Anti-CXCR2 antibodies and uses thereof
Disclosed herein are human antibody molecules that immunospecifically bind to human CXCR2. The disclosed human antibody molecules are potent and selective antagonists of CXCR2 functions and prevent the recruitment of neutrophils into tissues without strongly depleting circulating neutrophil numbers. Pharmaceutical compositions, nucleic acid molecules, vectors, cells, and uses of the disclosed antibodies are also provided.
1. A method of treating airway neutrophilia or acute lung inflammation in a subject, the method comprising:
administering to the subject a therapeutically effective amount of a human antibody molecule that immunospecifically binds to human CXCR2 and comprises a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 182, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 192, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 195, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 201, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 205, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 213 to thereby treat the airway neutrophilia or acute lung inflammation.
2. The method of claim 1 , wherein the airway neutrophilia or acute lung inflammation or both are chronic obstructive pulmonary disease, severe neutrophilic asthma, or both.
3. The method of claim 1 , wherein the human antibody molecule comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 108 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 110.
4. The method of claim 1 , wherein the human antibody molecule comprises a human IgG1 heavy chain constant region.
5. The method of claim 4 , wherein the human IgG1 heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 122 or 124.
6. The method of claim 1 , wherein the human antibody molecule comprises a human IgG2 heavy chain constant region.
7. The method of claim 6 , wherein the human IgG2 heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 120.
8. The method of claim 1 , wherein the human antibody molecule comprises a human IgG4 heavy chain constant region.
9. The method of claim 1 , wherein the human antibody molecule is an Fab fragment, an F(ab) 2 fragment, or a single chain antibody.
10. A method of blocking chemotaxis migration of neutrophils into the lungs of a subject, the method comprising exposing neutrophils to a human antibody molecule that immunospecifically binds to human CXCR2 and comprises a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 182, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 192, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 195, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 201, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 205, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 213 to thereby block chemotaxis migration of the neutrophils into the lungs.
11. The method of claim 10 , wherein the human antibody molecule comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 108 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 110.
12. The method of claim 10 , wherein the human antibody molecule comprises a human IgG1 heavy chain constant region.
13. The method of claim 12 , wherein the human IgG1 heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 122 or 124.
14. The method of claim 10 , wherein the human antibody molecule comprises a human IgG2 heavy chain constant region.
15. The method of claim 14 , wherein the human IgG2 heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 120.
16. The method of claim 10 , wherein the human antibody molecule comprises a human IgG4 heavy chain constant region.
17. The method of claim 10 , wherein the human antibody molecule is an Fab fragment, an F(ab)2 fragment, or a single chain antibody.
18. A method of blocking CXCR2 mediated beta-arrestin signaling or CXCR2 mediated calcium flux in response to CXCL1 and/or CXCL5 in a cell expressing CXCR2 in vitro, the method comprising exposing the cell to a human antibody molecule that immunospecifically binds to human CXCR2 and comprises a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 182, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 192, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 195, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 201, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 205, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 213 to thereby block the CXCR2 mediated beta-arrestin signaling or CXCR2 mediated calcium flux.
19. The method of claim 18 , wherein the human antibody molecule comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 108 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 110.
20. The method of claim 18 , wherein the human antibody molecule comprises a human IgG1 heavy chain constant region.
21. The method of claim 20 , wherein the human IgG1 heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 122 or 124.
22. The method of claim 18 , wherein the antibody comprises a human IgG2 heavy chain constant region.
23. The method of claim 22 , wherein the human IgG2 heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 120.
24. The method of claim 18 , wherein the antibody comprises a human IgG4 heavy chain constant region.
25. The method of claim 18 , wherein the antibody molecule is an Fab fragment, an F(ab) 2 fragment, or a single chain antibody.