Anti-B7-H4 antibodies and immunoconjugates

Patent metadata

Field	Value
Publication number	US-10059768-B2
Application number	US-201514851003-A
Country	US
Kind code	B2
Filing date	Sep 11, 2015
Priority date	Sep 12, 2014
Publication date	Aug 28, 2018
Grant date	Aug 28, 2018

Abstract

The invention provides anti-B7-H4 antibodies and immunoconjugates and methods of using the same.

First claim

What is claimed is:

1. A bi-epitopic antibody comprising a first half antibody and a second half antibody, wherein the first half antibody comprises a first VH/VL unit that binds a first epitope of B7-H4, and wherein the second half antibody comprises a second VH/VL unit that binds a second epitope of B7-H4, wherein the first half antibody binds an epitope within all or a portion of the B7-H4 Ig-V containing domain and the second half antibody binds an epitope within all or a portion of the B7-H4 Ig-V and Ig-C containing domains; or wherein the first half antibody binds an epitope within all or a portion of the B7-H4 Ig-V and Ig-C containing domains and the second half antibody binds an epitope within all or a portion of the B7-H4 Ig-V containing domain.

2. The bi-epitopic antibody of claim 1 , wherein the B7-H4 Ig-V containing domain has the sequence of amino acids 29-157 of SEQ ID NO: 73.

3. The bi-epitopic antibody of claim 1 , wherein B7-H4 Ig-C containing domain has the sequence of amino acids 158-250 of SEQ ID NO: 73.

4. The bi-epitopic antibody of claim 1 , wherein the first half antibody comprises:
(a) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 39, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 40, (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 128, (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 42, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 43, and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 129;
(b) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 39, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 40, (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 41, (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 42, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 43, and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 129;
(c) a VH sequence of SEQ ID NO: 38 and a VL sequence of SEQ ID NO: 126; or
(d) a VH sequence of SEQ ID NO: 127 and a VL sequence of SEQ ID NO: 126.

5. The bi-epitopic antibody of claim 1 , wherein the second half antibody comprises
(a) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 58, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 59, (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 60, (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 61, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 62, and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 63; or
(b) a VH sequence of SEQ ID NO: 56 and a VL sequence of SEQ ID NO: 55.

6. The bi-epitopic antibody of claim 4 , wherein the second half antibody comprises:
(a) (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 58, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 59, (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 60, (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 61, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 62, and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 63; or
(b) a VH sequence of SEQ ID NO: 56 and a VL sequence of SEQ ID NO: 55.

7. The bi-epitopic antibody of claim 1 , wherein the antibody is an IgG1 or IgG4 antibody.

8. The bi-epitopic antibody of claim 1 , wherein the first half antibody comprises a first heavy chain constant region comprising a knob mutation and the second heavy chain comprises a second heavy chain constant region comprising a hole mutation; or wherein the first half antibody comprises a first heavy chain constant region comprising a hole mutation and the second heavy chain comprises a second heavy chain constant region comprising a knob mutation.

9. The bi-epitopic antibody of claim 8 , wherein the antibody is an IgG1 antibody and wherein the knob mutation comprises a T366W mutation.

10. The bi-epitopic antibody of claim 9 , wherein the antibody is an IgG1 antibody and wherein the hole mutation comprises at least one, at least two, or three mutations selected from T366S, L368A, and Y407V.

11. The bi-epitopic antibody of claim 8 , wherein the antibody is an IgG4 antibody and wherein the knob mutation comprises a T366W mutation.

12. The bi-epitopic antibody of claim 11 , wherein the antibody is an IgG4 antibody and wherein the hole mutation comprises at least one, at least two, or three mutations selected from T366S, L368A, and Y407V mutations.

13. The bi-epitopic antibody of claim 1 , wherein:
a) the first half antibody comprises a heavy chain sequence of SEQ ID NO: 159 or 163 and a light chain sequence of SEQ ID NO: 145 or 146;
b) the first half antibody comprises a heavy chain sequence of SEQ ID NO: 160 or 164 and a light chain sequence of SEQ ID NO: 145 or 146;
c) the first half antibody comprises a heavy chain sequence of SEQ ID NO: 161 or 165 and a light chain sequence of SEQ ID NO: 147 or 148; or
d) the first half antibody comprises a heavy chain sequence of SEQ ID NO: 162 or 166 and a light chain sequence of SEQ ID NO: 147 or 148.

14. The bi-epitopic antibody of claim 1 , wherein:
a) the first half antibody comprises a heavy chain sequence of SEQ ID NO: 159 or 163 and a light chain sequence of SEQ ID NO: 145 or 146, and the second half antibody comprises a heavy chain sequence of SEQ ID NO: 162 or 166 and a light chain sequence of SEQ ID NO: 147 or 148; or
b) the first half antibody comprises a heavy chain sequence of SEQ ID NO: 161 or 165 and a light chain sequence of SEQ ID NO: 147 or 148, and the second half antibody comprises a heavy chain sequence of SEQ ID NO: 160 or 164 and a light chain sequence of SEQ ID NO: 145 or 146.

15. A bi-epitopic antibody comprising a first half antibody and a second half antibody, wherein the first half antibody comprises a first VH/VL unit that binds a first epitope of B7-H4, and wherein the second half antibody comprises a second VH/VL unit that binds a second epitope of B7-H4, wherein the first half antibody comprises a heavy chain sequence of SEQ ID NO: 159 or 163 and a light chain sequence of SEQ ID NO: 145, and the second half antibody comprises a heavy chain sequence of SEQ ID NO: 162 or 166 and a light chain sequence of SEQ ID NO: 147.

16. A bi-epitopic antibody comprising a first half antibody and a second half antibody, wherein the first half antibody comprises a first VH/VL unit that binds a first epitope of B7-H4, and wherein the second half antibody comprises a second VH/VL unit that binds a second epitope of B7-H4, wherein the first half antibody comprises a heavy chain sequence of SEQ ID NO: 161 or 165 and a light chain sequence of SEQ ID NO: 147, and the second half antibody comprises a heavy chain sequence of SEQ ID NO: 160 or 164 and a light chain sequence of SEQ ID NO: 145.

17. The bi-epitopic antibody of claim 1 conjugated to a label.

18. The bi-epitopic antibody of claim 17 , wherein the label is a positron emitter.

19. The bi-epitopic antibody of claim 18 , wherein the positron emitter is 89 Zr.

Assignees

• Genentech Inc

Inventors

• Leong Steven R
• Polson Andrew
• Polakis Paul
• Wu Yan
• Liang Wei-Ching
• Firestein Ron

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P15/00

  Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives · CPC title

• G01N33/5759

  involving compounds localised on the membrane of tumour or cancer cells · CPC title