Anti-TrkB antibodies
View Patent ↗The present invention provides improved antibodies or antigen-binding molecules that specifically recognize and agonize the tyrosine receptor kinase B (TrkB) receptor, and methods of their use. Also provided in the invention are polynucleotides and vectors that encode such molecules and host cells that harbor the polynucleotides or vectors.
1. A purified antibody that specifically binds TrkB, wherein the antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region and the light chain variable region each comprise the following three complementary determining regions (CDRs): CDR1, CDR2 and CDR3; wherein:
i) the CDR1 of the heavy chain variable region comprises an amino acid sequence of SEQ ID NO:25;
ii) the CDR2 of the heavy chain variable region comprises an amino acid sequence selected from the group consisting of SEQ ID NO:28, SEQ ID NO:29 and SEQ ID NO:30;
iii) the CDR3 of the heavy chain variable region comprises an amino acid sequence selected from the group consisting of SEQ ID NO:32 and SEQ ID NO:33;
iv) the CDR1 of the light chain variable region comprises an amino acid sequence selected from the group consisting of SEQ ID NO:35, SEQ ID NO:36 and SEQ ID NO:37;
v) the CDR2 of the light chain variable region comprises an amino acid sequence of SEQ ID NO:39;
vi) the CDR3 of the light chain variable region comprises an amino acid sequence selected from the group consisting of SEQ ID NO:40 and SEQ ID NO:41.
2. The antibody of claim 1 , wherein the heavy chain V-segment of the heavy chain variable region shares at least 90% sequence identity to SEQ ID NO:16, and wherein the Tight chain V-segment of the light chain variable region shares at least 90% sequence identity to SEQ ID NO:24.
3. The antibody of claim 1 , wherein the heavy chain V-segment of the heavy chain variable region shares at least 90% sequence identity to an amino acid selected from the group consisting of SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14 and SEQ ID NO:15, and wherein the light chain V-segment of the light chain variable region shares at least 90% sequence identity to an amino acid selected from the group consisting of SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22 and SEQ ID NO:23.
4. The antibody of claim 1 , wherein the heavy chain FR4 of the heavy chain variable region is a human germline FR4.
5. The antibody of claim 4 , wherein the heavy chain FR4 is SEQ ID NO:50.
6. The antibody of claim 4 , wherein the heavy chain J-segment of the heavy chain variable region comprises the human germline JH4 partial sequence WGQGTLVTVSS (SEQ ID NO:50).
7. The antibody of claim 1 , wherein the light chain FR4 of the light chain variable region is a human germline FR4.
8. The antibody of claim 7 , wherein the light chain FR4 is SEQ ID NO:61.
9. The antibody of claim 7 , wherein the light chain J-segment of the light chain variable region comprises the human germline Jk2 partial sequence FGQGKLEIK (SEQ ID NO:61).
10. The antibody of claim 1 , wherein
i) the CDR1 comprises SEQ ID NO:25;
ii) the CDR2 comprises SEQ ID NO:28;
iii) the heavy chain CDR3 comprises SEQ ID NO:32;
iv) the CDR1 comprises SEQ ID NO:35;
v) the CDR2 comprises SEQ ID NO:39; and
vi) the light chain CDR3 comprises SEQ ID NO:41.
11. The antibody of claim 1 , wherein
i) the CDR1 comprises SEQ ID NO:25;
ii) the CDR2 comprises SEQ ID NO:28;
iii) the heavy chain CDR3 comprises SEQ ID NO:32;
iv) the CDR1 comprises SEQ ID NO:36;
v) the CDR2 comprises SEQ ID NO:39; and
vi) the light chain CDR3 comprises SEQ ID NO:40.
12. The antibody of claim 1 , wherein
i) the CDR1 comprises SEQ ID NO:25;
ii) the CDR2 comprises SEQ ID NO:28;
iii) the heavy chain CDR3 comprises SEQ ID NO:32;
iv) the CDR1 comprises SEQ ID NO:37;
v) the CDR2 comprises SEQ ID NO:39; and
vi) the light chain CDR3 comprises SEQ ID NO:40.
13. The antibody of claim 1 , wherein
i) the CDR1 comprises SEQ ID NO:25;
ii) the CDR2 comprises SEQ ID NO:29;
iii) the heavy chain CDR3 comprises SEQ ID NO:32;
iv) the CDR1 comprises SEQ ID NO:35;
v) the CDR2 comprises SEQ ID NO:39; and
vi) the light chain CDR3 comprises SEQ ID NO:41.
14. The antibody of claim 1 , wherein the heavy chain variable region shares at least 90% amino acid sequence identity to the variable region of SEQ ID NO:4 and the light chain variable region shares at least 90% amino acid sequence identity to the variable region of SEQ ID NO:11.
15. The antibody of claim 1 , wherein the heavy chain variable region shares at least 90% amino acid sequence identity to the variable region selected from the group consisting of SEQ ID NO:1, SEQ ID NO:2 and SEQ ID NO:3 and the light chain variable region shares at least 90% amino acid sequence identity to the variable region selected from the group consisting of SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9 and SEQ ID NO:10.
16. The antibody of claim 1 , wherein the heavy chain variable region shares at least 95% amino acid sequence identity to the variable region selected from the group consisting of SEQ ID NO:1, SEQ ID NO:2 and SEQ ID NO:3 and the light chain variable region shares at least 95% amino acid sequence identity to the variable region selected from the group consisting of SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9 and SEQ ID NO:10.
17. The antibody of claim 1 , wherein the heavy chain variable region comprises an amino acid sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:2 and SEQ ID NO:3 and the light chain variable region comprises an amino acid sequence selected from the group consisting of SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9 and SEQ ID NO:10.
18. The antibody of claim 1 , wherein the antibody is a FAb′ fragment.
19. The antibody of claim 1 , wherein the antibody is an IgG.
20. The antibody of claim 1 , wherein the antibody is a single chain antibody (scFv).
21. The antibody of claim 1 , wherein the antibody comprises human constant regions.
22. The antibody of claim 1 , wherein the antibody does not bind to Tyrosine Kinase Receptor A or Tyrosine Kinase Receptor C.
23. The antibody of claim 1 , wherein the antibody binds to the Ligand Binding Domain (LBD) of TrkB.
24. The antibody of claim 1 , wherein the antibody competes with the binding of Brain Derived Neurotrophic Factor (BDNF) to TrkB.
25. The antibody of claim 1 , wherein the antibody comprises a heavy chain comprising SEQ ID NO:1 and a light chain comprising SEQ ID NO:8.
26. The antibody of claim 1 , wherein the antibody comprises a heavy chain comprising SEQ ID NO:1 and a light chain comprising SEQ ID NO:9.
27. The antibody of claim 1 , wherein the antibody comprises a heavy chain comprising SEQ ID NO:1 and a light chain comprising SEQ ID NO:10.
28. The antibody of claim 1 , wherein the antibody comprises a heavy chain comprising SEQ ID NO:3 and a light chain comprising SEQ ID NO:8.
29. A pharmaceutically acceptable composition comprising an antibody of claim 1 and a physiologically compatible excipient.
30. The composition of claim 29 , wherein the pharmaceutical composition further comprises an agent that reduces blood glucose levels in an individual.
31. The composition of claim 29 , wherein the pharmaceutical composition further comprises an agent that reduces body weight in an individual.