Anti-tryptase antibodies, compositions thereof, and uses thereof
The invention provides compositions including anti-tryptase antibodies and pharmaceutical compositions thereof, as well as methods of using the same.
1. A method of treating asthma in a human subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an isolated antibody that binds to human tryptase beta 1, or an antigen-binding fragment thereof, wherein the antibody comprises the following six hypervariable regions (HVRs):
(a) an HVR-H1 comprising the amino acid sequence of DYGMV (SEQ ID NO: 7);
(b) an HVR-H2 comprising the amino acid sequence of FISSGSSTVYYADTMKG (SEQ ID NO: 2);
(c) an HVR-H3 comprising the amino acid sequence of RNYDDWYFDV (SEQ ID NO: 8);
(d) an HVR-L1 comprising the amino acid sequence of SASSSVTYMY (SEQ ID NO: 4);
(e) an HVR-L2 comprising the amino acid sequence of RTSDLAS (SEQ ID NO: 5); and
(f) an HVR-L3 comprising the amino acid sequence of QHYHSYPLT (SEQ ID NO: 6).
2. The method of claim 1 , wherein the method further comprises administering an additional therapeutic agent to the subject.
3. The method of claim 1 , wherein the antibody is administered subcutaneously, intravenously, intramuscularly, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, or intranasally.
4. The method of claim 1 , wherein the antibody comprises (a) a heavy chain variable (VH) domain comprising an amino sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 9; and (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 10.
5. The method of claim 1 , wherein the VH domain comprises the amino acid sequence of SEQ ID NO: 9 and the VL domain comprises the amino acid sequence of SEQ ID NO: 10.
6. The method of claim 1 , wherein the antibody comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 76 or SEQ ID NO:78 and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 77.
7. The method of claim 1 , wherein the antibody is capable of inhibiting the enzymatic activity of human tryptase beta 1.
8. The method of claim 7 , wherein the antibody binds the tryptase with a K D of between about 120 pM and about 0.5 nM.
9. The method of claim 8 , wherein the antibody binds tryptase with a K D of about 400 pM.
10. The method of claim 7 , wherein the antibody inhibits the activity of tryptase with an 1050 of about 2.5 nM or lower as determined by a human tryptase beta enzymatic assay using a colorimetric synthetic peptide substrate.
11. The method of claim 7 , wherein:
(i) the antibody is capable of inhibiting the enzymatic activity of human tryptase beta 1 at pH 6;
(ii) the antibody is capable of inhibiting tryptase-mediated stimulation of bronchial smooth muscle cell proliferation and/or collagen-based contraction;
(iii) the antibody is capable of inhibiting mast cell histamine release;
(iv) the antibody is capable of inhibiting IgE-triggered histamine release and/or tryptase-triggered histamine release;
(v) the antibody is capable of inhibiting tryptase activity in cynomolgus monkey bronchoalveolar lavage (BAL) or nasosorption samples;
(vi) the antibody is capable of dissociating tetrameric human tryptase beta 1;
(vii) the antibody is capable of dissociating tetrameric human tryptase beta 1 when in a monovalent format; and/or
(viii) the antibody is capable of dissociating tetrameric human tryptase beta 1 in the presence of heparin.
12. The method of claim 1 , wherein the antibody is capable of dissociating both the small interface of tetrameric human tryptase beta 1 and the large interface of tetrameric human tryptase beta 1.
13. The method of claim 1 , wherein the antibody is humanized.
14. The method of claim 1 , wherein the antibody is an IgG antibody.
15. The method of claim 14 , wherein the IgG antibody is an IgG1 antibody or an IgG4 antibody.
16. The method of claim 15 , wherein the IgG4 antibody is a human IgG4 antibody, and said antibody comprises an S228P mutation in the heavy chain constant region according to the EU numbering system.
17. The method of claim 1 , wherein the antibody is a monospecific antibody.
18. The method of claim 1 , wherein the antibody is a multispecific antibody.
19. The method of claim 18 , wherein the multispecific antibody is a bispecific antibody.
20. The method of claim 1 , wherein the antibody is comprised in a pharmaceutical composition comprising a pharmaceutically acceptable carrier, excipient, or diluent.
21. A method of treating mastocytosis in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an isolated antibody that binds to human tryptase beta 1, or an antigen-binding fragment thereof, wherein the antibody comprises the following six HVRs:
(a) an HVR-H1 comprising the amino acid sequence of DYGMV (SEQ ID NO: 7);
(b) an HVR-H2 comprising the amino acid sequence of FISSGSSTVYYADTMKG (SEQ ID NO: 2);
(c) an HVR-H3 comprising the amino acid sequence of RNYDDWYFDV (SEQ ID NO: 8);
(d) an HVR-L1 comprising the amino acid sequence of SASSSVTYMY (SEQ ID NO: 4);
(e) an HVR-L2 comprising the amino acid sequence of RTSDLAS (SEQ ID NO: 5); and
(f) an HVR-L3 comprising the amino acid sequence of QHYHSYPLT (SEQ ID NO: 6).
22. The method of claim 21 , wherein the mastocytosis is nonacute systemic mastocytosis.
23. The method of claim 21 , wherein the antibody comprises (a) a heavy chain variable (VH) domain comprising an amino sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 9; and (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 10.
24. The method of claim 21 , wherein the VH domain comprises the amino acid sequence of SEQ ID NO: 9 and the VL domain comprises the amino acid sequence of SEQ ID NO: 10.
25. The method of claim 21 , wherein the antibody comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 76 or SEQ ID NO:78 and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 77.
26. The method of claim 21 , wherein the antibody is humanized.
27. The method of claim 21 , wherein the antibody is an IgG antibody.
28. The method of claim 27 , wherein the IgG antibody is an IgG1 antibody or an IgG4 antibody.
29. The method of claim 28 , wherein the IgG4 antibody is a human IgG4 antibody, and said antibody comprises an S228P mutation in the heavy chain constant region according to the EU numbering system.
30. The method of claim 21 , wherein the antibody is a monospecific antibody.
31. The method of claim 21 , wherein the antibody is a multispecific antibody.
32. The method of claim 31 , wherein the multispecific antibody is a bispecific antibody.
33. The method of claim 21 , wherein the antibody is comprised in a pharmaceutical composition comprising a pharmaceutically acceptable carrier, excipient, or diluent.