Anti-C5a binding moieties with high blocking activity

1. An antibody or an antigen-binding fragment thereof comprising:

(i) a heavy chain CDR3 sequence as set forth in SEQ ID NO: 6, a light chain CDR3 sequence as set forth in SEQ ID NO: 8, a heavy chain CDR2 sequence according to SEQ ID NO: 10, and a light chain CDR2 sequence according to SEQ ID NO: 12; or

(ii) a heavy chain CDR3 sequence as set forth in SEQ ID NO: 7, a light chain CDR3 sequence as set forth in SEQ ID NO: 9, a heavy chain CDR2 sequence according to SEQ ID NO: 11, and a light chain CDR2 sequence according to SEQ ID NO: 13;

wherein said antibody or said antigen-binding fragment thereof specifically binds to human C5a; and

wherein said antibody or said antigen-binding fragment thereof has a binding constant to human C5a with a Kd value of 100 nM or less.

2. The antibody or the antigen-binding fragment thereof according to claim 1 , further comprising:

(iii) a heavy chain CDR1 sequence according to SEQ ID NO: 14; or

(iv) a heavy chain CDR1 sequence according to SEQ ID NO: 15;

wherein the heavy chain CDR1 sequence optionally has 1 amino acid exchange, 1 amino acid deletion and/or 1 amino acid addition.

3. The antibody or the antigen-binding fragment thereof according to claim 1 , further comprising:

(v) a light chain CDR1 sequence according to SEQ ID NO: 16; or

(vi) a light chain CDR1 sequence according to SEQ ID NO: 17;

wherein the light chain CDR1 sequence optionally has 1 amino acid exchange, 1 amino acid deletion and/or 1 amino acid addition.

4. The antibody or the antigen-binding fragment thereof according to claim 1 , further comprising

(vii) a heavy chain CDR1 sequence according to SEQ ID NO: 14 and a light chain CDR1 sequence according to SEQ ID NO: 16;

or

(viii) a heavy chain CDR1 sequence according to SEQ ID NO: 15 and a light chain CDR1 sequence according to SEQ ID NO: 17;

wherein the heavy chain CDR1 sequence optionally has 1 amino acid exchange, 1 amino acid deletion and/or 1 amino acid addition; and

wherein the light chain CDR1 sequence optionally has 1 amino acid exchange, 1 amino acid deletion and/or 1 amino acid addition.

5. The antibody or the antigen-binding fragment thereof according to claim 1 , wherein said antibody or an antigen-binding fragment thereof comprises one of the following sets of heavy chain CDR3, light chain CDR3, heavy chain CDR2, light chain CDR2, heavy chain CDR1, and light chain CDR1 sequences:

(ix) a heavy chain CDR3 sequence according to SEQ ID NO: 6, a light chain CDR3 sequence according to SEQ ID NO: 8, a heavy chain CDR2 sequence according to SEQ ID NO: 10, a light chain CDR2 sequence according to SEQ ID NO: 12, a heavy chain CDR1 sequence according to SEQ ID NO: 14, and a light chain CDR1 sequence according to SEQ ID NO: 16; or

(x) a heavy chain CDR3 sequence according to SEQ ID NO: 7, a light chain CDR3 sequence according to SEQ ID NO: 9, a heavy chain CDR2 sequence according to SEQ ID NO: 11, a light chain CDR2 sequence according to SEQ ID NO: 13, a heavy chain CDR1 sequence according to SEQ ID NO: 15, and a light chain CDR1 sequence according to SEQ ID NO: 17;

wherein the heavy chain CDR1 sequence optionally has 1 amino acid exchange, 1 amino acid deletion and/or 1 amino acid addition; and

wherein the light chain CDR1 sequence optionally has 1 amino acid exchange, 1 amino acid deletion and/or 1 amino acid addition.

6. The antibody or the antigen-binding fragment thereof according to claim 1 , wherein said antibody or said antigen-binding fragment thereof exhibits one or more of the following properties:

said antibody or said antigen-binding fragment thereof has a binding constant to C5a with a K d value of 10 nM or less;

said antibody or said antigen-binding fragment thereof exhibits at least 80% blocking activity for biological effects induced by one molecule C5a;

said antibody or said antigen-binding fragment thereof does not inhibit CH50 activity in human plasma; and

said antibody or said antigen-binding fragment thereof is capable of reducing E. coli induced IL-8 production in human whole blood.

