Antibodies against BACE1 and use thereof for neural disease immunotherapy

1. An isolated antibody that binds to BACE1, wherein the antibody comprises:

an HVR-H1 sequence selected from SEQ ID NOs: 15, 218, and 222 to 224; an HVR-H2 sequence selected from SEQ ID NOs: 29, 219, and 225; an HVR-H3 sequence selected from SEQ ID NOs: 52, 220, 221, 226, and 227; the HVR-L1 sequence of SEQ ID NO: 65; an HVR-L2 sequence selected from SEQ ID NOs: 71, 73 and 217; and the HVR-L3 sequence of SEQ ID NO: 80.

2. The isolated antibody of claim 1 , wherein the antibody comprises:

a) a heavy chain variable domain sequence having at least 90% sequence identity to a heavy chain variable domain sequence selected from SEQ ID NOs: 138, 194 to 200, and 209 to 216; or

b) a light chain variable domain sequence having at least 90% sequence identity to a light chain variable domain sequence selected from SEQ ID NOs: 156, 187 to 193, and 201 to 208; or

c) a heavy chain variable domain sequence as in (a) and a light chain variable domain sequence as in (b).

3. The isolated antibody of claim 1 , wherein the antibody comprises:

a) a heavy chain variable domain sequence selected from SEQ ID NOs: 138, 194 to 200, and 209 to 216; or

b) a light chain variable domain sequence selected from SEQ ID NOs: 156, 187 to 193, and 201 to 208; or

c) a heavy chain variable domain sequence as in (a) and a light chain variable domain sequence as in (b).

4. The isolated antibody of claim 1 , wherein the antibody inhibits the activity of BACE1.

5. The isolated antibody of claim 4 , wherein the antibody inhibits BACE1 activity in a homogeneous time-resolved fluorescence (HTRF) assay.

6. The isolated antibody of claim 4 , wherein the antibody inhibits BACE1 activity in a cell line that expresses a BACE1 substrate.

7. The isolated antibody of claim 6 , wherein the BACE1 substrate is amyloid precursor protein (APP).

8. The isolated antibody of claim 4 , wherein the antibody inhibits BACE1 activity in tissue from an animal that has been administered the anti-BACE1 antibody.

9. The isolated antibody of claim 8 , wherein the tissue is brain tissue.

10. The isolated antibody of claim 8 , wherein the animal is selected from a mouse, rat, rabbit, dog, monkey, and non-human primate.

11. The isolated antibody of claim 4 , wherein the antibody achieves a maximum inhibition of BACE1 activity of greater than 60%, as measured using the dissociated cortical neuron culture assay.

12. The isolated antibody of claim 1 , wherein the antibody is a monoclonal antibody.

13. The isolated antibody of claim 12 , wherein the antibody is a human antibody or a chimeric antibody.

14. A pharmaceutical formulation comprising the antibody of claim 4 and a pharmaceutically acceptable carrier.

15. The isolated antibody of claim 1 , wherein the antibody binds BACE1 with an affinity (KD) of between 0.1 nM and 10 nM, as measured by surface plasmon resonance (SPR).

16. The isolated antibody of claim 1 , wherein the antibody is an antibody fragment.

17. The isolated antibody of claim 16 , wherein the antibody fragment is selected from a Fab, Fab′, Fab′-SH, F(ab′)2, Fv, and scFv.

18. The isolated antibody of claim 1 , wherein the antibody is a full length IgG1 antibody.

19. An immunoconjugate comprising the antibody of claim 1 and a cytotoxic agent.

20. The antibody of claim 1 , wherein the antibody comprises:

(a) the HVR-H1 sequence of SEQ ID NO: 15; the HVR-H2 sequence of SEQ ID NO: 29; the HVR-H3 sequence of SEQ ID NO: 52; the HVR-L1 sequence of SEQ ID NO: 65; the HVR-L2 sequence of SEQ ID NO: 71; and the HVR-L3 sequence of SEQ ID NO: 80; or

