising the amino acid residues 21-127 of SEQ ID NO: 16;

d) a VH comprising the amino acid residues 20-144 of SEQ ID NO: 19, and a VL comprising the amino acid residues 21-127 of SEQ ID NO: 7;

e) a VH comprising the amino acid residues 20-144 of SEQ ID NO: 22, and a VL comprising the amino acid residues 21-127 of SEQ ID NO: 25;

f) a VH comprising the amino acid residues 20-144 of SEQ ID NO: 28, and a VL comprising the amino acid residues 21-127 of SEQ ID NO: 31;

g) a VH comprising the amino acid residues 20-144 of SEQ ID NO: 36, and a VL comprising the amino acid residues 21-127 of SEQ ID NO: 7;

h) a VH comprising the amino acid residues 20-144 of SEQ ID NO: 41, and a VL comprising the amino acid residues 21-127 of SEQ ID NO: 25;

i) a VH comprising the amino acid residues 20-144 of SEQ ID NO: 46, and a VL comprising the amino acid residues 21-127 of SEQ ID NO: 25;

j) a VH comprising the amino acid residues 20-144 of SEQ ID NO: 51, and a VL comprising the amino acid residues 21-127 of SEQ ID NO: 25;

k) a VH comprising the amino acid residues 20-144 of SEQ ID NO: 56, and a VL comprising the amino acid residues 21-127 of SEQ ID NO: 25;

l) a VH comprising the amino acid residues 20-144 of SEQ ID NO: 64, and a VL comprising the amino acid residues 21-127 of SEQ ID NO: 25;

m) a VH comprising the amino acid residues 20-144 of SEQ ID NO: 67, and a VL comprising the amino acid residues 21-127 of SEQ ID NO: 25; or

n) a VH comprising the amino acid residues 20-144 of SEQ ID NO: 70, and a VL comprising the amino acid residues 21-127 of SEQ ID NO: 25.

4. The anti-human C5 antibody or antigen-binding fragment thereof of claim 1 , wherein the anti-human C5 antibody or antigen-binding fragment thereof is a full-length antibody, a Fab, a Fab′, a F(ab)2, a F(ab′)2, an scFv, or a combination thereof.

5. The anti-human C5 antibody or antigen-binding fragment thereof of claim 1 , wherein the anti-human C5 antibody is a full-length antibody.

6. The anti-human C5 antibody of claim 5 , wherein the anti-human C5 full-length antibody comprises an Fc fragment derived from a human IgG4 Fc.

7. The anti-human C5 antibody of claim 5 , wherein the anti-human C5 full-length antibody comprises:

a) a human IgG4 heavy chain constant domain comprising the amino acid sequence of SEQ ID NO: 32;

b) a human IgG4 heavy chain constant domain comprising the amino acid sequence of SEQ ID NO: 33;

c) a human IgG4 heavy chain constant domain having an S108P mutation, a M308L mutation, and a N314A mutation relative to SEQ ID NO: 32; or

d) a human IgG4 heavy chain constant domain comprising the amino acid sequence of SEQ ID NO: 61.

8. A fusion protein comprising the anti-human C5 antibody or antigen-binding fragment thereof of claim 1 fused to an effector molecule, an FcRn molecule, or a targeting moiety.

9. An isolated nucleic acid encoding the anti-human C5 antibody or antigen-binding fragment thereof of claim 1 .

10. A vector comprising the isolated nucleic acid of claim 9 .

11. The vector of claim 10 , which is a viral vector.

12. The vector of claim 11 , wherein the viral vector is a retrovirus vector, an adenovirus vector, an adeno-associated virus vector, an herpes virus vector, a lentivirus vector, a murine stem cell virus vector, a moloney murine leukemia virus vector, or a human immunodeficiency virus vector.

13. A host cell comprising the isolated nucleic acid of claim 9 .

14. A method of producing an anti-human C5 antibody or antigen-binding fragment thereof, comprising:

i) culturing the host cell of claim 13 under a condition suitable for the expression of the encoded anti-human C5 antibody or antigen-binding fragment thereof; and

ii) recovering the expressed anti-human C5 antibody or antigen-binding fragment thereof from the cell culture.

15. A pharmaceutical composition comprising the anti-human C5 antibody or antigen-binding fragment thereof of claim 1 , and a pharmaceutically acceptable carrier.

16. A method of treating a complement pathway-mediated disease or disorder in an individual, comprising administering to said individual the anti-human C5 antibody or antigen-binding fragment thereof of claim 1 .

17. A method of treating a complement pathway-mediated disease or disorder in an individual, comprising administering to said individual the vector of claim 11 .

18. A method of reducing the activity of a complement system of an individual, wherein the method comprises administering to the individual the anti-human C5 antibody or antigen-binding fragment thereof of claim 1 .

19. The method of claim 16 , wherein the individual is a human.

20. The method of claim 18 , wherein the individual is a human.