Anti-human transferrin receptor antibody capable of penetrating blood-brain barrier

Patent metadata

Field	Value
Publication number	US-10759864-B2
Application number	US-201716473446-A
Country	US
Kind code	B2
Filing date	Dec 26, 2017
Priority date	Dec 26, 2016
Publication date	Sep 1, 2020
Grant date	Sep 1, 2020

Abstract

Provided is an anti-human transferrin receptor antibody or an analog thereof, wherein in the heavy chain variable region of the antibody, (a) CDR1 comprises the amino acid sequence set forth as SEQ ID NO: 62 or SEQ ID NO: 63, (b) CDR2 comprises the amino acid sequence set forth as SEQ ID NO: 13 or SEQ ID NO: 14, and (c) CDR3 comprises the amino acid sequence set forth as SEQ ID NO: 15 or SEQ ID NO: 16, and an analogue thereof.

First claim

The invention claimed is:

1. An anti-human transferrin receptor antibody, wherein in the heavy chain variable region of the antibody,
(a) CDR1 comprises the amino acid sequence set forth as SEQ ID NO: 62 or SEQ ID NO: 63,
(b) CDR2 comprises the amino acid sequence set forth as SEQ ID NO: 13 or SEQ ID NO: 14, and
(c) CDR3 comprises the amino acid sequence set forth as SEQ ID NO: 15 or SEQ ID NO: 16, and
in the light chain variable region of the antibody,
(a) CDR1 comprises the amino acid sequence set forth as SEQ ID NO: 6 or SEQ ID NO: 7,
(b) CDR2 comprises the amino acid sequence set forth as SEQ ID NO: 8 or SEQ ID NO: 9, or the amino acid sequence Lys-Val-Ser, and
(c) CDR3 comprises the amino acid sequence set forth as SEQ ID NO: 10.

2. The antibody according to claim 1 , wherein the light chain variable region of the antibody comprises the amino acid sequence set forth as SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21 or SEQ ID NO: 22.

3. The antibody according to claim 1 , wherein the light chain of the antibody comprises the amino acid sequence set forth as SEQ ID NO: 23, SEQ ID NO: 25, SEQ ID NO: 27 or SEQ ID NO: 29.

4. The antibody according to claim 1 , wherein the antibody is Fab antibody, F(ab′) 2 antibody, or F(ab′) antibody.

5. The antibody according to claim 1 , wherein the framework region 3 of the heavy chain comprises the amino acid sequence set forth as SEQ ID NO: 64.

6. The antibody according to claim 5 , wherein the heavy chain variable region comprises the amino acid sequence set forth as SEQ ID NO: 65.

7. The antibody according to claim 6 , wherein the heavy chain comprises the amino acid sequence set forth as SEQ ID NO: 66 or SEQ ID NO: 68.

8. The antibody according to claim 1 , wherein the antibody has an affinity to both the extracellular region of human transferrin receptor and the extracellular region of monkey transferrin receptor.

9. The antibody according to claim 8 , wherein the dissociation constant of its complex with the extracellular region of human transferrin receptor is not greater than 1×10 −10 M, and the dissociation constant of its complex with the extracellular region of monkey transferrin receptor is not greater than 1×10 −9 M.

10. The anti-human transferrin receptor antibody according to claim 1 , wherein the antibody is a single-chain antibody selected from the group consisting of scFab, scF(ab′), scF(ab′) 2 and scFv.

11. The antibody according to claim 10 , wherein the light chain is linked, via a linker sequence, to the heavy chain on the C-terminal side of the heavy chain.

12. The antibody according to claim 10 , wherein the light chain and the heavy chain of the antibody are linked via a linker sequence.

13. The antibody according to claim 12 , wherein the heavy chain is linked, via a linker sequence, to the light chain on the C-terminal side of the light chain.

14. The antibody according to claim 12 , wherein the linker sequence consists of 2 to 50 amino acid residues.

15. The antibody according to claim 14 , wherein the linker sequence is selected from the group consisting of the amino acid sequence Gly-Ser, the amino acid sequence Gly-Gly-Ser, the amino acid sequence Gly-Gly-Gly, the amino acid sequences set forth as SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, the amino acid sequence consisting of three consecutively linked amino acid sequences each set forth as SEQ ID NO: 3, and the amino acid sequences consisting of 2 to 10 repeats of any of the aforementioned sequences that are consecutively linked.

