HK1-binding proteins
View Patent ↗The invention features hK1 binding polypeptides as well as compositions comprising such polypeptides and methods of making and using such polypeptides.
1. A method of treating or delaying the onset or recurrence of an hK1 associated disorder, wherein the disorder is selected from the group consisting of: asthma, rheumatoid arthritis, osteoarthritis, or at least one symptom thereof, the method comprising:
administering an antibody that comprises an immunoglobulin heavy chain (HC) variable domain sequence and an immunoglobulin light chain (LC) variable domain sequence, wherein the HC variable domain sequence and the LC variable domain sequence form an antigen binding site that binds to hK1 and inhibits enzymatic activity of hK1 (SEQ ID NO:1021) with a Ki of less than 10 nM, said HC variable domain sequence having:
a CDR1 that comprises an amino acid sequence: Xaa1-Tyr-Xaa2-Met-Xaa3 (SEQ ID NO:31), wherein Xaa 1 is selected from Lys and His; Xaa2 is selected from Lys, Val and Ser; Xaa3 is selected from Val, Ile and Thr;
a CDR2 that comprises an amino acid sequence: Xaa1-Ile-Tyr-Pro-Ser-Gly-Gly-Xaa2-Thr-Xaa3-Tyr-Ala-Asp-Ser-Val-Lys-Gly (SEQ ID NO:32), wherein Xaa1 is selected from Ser, Trp and Arg; Xaa2 is selected from Ile, Asn and Arg; Xaa3 is selected from Ala, Ile and Gly; and
a CDR3 that comprises the sequence DITPGGGSGFRLPKNYYYYGMDV (SEQ ID NO:12), VGVWYGMDV (SEQ ID NO:114), or DSGGYYYGMDV (SEQ ID NO:156); and
said LC variable domain sequence having:
a CDR1 that comprises an amino acid sequence: Arg-Ala-Ser-Gln-Ser-Xaa1-Ser-Ser-Xaa2-Xaa3-Xaa4-Xaa5 (SEQ ID NO:284), wherein Xaa1 is selected from Ile and Val; Xaa2 is selected from Tyr and Ser; Xaa3 is selected from Leu and Tyr; Xaa4 is selected from Asn, Ala and Leu; and Xaa5 is Ala or is absent;
a CDR2 that comprises an amino acid sequence: Xaa1-Ala-Ser-Xaa2-Xaa3-Xaa4 (SEQ ID NO:314), wherein Xaa1 is selected from Ala, Asp and Gly; Xaa2 is selected from Ser and Asn; Xaa3 is selected from Leu and Arg; Xaa4 is selected from Gln, Ala, Ser and Thr; and
a CDR3 that comprises the sequence QQSYSTPLT (SEQ ID NO:9), QQRSNWPSPIA (SEQ ID NO:111), or QQYGSSLT (SEQ ID NO:153)
to a subject in an amount effective to treat or delay the onset or recurrence of the hK1 associated disorder, or the at least one symptom thereof.
2. The method of claim 1 , wherein the disorder is asthma and the asthma is allergic or non-allergic asthma.
3. The method of claim 2 , wherein the antibody is administered by inhalation.
4. The method of claim 3 , wherein the antibody is administered using an inhaler.
5. A method of modulating an hK1 activity, the method comprising:
providing an antibody that comprises an immunoglobulin heavy chain (HC) variable domain sequence and an immunoglobulin light chain (LC) variable domain sequence, wherein the HC variable domain sequence and the LC variable domain sequence form an antigen binding site that binds to hK1 and inhibits enzymatic activity of hK1 (SEQ ID NO:1021) with a Ki of less than 10 nM, said HC variable domain sequence having:
a CDR1 that comprises an amino acid sequence: Xaa1-Tyr-Xaa2-Met-Xaa3 (SEQ ID NO:31), wherein Xaa 1 is selected from Lys and His; Xaa2 is selected from Lys, Val and Ser; Xaa3 is selected from Val, Ile and Thr;
a CDR2 that comprises an amino acid sequence: Xaa1-Ile-Tyr-Pro-Ser-Gly-Gly-Xaa2-Thr-Xaa3-Tyr-Ala-Asp-Ser-Val-Lys-Gly (SEQ ID NO:32), wherein Xaa1 is selected from Ser, Trp and Arg; Xaa2 is selected from Ile, Asn and Arg; Xaa3 is selected from Ala, Ile and Gly; and
a CDR3 that comprises the sequence DITPGGGSGFRLPKNYYYYGMDV (SEQ ID NO:12), VGVWYGMDV (SEQ ID NO:114), or DSGGYYYGMDV (SEQ ID NO:156); and
said LC variable domain sequence having:
a CDR1 that comprises an amino acid sequence: Arg-Ala-Ser-Gln-Ser-Xaa1-Ser-Ser-Xaa2-Xaa3-Xaa4-Xaa5 (SEQ ID NO:284), wherein Xaa1 is selected from Ile and Val; Xaa2 is selected from Tyr and Ser; Xaa3 is selected from Leu and Tyr; Xaa4 is selected from Asn, Ala and Leu; and Xaa5 is Ala or is absent;
a CDR2 that comprises an amino acid sequence: Xaa1-Ala-Ser-Xaa2-Xaa3-Xaa4 (SEQ ID NO:314), wherein Xaa1 is selected from Ala, Asp and Gly; Xaa2 is selected from Ser and Asn; Xaa3 is selected from Leu and Arg; Xaa4 is selected from Gln, Ala, Ser and Thr; and
a CDR3 that comprises the sequence QQSYSTPLT (SEQ ID NO:9), QQRSNWPSPIA (SEQ ID NO:111), or QQYGSSLT (SEQ ID NO:153); and
contacting the antibody to hK1, in an amount sufficient to modulate an hK1 activity.