(b) the HVR-H1 sequence of SEQ ID NO: 218; the HVR-H2 sequence of SEQ ID NO: 219; the HVR-H3 sequence of SEQ ID NO: 52; the HVR-L1 sequence of SEQ ID NO: 65; the HVR-L2 sequence of SEQ ID NO: 71; and the HVR-L3 sequence of SEQ ID NO: 80; or

(c) the HVR-H1 sequence of SEQ ID NO: 218; the HVR-H2 sequence of SEQ ID NO: 219; the HVR-H3 sequence of SEQ ID NO: 52; the HVR-L1 sequence of SEQ ID NO: 65; the HVR-L2 sequence of SEQ ID NO: 73; and the HVR-L3 sequence of SEQ ID NO: 80; or

(d) the HVR-H1 sequence of SEQ ID NO: 218; the HVR-H2 sequence of SEQ ID NO: 219; the HVR-H3 sequence of SEQ ID NO: 52; the HVR-L1 sequence of SEQ ID NO: 65; the HVR-L2 sequence of SEQ ID NO: 217; and the HVR-L3 sequence of SEQ ID NO: 80; or

(e) the HVR-H1 sequence of SEQ ID NO: 218; the HVR-H2 sequence of SEQ ID NO: 219; the HVR-H3 sequence of SEQ ID NO: 52; the HVR-L1 sequence of SEQ ID NO: 65; the HVR-L2 sequence of SEQ ID NO: 73; and the HVR-L3 sequence of SEQ ID NO: 80; or

(f) the HVR-H1 sequence of SEQ ID NO: 218; the HVR-H2 sequence of SEQ ID NO: 219; the HVR-H3 sequence of SEQ ID NO: 220; the HVR-L1 sequence of SEQ ID NO: 65; the HVR-L2 sequence of SEQ ID NO: 73; and the HVR-L3 sequence of SEQ ID NO: 80; or

(g) the HVR-H1 sequence of SEQ ID NO: 218; the HVR-H2 sequence of SEQ ID NO: 219; the HVR-H3 sequence of SEQ ID NO: 220; the HVR-L1 sequence of SEQ ID NO: 65; the HVR-L2 sequence of SEQ ID NO: 217; and the HVR-L3 sequence of SEQ ID NO: 80; or

(h) the HVR-H1 sequence of SEQ ID NO: 218; the HVR-H2 sequence of SEQ ID NO: 219; the HVR-H3 sequence of SEQ ID NO: 221; the HVR-L1 sequence of SEQ ID NO: 65; the HVR-L2 sequence of SEQ ID NO: 217; and the HVR-L3 sequence of SEQ ID NO: 80; or

(i) the HVR-H1 sequence of SEQ ID NO: 222; the HVR-H2 sequence of SEQ ID NO: 29; the HVR-H3 sequence of SEQ ID NO: 226; the HVR-L1 sequence of SEQ ID NO: 65; the HVR-L2 sequence of SEQ ID NO: 217; and the HVR-L3 sequence of SEQ ID NO: 80; or

(j) the HVR-H1 sequence of SEQ ID NO: 222; the HVR-H2 sequence of SEQ ID NO: 29; the HVR-H3 sequence of SEQ ID NO: 226; the HVR-L1 sequence of SEQ ID NO: 65; the HVR-L2 sequence of SEQ ID NO: 73; and the HVR-L3 sequence of SEQ ID NO: 80; or

(k) the HVR-H1 sequence of SEQ ID NO: 15; the HVR-H2 sequence of SEQ ID NO: 29; the HVR-H3 sequence of SEQ ID NO: 52; the HVR-L1 sequence of SEQ ID NO: 65; the HVR-L2 sequence of SEQ ID NO: 73; and the HVR-L3 sequence of SEQ ID NO: 80; or

(l) the HVR-H1 sequence of SEQ ID NO: 15; the HVR-H2 sequence of SEQ ID NO: 29; the HVR-H3 sequence of SEQ ID NO: 52; the HVR-L1 sequence of SEQ ID NO: 65; the HVR-L2 sequence of SEQ ID NO: 217; and the HVR-L3 sequence of SEQ ID NO: 80; or

