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 that binds to human Sortilin, wherein the anti-Sortilin antibody decreases cellular levels of Sortilin and inhibits interaction between Sortilin and Progranulin, wherein the anti-Sortilin antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 30, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 100, and wherein the heavy chain variable domain comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 142, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 170, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 233.
2. The anti-Sortilin antibody of claim 1 , wherein the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 430 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 431.
3. 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: 10;
(b) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 30; and
(c) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 100; and
wherein the heavy chain variable domain comprises:
(a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 142;
(b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 170; and
(c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 233.
4. The anti-Sortilin antibody of claim 3 , wherein the anti-Sortilin antibody comprises a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 430 and a heavy chain variable domain comprising the amino acid sequence selected of SEQ ID NO: 431.
5. An isolated anti-Sortilin antibody, wherein the anti-Sortilin antibody binds to an epitope of human Sortilin that is the same as the Sortilin epitope bound by a reference anti-Sortilin antibody, wherein the reference anti-Sortilin antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 30, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 100, and wherein the heavy chain variable domain comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 142, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 170, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 233.
6. The anti-Sortilin antibody of claim 5 , wherein the anti-Sortilin antibody has an IgG1 or IgG4 isotype.
7. The anti-Sortilin antibody of claim 6 , wherein the anti-Sortilin antibody has a human IgG4 isotype.
8. The anti-Sortilin antibody of claim 7 , wherein the anti-Sortilin antibody comprises an S228P amino acid substitution at residue position 228, an F234A amino acid substitution at residue position 234, and an L235A amino acid substitution at residue position 235, wherein the numbering of the residue position is according to EU numbering.
9. The anti-Sortilin antibody of claim 6 , wherein:
(a) the anti-Sortilin antibody has a human 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; or
(b) the anti-Sortilin antibody has a human IgG4 isotype and comprises one or more amino acid substitutions in the Fc region at a residue position selected from the group consisting of: E233P, F234V, L234A/F234A, L235A, G237A, E318A, S228P, L236E, S241P, L248E, T394D, M252Y, S254T, T256E, N297A, N297Q, and any combination thereof, wherein the numbering of the residues is according to EU numbering.
10. The anti-Sortilin antibody of claim 9 , wherein:
(a) the IgG1 Fc region further comprises one or more additional amino acid substitutions at a position selected from the group consisting of A330L, L234F[H], L235E, P331S, and any combination thereof, wherein the numbering of the residues is according to EU numbering;
(b) the IgG1 or IgG4 Fc region further comprises one or more additional amino acid substitutions at a position selected from the group consisting of M252Y, S254T, T256E, and any combination thereof, wherein the numbering of the residues is according to EU numbering; or
(c) the IgG4 Fc region further comprises a S228P amino acid substitution according to EU numbering.
11. The anti-Sortilin antibody of claim 9 , wherein the anti-Sortilin antibody has a human IgG1 isotype and comprises substitutions in the Fc region at the residue positions of L234A, L235A, and P331S, wherein the numbering of the residues is according to EU numbering.
12. The anti-Sortilin antibody of claim 5 , 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.
13. A pharmaceutical composition comprising the anti-Sortilin antibody of claim 5 , and a pharmaceutically acceptable carrier.
14. The anti-Sortilin antibody of claim 5 , wherein the reference anti-Sortilin antibody comprises a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 430 and a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 431.
15. The anti-Sortilin antibody of claim 5 , wherein the anti-Sortilin antibody has a dissociation constant (K D ) for human Sortilin, mouse Sortilin, or both, that is less than 0.005 nM.
16. An isolated anti-Sortilin antibody that binds to human Sortilin, wherein the anti-Sortilin antibody decreases cellular levels of Sortilin and inhibits interaction between Sortilin and Progranulin, wherein the anti-Sortilin antibody binds to an epitope of human Sortilin that is the same as the Sortilin epitope bound by a reference anti-Sortilin antibody, wherein the reference anti-Sortilin antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10, an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 30, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 100, and wherein the heavy chain variable domain comprises: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 142, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 170, and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 233.
17. The anti-Sortilin antibody of claim 16 , wherein the reference anti-Sortilin antibody comprises a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 430 and a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 431.