6. The method of claim 5 , wherein the contacting is in vitro.
7. The method of claim 5 , wherein the contacting is in vivo.
8. The method of claim 1 , wherein the antibody comprises the CDR regions of SEQ ID NOS:7-12.
9. The method of claim 1 , wherein the antibody comprises the heavy and light chain variable domain sequences that are identical to corresponding variable domain sequences of SEQ ID NOs: 1240 and 1159.
10. The method of claim 5 , wherein the antibody comprises the CDR regions of SEQ ID NOS:7-12.
11. The method of claim 5 , wherein the antibody comprises the heavy and light chain variable domain sequences that are identical to corresponding variable domain sequences of SEQ ID NOs: 1240 and 1159.
12. A method of treating or delaying the onset or recurrence of an hK1 associated disorder, wherein the disorder involves airway inflammation, eosinophilia, fibrosis and excess mucus production, or at least one symptom thereof, the method comprising:
administering an antibody that comprises an immunoglobulin heavy chain (HC) variable domain sequence and an immunoglobulin light chain (LC) variable domain sequence, wherein the HC variable domain sequence and the LC variable domain sequence form an antigen binding site that binds to hK1 and inhibits enzymatic activity of hK1 (SEQ ID NO:1021) with a Ki of less than 10 nM, said HC variable domain sequence having:
a CDR1 that comprises an amino acid sequence: Xaa1-Tyr-Xaa2-Met-Xaa3 (SEQ ID NO:31), wherein Xaa 1 is selected from Lys and His; Xaa2 is selected from Lys, Val and Ser; Xaa3 is selected from Val, Ile and Thr;
a CDR2 that comprises an amino acid sequence: Xaa1-Ile-Tyr-Pro-Ser-Gly-Gly-Xaa2-Thr-Xaa3-Tyr-Ala-Asp-Ser-Val-Lys-Gly (SEQ ID NO:32), wherein Xaa1 is selected from Ser, Trp and Arg; Xaa2 is selected from Ile, Asn and Arg; Xaa3 is selected from Ala, Ile and Gly; and
a CDR3 that comprises the sequence DITPGGGSGFRLPKNYYYYGMDV (SEQ ID NO:12), VGVWYGMDV (SEQ ID NO:114), or DSGGYYYGMDV (SEQ ID NO:156); and
said LC variable domain sequence having:
a CDR1 that comprises an amino acid sequence: Arg-Ala-Ser-Gln-Ser-Xaa1-Ser-Ser-Xaa2-Xaa3-Xaa4-Xaa5 (SEQ ID NO:284), wherein Xaa1 is selected from Ile and Val; Xaa2 is selected from Tyr and Ser; Xaa3 is selected from Leu and Tyr; Xaa4 is selected from Asn, Ala and Leu; and Xaa5 is Ala or is absent;
a CDR2 that comprises an amino acid sequence: Xaa1-Ala-Ser-Xaa2-Xaa3-Xaa4 (SEQ ID NO:314), wherein Xaa1 is selected from Ala, Asp and Gly; Xaa2 is selected from Ser and Asn; Xaa3 is selected from Leu and Arg; Xaa4 is selected from Gln, Ala, Ser and Thr; and
a CDR3 that comprises the sequence QQSYSTPLT (SEQ ID NO:9), QQRSNWPSPIA (SEQ ID NO:111), or QQYGSSLT (SEQ ID NO:153) to a subject in an amount effective to treat or delay the onset or recurrence of the hK1 associated disorder, or the at least one symptom thereof.
13. The method of claim 12 , wherein the disorder is cystic fibrosis or pulmonary fibrosis.
14. The method of claim 1 , wherein the antibody is a humanized antibody.
15. The method of claim 5 , wherein the antibody is a humanized antibody.
16. The method of claim 1 , wherein the antibody is a full length IgG antibody.
17. The method of claim 5 , wherein the antibody is a full length IgG antibody.
18. The method of claim 1 , wherein the antibody is an antigen binding fragment of an antibody, and does not include an Fc domain.
19. The method of claim 5 , wherein the antibody is an antigen binding fragment of an antibody, and does not include an Fc domain.
20. The method of claim 1 , wherein the antibody comprises a human FR1, FR2, FR3, and FR4 in the heavy chain variable domain sequence and a human FR1, FR2, FR3, and FR4 in the light chain variable domain sequence.
21. The method of claim 5 , wherein the antibody comprises a human FR1, FR2, FR3, and FR4 in the heavy chain variable domain sequence and a human FR1, FR2, FR3, and FR4 in the light chain variable domain sequence.
22. The method of claim 12 , wherein the antibody comprises the CDR regions of SEQ ID NOS: 7-12.
23. The method of claim 12 , wherein the antibody comprises the heavy and light chain variable domain sequences that are identical to corresponding variable domain sequences of SEQ ID NOs: 1240 and 1159.
24. The method of claim 12 , wherein the antibody is a humanized antibody.
25. The method of claim 12 , wherein the antibody is a full length IgG antibody.
26. The method of claim 12 , wherein the antibody is an antigen binding fragment of an antibody, and does not include an Fc domain.
27. The method of claim 12 , wherein the antibody comprises a human FR1, FR2, FR3, and FR4 in the heavy chain variable domain sequence and a human FR1, FR2, FR3, and FR4 in the light chain variable domain sequence.