Anti-transferrin receptor antibodies and methods of use

Patent metadata

Field	Value
Publication number	US-10808036-B2
Application number	US-201715614149-A
Country	US
Kind code	B2
Filing date	Jun 5, 2017
Priority date	May 20, 2013
Publication date	Oct 20, 2020
Grant date	Oct 20, 2020

Abstract

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

First claim

What is claimed is:

1. A method of transporting a compound across the blood brain barrier (BBB) in a subject comprising exposing an antibody coupled to the compound to the BBB such that the antibody transports the compound coupled thereto across the BBB, wherein the antibody binds to human transferrin receptor (TfR) and 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. A method of increasing exposure of the CNS of a subject to a compound, comprising exposing an antibody coupled to the compound to the blood brain barrier (BBB) such that the antibody transports the compound coupled thereto across the BBB, wherein the antibody binds to human transferrin receptor (TfR) and 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.

3. A method of increasing retention in the CNS of a compound administered to a subject, comprising exposing an antibody coupled to the compound to the blood brain barrier (BBB) such that the retention in the CNS of the compound is increased, wherein the antibody binds to human transferrin receptor (TfR) and 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.

4. A method of treating a neurological disorder in a mammal comprising treating the mammal with an antibody coupled to a therapeutic compound, wherein the antibody binds to human transferrin receptor (TfR) and 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; and wherein (a) the therapeutic compound is a neurological disorder drug or (b) the antibody is a multispecific antibody, the therapeutic compound forms one portion of the antibody, and the multispecific antibody comprises a first antigen binding site which binds TfR and a second antigen binding site which binds a brain antigen.

5. The method of claim 4 , wherein the neurological disorder is selected from a neuropathy disorder, a neurodegenerative disease, cancer, an ocular disease disorder, a seizure disorder, a lysosomal storage disease, amyloidosis, a viral or microbial disease, ischemia, a behavioral disorder, and CNS inflammation.

6. The method of claim 4 , wherein the neurological disorder is in a human subject.

7. The method of claim 6 , wherein the antibody is administered intravenously, and wherein the dose amount and/or frequency of the antibody is modulated to reduce the concentration of antibody to which the red blood cells are exposed.

8. The method of claim 6 , further comprising the step of monitoring the subject for depletion of red blood cells.

9. The method of claim 6 , wherein the antibody coupled to the therapeutic compound is administered at a therapeutic dose.

10. The method of claim 9 , wherein the therapeutic dose is TfR-saturating.

11. The method of claim 6 , wherein administration of the antibody is at a dose and/or dose frequency calibrated to minimize acute clinical symptoms of the antibody administration.

12. The method of claim 4 , wherein the antibody is a monoclonal antibody.

13. The method of claim 4 , wherein the antibody is a humanized or chimeric antibody.

14. The method of claim 4 , wherein the antibody is an antibody fragment that binds human TfR.

15. The method of claim 4 , wherein the antibody comprises (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).

16. The method of claim 15 , wherein the antibody comprises a VH sequence of SEQ ID NO: 153 and a VL sequence of SEQ ID NO: 105.

17. The method of claim 4 , wherein 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.

18. The method of claim 4 , 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.

19. The method of claim 4 , wherein the Fc region comprises a mutation at one or more of the following positions: 234, 235, 265, 297 and 329.

20. The method of claim 19 , wherein the Fc region comprises a mutation at position 297 or comprises mutations at positions 265 and 297.

21. The method of claim 19 , wherein the Fc region comprises mutations at positions 234, 235 and 329.

22. The method of claim 20 , wherein the Fc region comprises a N297G mutation; or D265A and N297A mutations; or D265A and N297G mutations.

23. The method of claim 21 , wherein the Fc region comprises L234A, L235A, and P329G mutations.

24. 1The method of claim 4 , wherein the Fc region comprises a mutation at one or more of the following positions: 252, 254, 256, 434 and 436.

25. The method of claim 24 , wherein the Fc region comprises mutations at positions 252, 254 and 256.

26. The method of claim 24 , wherein the Fc region comprises mutations at positions 434 and 436.

27. The method of claim 25 , wherein the Fc region comprises M252Y, S254T and T256E mutations.

28. The method of claim 26 , wherein the Fc region comprises N434A and Y436I mutations.

29. The method of claim 4 , wherein the antibody has a KD or IC50 for TfR of about 1 pM to about 100 μM.

30. The method of claim 4 , wherein the antibody is a multispecific antibody and the therapeutic compound forms one portion of the multispecific antibody; and wherein the multispecific antibody comprises a first antigen binding site which binds TfR and a second antigen binding site which binds a brain antigen.

31. The method of claim 30 , wherein the brain antigen is selected from 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

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

• A61K47/6849

  the antibody targeting a receptor, a cell surface antigen or a cell surface determinant · CPC title

• C07K2317/565

  Complementarity determining region [CDR] · CPC title

• C07K16/2881 Primary

  against CD71 · CPC title

• A61K39/3955

  against proteinaceous materials, e.g. enzymes, hormones, lymphokines · CPC title

• C07K2317/71

  Decreased effector function due to an Fc-modification · CPC title