Antigen binding molecules that bind EGFR, vectors encoding same, and uses thereof

Patent metadata

Field	Value
Publication number	US-9309317-B2
Application number	US-201314084303-A
Country	US
Kind code	B2
Filing date	Nov 19, 2013
Priority date	Feb 7, 2005
Publication date	Apr 12, 2016
Grant date	Apr 12, 2016

Abstract

The present invention relates to antigen binding molecules (ABMs). In particular embodiments, the present invention relates to recombinant monoclonal antibodies, including chimeric, primatized or humanized antibodies specific for human EGFR. In addition, the present invention relates to nucleic acid molecules encoding such ABMs, and vectors and host cells comprising such nucleic acid molecules. The invention further relates to methods for producing the ABMs of the invention, and to methods of using these ABMs in treatment of disease. In addition, the present invention relates to ABMs with modified glycosylation having improved therapeutic properties, including antibodies with increased Fc receptor binding and increased effector function.

First claim

What is claimed is:

1. An isolated polypeptide comprising a sequence selected from the group consisting of: SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:21, SEQ ID NO:23, SEQ ID NO:25, SEQ ID NO:27, SEQ ID NO:29, SEQ ID NO:31, SEQ ID NO:33, SEQ ID NO:35, SEQ ID NO:37, SEQ ID NO:39, SEQ ID NO:121, SEQ ID NO:49, and SEQ ID NO:51.

2. An isolated polypeptide comprising the sequence of SEQ ID NO:45 having an amino acid substitution selected from the group consisting of: N30R, Y32W, N34G, N50T, T51A, N52S, N53S, T56S, and F94Y.

3. An antigen binding molecule that specifically binds EGFR, comprising:
a heavy chain variable domain comprising:
(a) a CDR1 selected from the group consisting of: SEQ ID NO:55, SEQ ID NO:57, SEQ ID NO:123, SEQ ID NO:59, SEQ ID NO:61, SEQ ID NO:63, SEQ ID NO:65, SEQ ID NO:67, SEQ ID NO:69, SEQ ID NO:71, SEQ ID NO:73, and SEQ ID NO:125;
(b) the CDR2 of SEQ ID NO:79;
(c) the CDR3 of SEQ ID NO:107; and

a light chain variable domain comprising:
(a) the CDR1 of SEQ ID NO:111 or SEQ ID NO:113;
(b) the CDR2 of SEQ ID NO:115; and
(c) the CDR3 of SEQ ID NO:117.

4. The antigen binding molecule of claim 3 , wherein:
the heavy chain variable domain comprises:
(a) the CDR1 of SEQ ID NO:59 or SEQ ID NO:65;
(b) the CDR2 of SEQ ID NO:79;
(c) the CDR3 of SEQ ID NO:107; and

the light chain variable domain comprises:
(a) the CDR1 of SEQ ID NO:113;
(b) the CDR2 of SEQ ID NO:115; and
(c) the CDR3 of SEQ ID NO:117.

5. An antigen binding molecule that specifically binds EGFR, comprising:
a heavy chain variable domain comprising:
(a) a CDR1 selected from the group consisting of: SEQ ID NO:53, SEQ ID NO:55, SEQ ID NO:57, SEQ ID NO:123, SEQ ID NO:59, SEQ ID NO:61, SEQ ID NO:63, SEQ ID NO:65, SEQ ID NO:67, SEQ ID NO:69, SEQ ID NO:71, SEQ ID NO:73, and SEQ ID NO:125;
(b) a CDR2 selected from the group consisting of: SEQ ID NO:75, SEQ ID NO:77, SEQ ID NO:81, SEQ ID NO:83, SEQ ID NO:85, SEQ ID NO:87, SEQ ID NO:89, SEQ ID NO:127, SEQ ID NO:91, SEQ ID NO:93, SEQ ID NO:95, SEQ ID NO:97, SEQ ID NO:99, SEQ ID NO:101, SEQ ID NO:103, and SEQ ID NO:105;
(c) the CDR3 of SEQ ID NO:107; and

a light chain variable domain comprising:
(a) the CDR1 of SEQ ID NO:113;
(b) the CDR2 of SEQ ID NO:115; and
(c) the CDR3 of SEQ ID NO:117.

6. The antigen binding molecule of claim 5 , wherein:
the heavy chain variable domain comprises:
(a) a CDR1 selected from the group consisting of: SEQ ID NO:53, SEQ ID NO:59, and SEQ ID NO:65;
(b) the CDR2 of SEQ ID NO:91 or SEQ ID NO:97;
(c) the CDR3 of SEQ ID NO:107; and

the light chain variable domain comprises:
(a) the CDR1 of SEQ ID NO:113;
(b) the CDR2 of SEQ ID NO:115; and
(c) the CDR3 of SEQ ID NO:117.

