IP Library › Granted Patent US 10,377,825
Granted Patent B2
US 10,377,825 · App. 15/842,590 · Granted Aug 13, 2019

Anti-HER2 antibodies and methods of use

Inventors: Mary Mathieu (South San Francisco, CA); Mark Dennis (San Carlos, CA)
Assignee: Genentech, Inc.
C07K16/2809A61K39/39558A61P35/00C07K16/32C07K2317/24C07K2317/31C07K2317/73C07K2317/74C07K2317/92C07K2317/94
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Quick Facts
Patent No.
US 10,377,825
App. No.
15/842,590
Granted
Aug 13, 2019
Kind
B2
Abstract

The invention provides anti-HER2 antibodies, including anti-HER2 antibodies of improved stability or affinity, and methods of using the same.

Claims (58)

1. An isolated anti-HER2 antibody comprising a HER2 binding domain comprising

i. (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO:50; (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO:57; (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO:62; (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 53; (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO:48; and (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:49; or

ii. (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO:50; (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO:57; (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO:63; (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 54; (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO:48; and (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:49; or

iii. (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO:50; (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO:58; (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO:63; (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 54; (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO:48; and (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:49; or

iv. (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO:50; (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO:51; (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO:62; (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 54; (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO:48; and (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:49; or

v. (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO:50; (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO:58; (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO:63; (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 55; (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO:48; and (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:49; or

vi. (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO:50; (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO:51; (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO:63; (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 54; (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO:48; and (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:49; or

vii. (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO:50; (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO:51; (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO:65; (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO:54; (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO:48; and (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:49;

viii. (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO:50; (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO:58; (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO:63; (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO:53; (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO:48; and (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:49; or

ix. (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO:50; (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO:51; (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO:63; (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO:55; (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO:48; and (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:49.

2. An isolated anti-HER2 antibody comprising a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 3 and a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO: 4.

3. An isolated anti-HER2 antibody comprising a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 3 and a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO: 5.

4. The anti-HER2 antibody of claim 1 , comprising a HER2 binding domain comprising:

i. a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 6 and a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO: 7; or

ii. a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 8 and a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO: 9; or

iii. a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 10 and a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO: 11; or

iv. a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 12 and a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO: 13; or

v. a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 14 and a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO: 15; or

vi. a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 16 and a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO: 17; or

vii. a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 18 and a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO: 19; or

viii. a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 20 and a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO: 21; or

ix. a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 22 and a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO: 23.

5. The anti-HER2 antibody of claim 1 , wherein the anti-HER2 antibody further comprises an anti-CD3 binding domain.

6. The anti-HER2 antibody of claim 5 , wherein the anti-CD3 binding domain comprises:

i. (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:84 (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:85; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:86; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:69; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:87, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:88; or

ii. (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:66; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:67; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:68; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:69; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:70, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:71; or

iii. a VH domain comprising the amino acid sequence of SEQ ID NO:77 and a VL domain comprising the amino acid sequence of SEQ ID NO:78; or

iv. (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:72; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:73; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:74; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:69; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:75; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:76; or

v. a VH domain comprising the amino acid sequence of SEQ ID NO:79 and a VL domain comprising the amino acid sequence of SEQ ID NO:81.

7. The anti-HER2 antibody of claim 1 , wherein the anti-HER2 antibody is a monoclonal, humanized, or chimeric antibody.

8. The anti-HER2 antibody of claim 1 , wherein the anti-HER2 antibody is an IgG antibody.

9. The anti-HER2 antibody of claim 1 , wherein the anti-HER2 antibody is a multispecific antibody.

10. The anti-HER2 antibody of claim 1 , wherein the anti-HER2 antibody is a full-length antibody.

11. The anti-HER2 antibody of claim 1 , wherein the anti-HER2 antibody comprises an aglycosylation site mutation.

12. The anti-HER2 antibody of claim 1 , wherein the aglycosylation site mutation is a substitution mutation.

13. The anti-HER2 antibody of claim 1 , wherein the anti-HER2 antibody has reduced effector function.

14. The anti-HER2 antibody of claim 1 , wherein the anti-HER2 antibody comprises a substitution mutation is at amino acid residue N297, L234, L235, D265, and/or P329G according to EU numbering.

15. The anti-HER2 antibody of claim 14 , wherein the substitution mutation is selected from the group consisting of N297G, N297A, L234A, L235A, D265A, and P329G according to EU numbering.

16. The anti-HER2 antibody of claim 15 , wherein the anti-HER2 antibody comprises an N297G substitution mutation at amino acid residue 297 according to EU numbering.

17. The anti-HER2 antibody of claim 1 , wherein the anti-HER2 antibody is an antibody fragment.

18. The anti-HER2 antibody of claim 17 , wherein the antibody fragment is selected from the group consisting of a Fab, Fab′-SH, Fv, scFv, and a (Fab′)2 fragment.

19. An isolated nucleic acid encoding the anti-HER2 antibody of claim 1 .

20. A vector comprising the isolated nucleic acid of claim 19 .

21. A host cell comprising the vector of claim 20 .

22. A method of producing the anti-HER2 antibody of claim 1 , the method comprising culturing the host cell of claim 21 in a culture medium.

23. A pharmaceutical composition comprising the anti-HER2 antibody of claim 1 .

24. A method of treating or delaying the progression of a cell proliferative disorder in a subject in need thereof, the method comprising administering to the subject the anti-HER2 antibody of claim 1 .

25. A method of enhancing immune function in a subject having a cell proliferative disorder, the method comprising administering to the subject an effective amount of the anti-HER2 antibody of claim 1 .

26. The method of claim 24 or 25 , wherein the cell proliferative disorder is a cancer.

27. The method of claim 26 , wherein the cancer expresses HER2.

28. The method of claim 26 , wherein the cancer is a HER2 positive cancer.

29. The method of claim 26 , wherein the cancer is breast cancer or gastric cancer.

30. The method of claim 26 , further comprising administering to the subject a PD-1 axis binding antagonist.

31. An isolated anti-HER2 antibody comprising a HER2 binding domain comprising (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO:50; (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO:58; (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO:63; (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 54; (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO:48; and (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:49.

32. The anti-HER2 antibody of claim 31 , wherein the anti-HER2 antibody further comprises an anti-CD3 binding domain comprising (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO:66; (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO:67; (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO:68; (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO:69; (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO:70, and (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO:71.

33. An isolated anti-HER2 antibody comprising a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 10 and a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO: 11.

34. The anti-HER2 antibody of claim 33 , wherein the anti-HER2 antibody further comprises an anti-CD3 binding domain comprising a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 77 and a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO: 78.

35. The anti-HER2 antibody of claim 34 , further comprising an N297G substitution mutation at amino acid residue 297 according to EU numbering.

Continuity (3)
Continuation PCTUS2016037891 · Jun 16, 2016
Provisional Application 62181106 · Jun 17, 2015
Related Publication 20180094056A1 · Apr 5, 2018
Cited By (2)
US 1,142,813 US 12,692,315