7. The antibody or the antigen-binding fragment thereof according to claim 1 , wherein said antibody or said antigen-binding fragment is an antibody selected from the group consisting of polyclonal antibodies, monoclonal antibodies, chimeric antibodies, humanized antibodies, and human antibodies.

8. The antibody or the antigen-binding fragment thereof according to claim 1 , wherein said antibody or said antigen-binding fragment is an antigen-binding fragment of an antibody selected from the group consisting of Fab fragments, Fab′ fragments, F(ab′) 2 fragments, Fd fragments, Fv fragments, disulfide-linked Fvs (dsFv), single domain antibodies and single chain Fv (scFv) antibodies.

9. A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof according to claim 1 and further comprising one or more pharmaceutically acceptable carriers, diluents, excipients, fillers, binders, lubricants, glidants, disintegrants, adsorbents, and/or preservatives.

10. A method of blocking C5a-induced biological effects in a patient with acute or chronic inflammation, wherein said method comprises administering to a patient in need of such blocking of C5a-induced biological effects, the pharmaceutical composition of claim 9 .

11. A method for the treatment of a disease involving acute or chronic inflammation, wherein said method comprises administering, to a patient in need of such treatment, the pharmaceutical composition of claim 9 .

12. The method of claim 11 , wherein the disease involving acute or chronic inflammation is selected from the group consisting of systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock, ischemia/reperfusion related injuries, acute lung injury, pneumonia, acute and chronic graft rejection in transplant patients, graft versus host reactions, renal glomerular diseases, glomerulonephritis, entities of renal failure, rheumatoid arthritis, auto-immune diseases, Bechterew's disease, lupus-type diseases, inflammatory bowel disease, Crohn's disease, tumor growth, and solid organ cancer.

13. An antibody or an antigen-binding fragment thereof, wherein said antibody or said antigen-binding fragment thereof comprises one of the following sets of heavy chain CDR3, heavy chain CDR2, and heavy chain CDR1 sequences:

(i) a heavy chain CDR3 sequence according to SEQ ID NO: 6, a heavy chain CDR2 sequence according to SEQ ID NO: 10, and a heavy chain CDR1 sequence according to SEQ ID NO: 14; or

(ii) a heavy chain CDR3 sequence according to SEQ ID NO: 7, a heavy chain CDR2 sequence according to SEQ ID NO: 11, and a heavy chain CDR1 sequence according to SEQ ID NO: 15;

wherein said antibody or said antigen-binding fragment thereof specifically binds to human C5a;

wherein said antibody or antigen-binding fragment thereof has a binding constant to human C5a with a K d value of 100 nM or less; and

wherein the heavy chain CDR1 sequence optionally has 1 amino acid exchange, 1 amino acid deletion and/or 1 amino acid addition.

14. The antibody or the antigen-binding fragment thereof according to claim 13 , wherein said antibody or said antigen-binding fragment thereof exhibits one or more of the following properties:

said antibody or said antigen-binding fragment thereof has a binding constant to C5a with a K d value of 10 nM or less;

said antibody or said antigen-binding fragment thereof exhibits at least 80% blocking activity for biological effects induced by one molecule C5a;

said antibody or said antigen-binding fragment thereof does not inhibit CH50 activity in human plasma; and

said antibody or said antigen-binding fragment thereof is capable of reducing E. coli induced IL-8 production in human whole blood.

15. The antibody or the antigen-binding fragment thereof according to claim 13 , wherein said antibody or said antigen-binding fragment is an antibody selected from the group consisting of polyclonal antibodies, monoclonal antibodies, chimeric antibodies, humanized antibodies, and human antibodies.

16. The antibody or the antigen-binding fragment thereof according to claim 13 , wherein said antibody or said antigen-binding fragment is an antigen-binding fragment of an antibody selected from the group consisting of Fab fragments, Fab′ fragments, F(ab′) 2 fragments, Fd fragments, Fv fragments, disulfide-linked Fvs (dsFv), single domain antibodies and single chain Fv (scFv) antibodies.

17. A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof according to claim 13 and further comprising one or more pharmaceutically acceptable carriers, diluents, excipients, fillers, binders, lubricants, glidants, disintegrants, adsorbents, and/or preservatives.