16. A fusion protein comprising an anti-human transferrin receptor antibody and a different protein (A),
wherein the anti-human transferrin receptor antibody is the antibody according to claim 1 , and
the protein (A) is linked to the light chain of the antibody on the C-terminal side or the N-terminal side of the light chain.

17. The fusion protein according to claim 16 , wherein the protein (A) is linked, directly or via a linker, to the light chain on the C-terminal side or the N-terminal side of the light chain.

18. The fusion protein according to claim 16 , wherein the protein (A) is a lysosomal enzyme, wherein the lysosomal enzyme is selected from the group consisting of α-L-iduronidase, iduronate 2-sulfatase, human acidic α-glucosidase, glucocerebrosidase, β-galactosidase, GM2 activator protein, β-hexosaminidase A, β-hexosaminidase B, N-acetylglucosamine-1-phosphotransferase, α-mannosidase, β-mannosidase, galactosylceramidase, saposin C, arylsulfatase A, α-L-fucosidase, aspartylglucosaminidase, α-N-acetylgalactosaminidase, acidic sphingomyelinase, α-galactosidase A,β-glucuronidase, heparan N-sulfatase, α-N-acetylglucosaminidase, acetyl CoA: α-glucosaminide N-acetyltransferase, N-acetylglucosamine-6-sulfate sulfatase, acid ceramidase, amylo-1,6-glucosidase, sialidase, palmitoyl protein thioesterase 1, tripeptidyl-peptidase 1, hyaluronidase 1, CLN1 and CLN2.

19. The fusion protein according to claim 16 , wherein the protein (A) is human iduronate 2-sulfatase, human acidic α-glucosidase, or human α-L-iduronidase.

20. The fusion protein according to claim 16 , wherein the protein (A) is linked, via a linker, to the light chain on the C-terminal side or the N-terminal side of the light chain.

21. The fusion protein according to claim 20 , wherein the linker is a peptide consisting of 1 to 50 amino acid residues.

22. The fusion protein according to claim 21 , wherein the linker is a peptide comprising an amino acid sequence selected from the group consisting of a single glycine, a single serine, the amino acid sequence Gly-Ser, the amino acid sequence Gly-Gly-Ser, the amino acid sequence set forth as SEQ ID NO: 3, the amino acid sequence set forth as SEQ ID NO: 4, the amino acid sequence set forth as SEQ ID NO: 5, and the amino acid sequences consisting of 2 to 10 of any of the aforementioned sequences that are consecutively linked.

23. The fusion protein according to claim 16 , wherein the protein (A) is a protein originating from human.

24. The fusion protein according to claim 23 , wherein the protein (A) is human acidic α-glucosidase, wherein
(1) the light chain of the antibody comprises the amino acid sequence set forth as SEQ ID NO: 23, and
(2) the heavy chain of the antibody is linked, on the C-terminal side of the heavy chain and via the amino acid sequence Gly-Ser, to the human acidic α-glucosidase, thereby forming the amino acid sequence set forth as SEQ ID NO: 57 or SEQ ID NO: 58.

25. The fusion protein according to claim 23 , wherein the protein (A) is human acidic α-glucosidase, wherein
(1) the light chain of the antibody comprises the amino acid sequence set forth as SEQ ID NO: 23, and
(2) the heavy chain of the antibody comprises the amino acid sequence set forth as SEQ ID NO: 66 or SEQ ID NO: 68, and the heavy chain is linked, on the C-terminal side of the heavy chain and via the amino acid sequence Gly-Ser, to the human acidic α-glucosidase having the amino acid sequence set forth as SEQ ID NO: 55 or 56.

26. The fusion protein according to claim 23 , wherein the protein (A) is human acidic α-glucosidase, wherein the antibody is Fab antibody, and wherein
(1) the light chain of the antibody comprises the amino acid sequence set forth as SEQ ID NO: 23, and
(2) the heavy chain of the antibody is linked, on the C-terminal side of the heavy chain and via the amino acid sequence consisting of three

Assignees

• Japan Chem Res

Inventors

• Sonoda Hiroyuki
• Takahashi Kenichi

Classifications

• C12Y310/01001

  N-Sulfoglucosamine sulfohydrolase (3.10.1.1) · CPC title

• C12N9/14

  Hydrolases (3) · CPC title

• C07K2317/24

  containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered · CPC title

• C07K2319/33

  fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies · CPC title

• C07K16/2881 Primary

  against CD71 · CPC title