Anti-B7-H4 antibodies and immunoconjugates
The invention provides anti-B7-H4 antibodies and immunoconjugates and methods of using the same.
1. An isolated antibody that binds to B7-H4, wherein the antibody comprises:
(a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 21, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 22, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 23.
2. The antibody of claim 1 , further comprising:
(a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 24, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26.
3. An isolated antibody that binds to B7-H4, wherein the antibody comprises:
(a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 24, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 25, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 26.
4. The antibody of claim 2 , wherein the antibody comprises
(a) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 20; or
(b) a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 19; or
(c) a VH sequence as in (a) and a VL sequence as in (b).
5. The antibody of claim 4 , comprising:
(a) a VH sequence of SEQ ID NO: 20; and/or
(b) a VL sequence of SEQ ID NO: 19.
6. The antibody of claim 5 , comprising: (a) a VH sequence of SEQ ID NO: 20 and a VL sequence of SEQ ID NO: 19.
7. The antibody of claim 2 , which is an IgG1, IgG2a, or IgG2b antibody.
8. Isolated nucleic acid encoding the antibody of claim 2 .
9. A host cell comprising the nucleic acid of claim 8 .
10. A method of producing an antibody comprising culturing the host cell of claim 9 so that the antibody is produced.
11. An immunoconjugate comprising the antibody of claim 2 and a cytotoxic agent.
12. The immunoconjugate of claim 11 having the formula Ab-(L-D)p, wherein:
(a) Ab is the antibody;
(b) L is a linker;
(c) D is a cytotoxic agent selected from a maytansinoid, an auristatin, a calicheamicin, a pyrrolobenzodiazepine, and a nemorubicin derivative; and
(d) p ranges from 1-8.
13. A pharmaceutical formulation comprising the immunoconjugate of claim 11 and a pharmaceutically acceptable carrier.
14. The pharmaceutical formulation of claim 13 , further comprising an additional therapeutic agent.
15. A method of treating an individual having a B7-H4-positive cancer, the method comprising administering to the individual an effective amount of the immunoconjugate of claim 11 .
16. A method of inhibiting proliferation of an B7-H4-positive cell, the method comprising exposing the cell to the immunoconjugate of claim 11 under conditions permissive for binding of the immunoconjugate to B7-H4 on the surface of the cell, thereby inhibiting proliferation of the cell.
17. A method of detecting human B7-H4 in a biological sample comprising contacting the biological sample with the anti-B7-H4 antibody of claim 2 under conditions permissive for binding of the anti-B7-H4 antibody to a naturally occurring human B7-H4, and detecting whether a complex is formed between the anti-B7-H4 antibody and a naturally occurring human B7-H4 in the biological sample.
18. A method for detecting an B7-H4-positive cancer comprising (i) administering a labeled anti-B7-H4 antibody to a subject having or suspected of having a B7-H4-positive cancer, wherein the labeled anti-B7-H4 antibody comprises the anti-B7-H4 antibody of claim 2 , and (ii) detecting the labeled anti-B7-H4 antibody in the subject, wherein detection of the labeled anti-B7-H4 antibody indicates a B7-H4-positive cancer in the subject.
19. The antibody of claim 1 , wherein the antibody has at least one of the following characteristics:
(a) binds to an epitope within all or a portion of the B7-H4 Ig-V containing domain (amino acids 29-157 of SEQ ID NO: 73); or binds to an epitope within all or a portion of the B7-H4 Ig-C containing domain (amino acids 158-250 of SEQ ID NO: 73); or binds to an epitope within all or a portion of the B7-H4 Ig-V and Ig-C domains (amino acids 29-250 of SEQ ID NO:73); or binds to an epitope within all or a portion of SEQ ID NO: 74 (mature human B7-H4); or binds to an epitope within all or a portion of SEQ ID NO: 73 (precursor human B7-H4), and
(b) binds to B7-H4 with an affinity of ≤50 nM.
20. The antibody of claim 2 , wherein the antibody has at least one of the following characteristics:
(a) binds to an epitope within all or a portion of the B7-H4 Ig-V containing domain (amino acids 29-157 of SEQ ID NO: 73); or binds to an epitope within all or a portion of the B7-H4 Ig-C containing domain (amino acids 158-250 of SEQ ID NO: 73); or binds to an epitope within all or a portion of the B7-H4 Ig-V and Ig-C domains (amino acids 29-250 of SEQ ID NO:73); or binds to an epitope within all or a portion of SEQ ID NO: 74 (mature human B7-H4); or binds to an epitope within all or a portion of SEQ ID NO: 73 (precursor human B7-H4), and
(b) binds to B7-H4 with an affinity of <50 nM.
21. The antibody of claim 3 , wherein the antibody has at least one of the following characteristics:
(a) binds to an epitope within all or a portion of the B7-H4 Ig-V containing domain (amino acids 29-157 of SEQ ID NO: 73); or binds to an epitope within all or a portion of the B7-H4 Ig-C containing domain (amino acids 158-250 of SEQ ID NO: 73); or binds to an epitope within all or a portion of the B7-H4 Ig-V and Ig-C domains (amino acids 29-250 of SEQ ID NO:73); or binds to an epitope within all or a portion of SEQ ID NO: 74 (mature human B7-H4); or binds to an epitope within all or a portion of SEQ ID NO: 73 (precursor human B7-H4), and
(b) binds to B7-H4 with an affinity of ≤50 nM.
22. The antibody of claim 2 , which is a monoclonal antibody.
23. The antibody of claim 22 , which is a humanized or chimeric antibody.