18. A method of blocking C5a-induced biological effects in a patient with acute or chronic inflammation, wherein said method comprises administering to a patient in need of such blocking of C5a-induced biological effects, the pharmaceutical composition of claim 17 .

19. A method for the treatment of a disease involving acute or chronic inflammation, wherein said method comprises administering, to a patient in need of such treatment, the pharmaceutical composition of claim 17 .

20. The method of claim 19 , wherein the disease involving acute or chronic inflammation is selected from the group consisting of systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock, ischemia/reperfusion related injuries, acute lung injury, pneumonia, acute and chronic graft rejection in transplant patients, graft versus host reactions, renal glomerular diseases, glomerulonephritis, entities of renal failure, rheumatoid arthritis, auto-immune diseases, Bechterew's disease, lupus-type diseases, inflammatory bowel disease, Crohn's disease, tumor growth, and solid organ cancer.

21. An antibody or an antigen-binding fragment thereof, wherein said antibody or said antigen-binding fragment thereof comprises one of the following sets of light chain CDR3, light chain CDR2, and light chain CDR1 sequences:

(i) a light chain CDR3 sequence according to SEQ ID NO: 8, a light chain CDR2 sequence according to SEQ ID NO: 12, and a light chain CDR1 sequence according to SEQ ID NO: 16; or

(ii) a light chain CDR3 sequence according to SEQ ID NO: 9, a light chain CDR2 sequence according to SEQ ID NO: 12, and a light chain CDR1 sequence according to SEQ ID NO: 17;

wherein said antibody or said antigen-binding fragment thereof specifically binds to human C5a;

wherein said antibody or antigen-binding fragment thereof has a binding constant to human C5a with a K d value of 100 nM or less; and

wherein the light chain CDR1 sequence optionally has 1 amino acid exchange, 1 amino acid deletions and/or 1 amino acid addition.

22. The antibody or the antigen-binding fragment thereof according to claim 21 , wherein said antibody or said antigen-binding fragment thereof exhibits one or more of the following properties:

said antibody or said antigen-binding fragment thereof has a binding constant to C5a with a K d value of 10 nM or less;

said antibody or said antigen-binding fragment thereof exhibits at least 80% blocking activity for biological effects induced by one molecule C5a;

said antibody or said antigen-binding fragment thereof does not inhibit CH50 activity in human plasma; and

said antibody or said antigen-binding fragment thereof is capable of reducing E. coli induced IL-8 production in human whole blood.

23. The antibody or the antigen-binding fragment thereof according to claim 21 , wherein said antibody or said antigen-binding fragment is an antibody selected from the group consisting of polyclonal antibodies, monoclonal antibodies, chimeric antibodies, humanized antibodies, and human antibodies.

24. The antibody or the antigen-binding fragment thereof according to claim 21 , wherein said antibody or said antigen-binding fragment is an antigen-binding fragment of an antibody selected from the group consisting of Fab fragments, Fab′ fragments, F(ab′) 2 fragments, Fd fragments, Fv fragments, disulfide-linked Fvs (dsFv), single domain antibodies and single chain Fv (scFv) antibodies.

25. A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof according to claim 21 and further comprising one or more pharmaceutically acceptable carriers, diluents, excipients, fillers, binders, lubricants, glidants, disintegrants, adsorbents, and/or preservatives.

26. A method of blocking C5a-induced biological effects in a patient with acute or chronic inflammation, wherein said method comprises administering to a patient in need of such blocking of C5a-induced biological effects, the pharmaceutical composition of claim 25 .

27. A method for the treatment of a disease involving acute or chronic inflammation, wherein said method comprises administering, to a patient in need of such treatment, the pharmaceutical composition of claim 25 .

28. The method of claim 27 , wherein the disease involving acute or chronic inflammation is selected from the group consisting of systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock, ischemia/reperfusion related injuries, acute lung injury, pneumonia, acute and chronic graft rejection in transplant patients, graft versus host reactions, renal glomerular diseases, glomerulonephritis, entities of renal failure, rheumatoid arthritis, auto-immune diseases, Bechterew's disease, lupus-type diseases, inflammatory bowel disease, Crohn's disease, tumor growth, and solid organ cancer.