Anti-Sortilin antibodies and methods of use thereof
The present disclosure is generally directed to compositions that include antibodies, e.g., monoclonal, chimeric, affinity-matured, humanized antibodies, antibody fragments, etc., that specifically bind a Sortilin protein, e.g., human Sortilin or mammalian Sortilin, and have improved and/or enhanced functional characteristics, and use of such compositions in preventing, reducing risk, or treating an individual in need thereof.
1. An antibody that binds to a Sortilin protein, wherein the antibody comprises a heavy chain variable region and a light chain variable region, wherein
the heavy chain variable region comprises an HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), an HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), and an HVR-H3 comprising the amino acid sequence ARQGSIKQGYYGMDV (SEQ ID NO: 6); and the light chain variable region comprises an HVR-L1 comprising the amino acid sequence RSSQSLLRSTGYNYLD (SEQ ID NO: 9), an HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and an HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO: 32).
2. The antibody of claim 1 , wherein the antibody:
(a) decreases cell surface levels of Sortilin more than the level of decrease caused by an anti-Sortilin antibody comprising a heavy chain variable region comprising the sequence of SEQ ID NO: 56 and a light chain variable region comprising the sequence of SEQ ID NO: 79;
(b) increases extracellular levels of Progranulin more than the level of increase caused by an anti-Sortilin antibody comprising a heavy chain variable region comprising the sequence of SEQ ID NO: 56 and a light chain variable region comprising the sequence of SEQ ID NO: 79;
(c) inhibits the interaction between Sortilin expressed on a cell and Progranulin more than the level of inhibition caused by an anti-Sortilin antibody comprising a heavy chain variable region comprising the sequence of SEQ ID NO: 56 and a light chain variable region comprising the sequence of SEQ ID NO: 79; or
(d) any combination of (a)-(c).
3. The antibody of claim 1 , wherein the antibody has a dissociation constant (K D ) for human Sortilin that is at least 1.1-fold lower than an anti-Sortilin antibody comprising a heavy chain variable region comprising the sequence of SEQ ID NO: 56 and a light chain variable region comprising the sequence of SEQ ID NO: 79, wherein the K D is determined by FACS.
4. The antibody of claim 1 , wherein the antibody has a dissociation constant (K D ) for human Sortilin that ranges from about 5.0E-10 M to about 1.0E-9 M wherein the K D is determined by FACS, or about 250-500 pM wherein the K D is determined by Bio-layer interferometry.
5. The antibody of claim 1 , wherein the Sortilin protein is a human Sortilin protein.
6. The antibody of claim 5 , wherein the human Sortilin protein comprises the amino acid sequence of SEQ ID NO: 81.
7. The antibody of claim 1 , wherein the Sortilin protein is a wild-type protein, a naturally occurring variant, or a disease variant.
8. The antibody of claim 1 , wherein the antibody is a human antibody, a bispecific antibody, a monoclonal antibody, a multivalent antibody, or a conjugated antibody.
9. The antibody of claim 8 , wherein the antibody is a bispecific antibody recognizing a first antigen and a second antigen.
10. The antibody of claim 9 , wherein the first antigen is Sortilin and the second antigen is an antigen facilitating transport across the blood-brain-barrier.
11. The antibody of claim 10 , wherein the second antigen is selected from the group consisting of transferrin receptor (TR), insulin receptor (HIR), insulin-like growth factor receptor (IGFR), low-density lipoprotein receptor related proteins 1 and 2 (LPR-1 and 2), diphtheria toxin receptor, CRM197, a llama single domain antibody, TMEM 30(A), a protein transduction domain, TAT, Syn-B, penetratin, a poly-arginine peptide, an angiopep peptide, basigin, Glut1, CD98hc, and ANG1005.
12. The antibody of claim 1 , wherein the antibody is an antibody fragment that binds to a human Sortilin protein.
13. The antibody of claim 12 , wherein the antibody fragment is an Fab, Fab′, Fab′-SH, F(ab′)2, Fv, or scFv fragment.
14. An antibody that binds to a Sortilin protein, wherein the antibody comprises
a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 56, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 60.
15. The antibody of claim 1 or claim 14 , wherein the antibody is of the IgG class, the IgM class, or the IgA class.
16. The antibody of claim 15 , wherein the antibody is of the IgG class and has an IgG1, IgG2, IgG3, or IgG4 isotype.
17. The antibody of claim 16 , wherein:
the antibody is an IgG1 or IgG2 isotype and the Fc region comprises an amino acid substitution at position P331S, wherein the numbering of the residue position is according to EU numbering;
the antibody is an IgG1 isotype and the Fc region comprises amino acid substitutions at positions L234A, L235A, and P331S, wherein the numbering of the residue position is according to EU numbering;
the antibody is an IgG1, IgG2, or IgG4 isotype and the Fc region comprises an amino acid substitution at position N297A, wherein the numbering of the residue position is according to EU numbering; or
the Fc region comprises an amino acid substitution at positions S267E and L328F, wherein the numbering of the residue position is according to EU numbering.
18. The antibody of claim 17 , wherein the antibody is an IgG1 isotype and the Fc region comprises amino acid substitutions at positions L234A, L235A, and P331S, wherein the numbering of the residue position is according to EU numbering.
19. A pharmaceutical composition comprising the antibody of any one of claim 1 , or 14 and a pharmaceutically acceptable carrier.
20. An isolated antibody that binds to Sortilin produced by a method comprising culturing a host cell;
wherein the host cell comprises a vector comprising a nucleic acid;
wherein the nucleic acid comprises a nucleic acid sequence encoding an antibody that binds to a Sortilin protein comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises an HVR-H1 comprising the amino acid sequence YSISSGYYWG (SEQ ID NO: 1), an HVR-H2 comprising the amino acid sequence TIYHSGSTYYNPSLKS (SEQ ID NO: 2), and an HVR-H3 comprising the amino acid sequence ARQGSIKQGYYGMDV (SEQ ID NO: 6); and the light chain variable region comprises an HVR-L1 comprising the amino acid sequence RSSQSLLRSTGYNYLD (SEQ ID NO: 9), an HVR-L2 comprising the amino acid sequence LGSNRAS (SEQ ID NO: 29), and an HVR-L3 comprising the amino acid sequence MQQQEAPLT (SEQ ID NO: 32); and
wherein the method comprises culturing the host cell so that the antibody encoded by the nucleic acid sequence is produced.
21. An antibody that binds to a Sortilin protein, wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 137 and a light chain comprising the amino acid sequence of SEQ ID NO: 142.
22. An antibody that binds to a Sortilin protein, wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 138 and a light chain comprising the amino acid sequence of SEQ ID NO: 142.