Anti-sortilin antibodies and methods of use thereof
The present disclosure is generally directed to compositions that include antibodies, e.g., monoclonal, chimeric, humanized antibodies, antibody fragments, etc., that specifically bind on or more epitopes within a Sortilin protein, e.g., human Sortilin or a mammalian Sortilin, and use of such compostions in preventing, reducing risk, or treating an individual in need thereof.
1. An isolated anti-Sortilin antibody, wherein the anti-Sortilin antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises:
(a) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 9;
(b) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 29; and
(c) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 55, and wherein the heavy chain variable domain comprises:
(a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 520;
(b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 533; and
(c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 553.
2. The anti-Sortilin antibody of claim 1 , wherein the anti-Sortilin antibody is a human antibody, a bispecific antibody, a monoclonal antibody, a multivalent antibody, a conjugated antibody, or a chimeric antibody.
3. The anti-Sortilin antibody of claim 1 , wherein the anti-Sortilin antibody is a multivalent antibody recognizing a second antigen.
4. The anti-Sortilin antibody of claim 3 , wherein the second antigen is an antigen facilitating transport across the blood-brain-barrier.
5. The anti-Sortilin antibody of claim 4 , 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, a protein transduction domain, penetratin, a poly-arginine peptide, and an angiopep peptide.
6. The anti-Sortilin antibody of claim 1 , wherein the anti-Sortilin antibody is an antibody fragment that binds to an epitope comprising amino acid residues on human Sortilin or a mammalian Sortilin protein.
7. The anti-Sortilin antibody of claim 6 , wherein the fragment is an Fab, Fab′, Fab′-SH, F(ab′)2, Fv, or scFv fragment.
8. The anti-Sortilin antibody of claim 1 , wherein the anti-Sortilin antibody has a human Fc IgG1 isotype.
9. The anti-Sortilin antibody of claim 1 , wherein the anti-Sortilin antibody has a human Fc IgG1 isotype and comprises one or more amino acid substitutions in the Fc region at a residue position selected from the group consisting of: N297A, N297Q, D265A, L234A, L235A, C226S, C229S, P238S, E233P, L234V, P238A, A327Q, A327G, P329A, K322A, L234F, L235E, P331S, T394D, A330L, M252Y, S254T, T256E, and any combination thereof, wherein the numbering of the residues is according to EU numbering.
10. The anti-Sortilin antibody of claim 1 , wherein the anti-Sortilin antibody has a human Fc IgG1 isotype and comprises an amino acid substitution in the Fc region at residue position L234A and L235A, wherein the numbering of the residues is according to EU numbering.
11. The anti-Sortilin antibody of claim 1 , wherein the anti-Sortilin antibody has an IgG4 isotype.
12. The anti-Sortilin antibody of claim 11 , wherein the anti-Sortilin antibody has a human Fc IgG4 isotype and comprises an amino acid substitution in the Fc region at residue position S228P, F234A, and L235A, wherein the numbering of the residue position is according to EU numbering.
13. The anti-Sortilin antibody of claim 1 , wherein the anti-Sortilin antibody increases extracellular levels of Progranulin.
14. The anti-Sortilin antibody of claim 13 , wherein the anti-Sortilin antibody decreases cellular levels of Sortilin.
15. The anti-Sortilin antibody of claim 14 , wherein the antibody decreases cell surface levels of Sortilin, decreases total levels of Sortilin, or any combination thereof.
16. The anti-Sortilin antibody of claim 15 , wherein the anti-Sortilin antibody induces Sortilin degradation, Sortilin internalization, Sortilin down regulation, or any combination thereof.
17. The anti-Sortilin antibody of claim 1 , wherein the anti-Sortilin antibody further inhibits interaction between Sortilin and pro-nerve growth factor (pro-NGF).
18. The anti-Sortilin antibody of claim 1 , wherein the anti-Sortilin antibody binds specifically to human Sortilin, mouse Sortilin, or both human Sortilin and mouse Sortilin.
19. The anti-Sortilin antibody of claim 18 , wherein the anti-Sortilin antibody has a dissociation constant (K D ) for human Sortilin, mouse Sortilin, or both, that ranges from about 100 nM to about 0.005 nM.
20. The anti-Sortilin antibody of claim 1 , wherein the anti-Sortilin antibody decreases expression of one or more pro-inflammatory mediators selected from the group consisting of IL-6, IL12p70, IL12p40, IL-1β, TNF-α, CXCL1, CCL2, CCL3, CCL4, and CCL5.
21. An isolated anti-Sortilin antibody, wherein the anti-Sortilin antibody comprises a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 343 and a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 648.