7. The antigen binding molecule of claim 5 , wherein:
the heavy chain variable domain comprises:
(a) the CDR1 of SEQ ID NO:59;
(b) the CDR2 of SEQ ID NO:91;
(c) the CDR3 of SEQ ID NO:107; and

the light chain variable domain comprises:
(a) the CDR1 of SEQ ID NO:113;
(b) the CDR2 of SEQ ID NO:115; and
(c) the CDR3 of SEQ ID NO:117.

8. The antigen binding molecule of claim 5 , wherein:
the heavy chain variable domain comprises:
(a) the CDR1 of SEQ ID NO:65;
(b) the CDR2 of SEQ ID NO:97;
(c) the CDR3 of SEQ ID NO:107; and

the light chain variable domain comprises:
(a) the CDR1 of SEQ ID NO:113;
(b) the CDR2 of SEQ ID NO:115; and
(c) the CDR3 of SEQ ID NO:117.

9. An antigen binding molecule that specifically binds EGFR, comprising:
a heavy chain variable domain comprising a sequence selected from the group consisting of: SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:21, SEQ ID NO:23, SEQ ID NO:25, SEQ ID NO:27, SEQ ID NO:29, SEQ ID NO:31, SEQ ID NO:33, SEQ ID NO:35, SEQ ID NO:37, SEQ ID NO:39, and SEQ ID NO:121, and
a light chain variable domain comprising the sequence of SEQ ID NO:43.

10. An antigen binding molecule that specifically binds EGFR, comprising:
(a) a heavy chain variable domain comprising a sequence selected from the group consisting of: SEQ ID No:1, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:21, SEQ ID NO:23, SEQ ID NO:25, SEQ ID NO:27, SEQ ID NO:29, SEQ ID NO:31, SEQ ID NO:33, SEQ ID NO:35, SEQ ID NO:37, SEQ ID NO:39, and SEQ ID NO:121, and
(b)(1) a light chain variable domain comprising a sequence selected from the group consisting of: SEQ ID NO:45, SEQ ID NO:49, and SEQ ID NO:51, or
(b)(2) a light chain variable domain comprising the sequence of SEQ ID NO:45 having an amino acid substitution selected from the group consisting of: N30R, Y32W, N34G, N50T, T51A, N52S, N53S, T56S, and F94Y.

11. An antigen binding molecule that specifically binds EGFR, comprising:
(a) a heavy chain variable domain comprising the sequence of SEQ ID NO:15, and
(b)(1) a light chain variable domain comprising a sequence selected from the group consisting of: SEQ ID NO:43, SEQ ID NO:49, and SEQ ID NO:51, or
(b)(2) a light chain variable domain comprising the sequence of SEQ ID NO:45 having an amino acid substitution selected from the group consisting of: N30R, Y32W, N34G, N50T, T51A, N52S, N53S, T56S, and F94Y.

12. The antigen binding molecule of claim 3 , wherein the antigen binding molecule is an antibody.

13. The antigen binding molecule of claim 3 , wherein the antigen binding molecule is an antibody fragment.

14. The antigen binding molecule of claim 13 , wherein the antibody fragment is selected from the group consisting of an scFv fragment, an Fv fragment, an F(ab′)2 fragment, a minibody, a diabody, a triabody, and a tetrabody.

15. The antigen binding molecule of claim 3 , wherein the antigen binding molecule comprises an Fc region.

16. The antigen binding molecule of claim 15 , wherein the Fc region is a human Fc region.

17. The antigen binding molecule of claim 16 , wherein the human Fc region is a human IgG Fc region.

18. The antigen binding molecule of claim 15 , wherein the antigen binding molecule has been glycoengineered to modify the oligosaccharides in the Fc region.

19. The antigen binding molecule of claim 18 , wherein the Fc region has a reduced number of fucose residues as compared to the nonglycoengineered antigen binding molecule.

20. The antigen binding molecule of claim 18 , wherein the glycoengineered antigen binding molecule has an increased ratio of GlcNAc residues to fucose residues in the Fc region compared to the nonglycoengineered antigen binding molecule.

21. The antigen binding molecule of claim 18 , wherein the Fc region has an increased proportion of bisected oligosaccharides as compared to the nonglycoengineered antigen binding molecule.

22. The antigen binding molecule of claim 18 , wherein the modified oligosaccharides are bisected complex.

23. The antigen binding molecule of claim 18 , wherein the modified oligosaccharides have an increased proportion of bisected, nonfucosylated oligosaccharides in the Fc region of the antigen binding molecule compared to the nonglycoengineered antigen binding molecule.

24. The antigen binding molecule of claim 23 , wherein the bisected, nonfucosylated Oligosaccharides are hybrid.

25. The antigen binding molecule of claim 23 , wherein the bisected, nonfucosylated oligosaccharides are complex.

26. The antigen binding

Assignees

• Roche Glycart Ag

Inventors

• Umaña Pablo
• Mössner Ekkehard

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07K2317/732

  Antibody-dependent cellular cytotoxicity [ADCC] · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K2039/505

  comprising antibodies · CPC title

• A61K39/39533

  against materials from animals · CPC title