Anti-transferrin receptor antibodies and methods of use

Patent metadata

Field	Value
Publication number	US-9708406-B2
Application number	US-201414283038-A
Country	US
Kind code	B2
Filing date	May 20, 2014
Priority date	May 20, 2013
Publication date	Jul 18, 2017
Grant date	Jul 18, 2017

Abstract

The present invention relates to anti-transferrin receptor antibodies and methods of their use.

First claim

What is claimed is:

1. An isolated antibody that binds to human transferrin receptor (TfR), wherein the antibody comprises an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 53, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 156, HVR-H3 comprising the amino acid sequence of SEQ ID NO: 55, HVR-L1 comprising the amino acid sequence of SEQ ID NO: 50, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 51, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 52.

2. The antibody of claim 1 , which is a monoclonal antibody.

3. The antibody of claim 1 , which is a humanized or chimeric antibody.

4. The antibody of claim 1 , which is an antibody fragment that binds human TfR.

5. The antibody of claim 1 , comprising (a) a VH sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 153; (b) a VL sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 105 or (c) a VH sequence as in (a) and a VL sequence as in (b).

6. The antibody of claim 5 , comprising a VH sequence of
SEQ ID NO: 153.

7. The antibody of claim 5 , comprising a VL sequence of
SEQ ID NO:105.

8. The antibody of claim 1 , wherein the antibody is produced in a non-mammalian cell production system, or where the antibody is produced synthetically.

9. The antibody of claim 1 , wherein the Fc region of the antibody comprises a mutation at position 297 such that the wild-type asparagine residue at that position is replaced with another amino acid that interferes with glycosylation at that position.

10. The antibody of claim 1 , wherein the Fc region of the antibody comprises a mutation at one or more of the following positions: 132, 234, 235, 238, 239, 248, 249, 252, 254, 256, 265, 268, 269, 270, 272, 278, 289, 292, 293, 294, 295, 296, 297, 298, 301, 303, 321, 322, 324, 327, 329, 333, 335, 338, 340, 373, 376, 382, 388, 389, 414, 416, 419, 434, 435, 436, 437, 438, and 439.

11. The antibody of claim 10 , wherein the Fc region comprises a mutation at one or more of the following positions: 234, 235, 265, 297 and 329.

12. The antibody of claim 11 , wherein the Fc region comprises a mutation at position 297 or comprises mutations at positions 265 and 297.

13. The antibody of claim 11 , wherein the Fc region comprises mutations at positions 234, 235 and 329.

14. The antibody of claim 12 , wherein the Fc region comprises a N297G mutation; or D265A and N297A mutations; or D265A and N297G mutations.

15. The antibody of claim 13 , wherein the Fc region comprises L234A, L235A, and P329G mutations.

16. The antibody of claim 10 , wherein the Fc region comprises a mutation at one or more of the following positions: 252, 254, 256, 434 and 436.

17. The antibody of claim 16 , wherein the Fc region comprises mutations at positions 252, 254 and 256.

18. The antibody of claim 16 , wherein the Fc region comprises mutations at positions 434 and 436.

19. The antibody of claim 17 , wherein the Fc region comprises M252Y, S254T and T256E mutations.

20. The antibody of claim 18 , wherein the Fc region comprises N434A and Y436I mutations.

21. The antibody of claim 1 , wherein the antibody has a KD or IC50for TfR of about 1 pM to about 100 μM.

22. The antibody of claim 1 , wherein the antibody is coupled to a therapeutic compound.

23. The antibody of claim 22 , wherein the antibody is a multispecific antibody and the therapeutic compound forms one portion of the multispecific antibody.

24. The antibody of claim 23 , wherein the multispecific antibody comprises a first antigen binding site which binds TfR and a second antigen binding site which binds a brain antigen.

25. The antibody of claim 24 , wherein the brain antigen is selected from the group consisting of: beta-secretase 1 (BACE1), Abeta, epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), tau, apolipoprotein E (ApoE), alpha-synuclein, CD20, huntingtin, prion protein (PrP), leucine rich repeat kinase 2 (LRRK2), parkin, presenilin 1, presenilin 2, gamma secretase, death receptor 6 (DR6), amyloid precursor protein (APP), p75 neurotrophin receptor (p75NTR), and caspase 6.

26. The antibody of claim 25 , wherein the multispecific antibody binds both TfR and BACE1.

27. The antibody of claim 25 , wherein the multispecific antibody binds both TfR and Abeta.

28. The antibody of claim 22 , wherein the therapeutic compound is a neurological disorder drug.

29. An isolated nucleic acid encoding the antibody of claim 1 .

30. A host cell comprising the nucleic acid of claim 29 .

31. A method of producing an antibody comprising culturing the host cell of claim 30 so that the antibody is produced and optionally further comprising recovering the antibody from the host cell.

32. A pharmaceutical formulation comprising the antibody of claim 1 and a pharmaceutically acceptable carrier.

33. The isolated antibody of claim 1 , wherein the antibody comprises a heavy chain variable region (VH) sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 153 and a light chain variable region (VL) sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 105.

34. An isolated antibody that binds to human transferrin receptor (TfR) wherein the antibody comprises a heavy chain variable region (VH) sequence having the amino acid sequence of SEQ ID NO: 153 and a light chain variable region (VL) sequence having the amino acid sequence of SEQ ID NO: 105.

35. The antibody of claim 34 , wherein the Fc region of the antibody comprises a mutation at one or more of the following positions: 132, 234, 235, 238, 239, 248, 249, 252, 254, 256, 265, 268, 269, 270, 272, 278, 289, 292, 293, 294, 295, 296, 297, 298, 301, 303, 321, 322, 324, 327, 329, 333, 335, 338, 340, 373, 376, 382, 388, 389, 414, 416, 419, 434, 435, 436, 437, 438, and 439.

36. The antibody of claim 35 , wherein the Fc region comprises a mutation at one or more of the following positions: 234, 235, 265, 297 and 329.

37. The antibody of claim 36 , wherein the antibody comprises mutations at positions 234, 235 and 329.

38. The antibody of claim 37 , wherein the Fc region comprises L234A, L235A, and P329G mutations.

39. The antibody of claim 38 , wherein the Fc region comprises mutations at positions 252, 254 and 256.

40. The antibody of claim 39 , wherein the Fc region comprises M252Y, S254T and T256E mutations.

41. The antibody of claim 34 , wherein the antibody is coupled to a therapeutic compound.

42. The antibody of claim 41 , wherein the antibody is a multispecific antibody and the therapeutic compound forms one portion of the multispecific antibody.

43. The antibody of claim 42 , wherein the multispecific antibody comprises a first antigen binding site which binds TfR and a second antigen binding site which binds a brain antigen.

44. The antibody of claim 43 , wherein the brain antigen is selected from the group consisting of: beta-secretase 1 (BACE1), Abeta, epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), tau, apolipoprotein E (ApoE), a

Assignees

• Genentech Inc

Inventors

• Zhang Yin
• Zuchero Joy Yu
• Atwal Jasvinder
• Couch Jessica
• Dennis Mark S
• Ernst James A
• Watts Ryan J
• Lazar Gregory A

Classifications

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P31/12

  Antivirals · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• A61P27/02

  Ophthalmic agents · CPC title