(m) the HVR-H1 sequence of SEQ ID NO: 223; the HVR-H2 sequence of SEQ ID NO: 29; the HVR-H3 sequence of SEQ ID NO: 52; the HVR-L1 sequence of SEQ ID NO: 65; the HVR-L2 sequence of SEQ ID NO: 71; and the HVR-L3 sequence of SEQ ID NO: 80; or

(n) the HVR-H1 sequence of SEQ ID NO: 224; the HVR-H2 sequence of SEQ ID NO: 29; the HVR-H3 sequence of SEQ ID NO: 52; the HVR-L1 sequence of SEQ ID NO: 65; the HVR-L2 sequence of SEQ ID NO: 71; and the HVR-L3 sequence of SEQ ID NO: 80; or

(o) the HVR-H1 sequence of SEQ ID NO: 15; the HVR-H2 sequence of SEQ ID NO: 225; the HVR-H3 sequence of SEQ ID NO: 227; the HVR-L1 sequence of SEQ ID NO: 65; the HVR-L2 sequence of SEQ ID NO: 71; and the HVR-L3 sequence of SEQ ID NO: 80; or

(p) the HVR-H1 sequence of SEQ ID NO: 15; the HVR-H2 sequence of SEQ ID NO: 29; the HVR-H3 sequence of SEQ ID NO: 221; the HVR-L1 sequence of SEQ ID NO: 65; the HVR-L2 sequence of SEQ ID NO: 71; and the HVR-L3 sequence of SEQ ID NO: 80.

21. The antibody of claim 1 , wherein the antibody comprises:

(a) the heavy chain variable domain sequence of SEQ ID NO: 138; and the light chain variable domain sequence of SEQ ID NO: 156; or

(b) the heavy chain variable domain sequence of SEQ ID NO: 194; and the light chain variable domain sequence of SEQ ID NO: 187; or

(c) the heavy chain variable domain sequence of SEQ ID NO: 195; and the light chain variable domain sequence of SEQ ID NO: 188; or

(d) the heavy chain variable domain sequence of SEQ ID NO: 196; and the light chain variable domain sequence of SEQ ID NO: 189; or

(e) the heavy chain variable domain sequence of SEQ ID NO: 197; and the light chain variable domain sequence of SEQ ID NO: 190; or

(f) the heavy chain variable domain sequence of SEQ ID NO: 198; and the light chain variable domain sequence of SEQ ID NO: 191; or

(g) the heavy chain variable domain sequence of SEQ ID NO: 199; and the light chain variable domain sequence of SEQ ID NO: 192; or

(h) the heavy chain variable domain sequence of SEQ ID NO: 200; and the light chain variable domain sequence of SEQ ID NO: 193; or

(i) the heavy chain variable domain sequence of SEQ ID NO: 209; and the light chain variable domain sequence of SEQ ID NO: 201; or

(j) the heavy chain variable domain sequence of SEQ ID NO: 210; and the light chain variable domain sequence of SEQ ID NO: 202; or

(k) the heavy chain variable domain sequence of SEQ ID NO: 211; and the light chain variable domain sequence of SEQ ID NO: 203; or

(l) the heavy chain variable domain sequence of SEQ ID NO: 212; and the light chain variable domain sequence of SEQ ID NO: 204; or

(m) the heavy chain variable domain sequence of SEQ ID NO: 213; and the light chain variable domain sequence of SEQ ID NO: 205; or

(n) the heavy chain variable domain sequence of SEQ ID NO: 214; and the light chain variable domain sequence of SEQ ID NO: 206; or

(o) the heavy chain variable domain sequence of SEQ ID NO: 215; and the light chain variable domain sequence of SEQ ID NO: 207; or

(p) the heavy chain variable domain sequence of SEQ ID NO: 216; and the light chain variable domain sequence of SEQ ID NO: 208.