Method for Delivering Drug to Muscle

Patent metadata

Field	Value
Publication number	US-2021038739-A1
Application number	US-201916963956-A
Country	US
Kind code	A1
Filing date	Feb 5, 2019
Priority date	Feb 5, 2018
Publication date	Feb 11, 2021
Grant date	—

Abstract

[Problems] To provide a technique for efficiently incorporating an agent having to function in muscle tissue, which is not sufficiently incorporated into muscle tissue when administered in body, into muscle tissue, particularly muscle tissue composed of skeletal muscle or cardiac muscle. [Solution] A conjugate of an anti-human transferrin receptor antibody and an agent, wherein the agent is a biologically active agent that should function in muscle tissue, e.g., a lysosomal enzyme such as acid α-glucosidase, α-galactosidase A.

First claim

1 . A conjugate of an anti-human transferrin receptor antibody and an agent, wherein the agent has a physiological activity to be exerted in muscle.

2 . The conjugate according to claim 1 , wherein the anti-human transferrin receptor antibody is a Fab antibody, a F(ab′) 2 antibody, or a F(ab′) antibody.

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

4 . The conjugate according to claim 3 , wherein in the single-chain antibody a light chain and a heavy chain of the anti-human transferrin receptor antibody are linked via a linker sequence.

5 . The conjugate according to claim 4 , wherein the light chain and the heavy chain of the anti-human transferrin receptor antibody are linked on the C-terminal side of the light chain via the linker sequence.

6 . The conjugate according to claim 4 , wherein the light chain and the heavy chain of the anti-human transferrin receptor antibody are linked on the C-terminal side of the heavy chain via the linker sequence.

7 . The conjugate according to claim 4 , wherein the linker sequence comprises 8 to 50 amino acid residues.

8 . The conjugate according to claim 7 , wherein the linker sequence comprises an amino acid sequence 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 sequence set forth as SEQ ID NO: 3, and the amino acid sequence set forth as SEQ ID NO: 4.

9 . The conjugate according to claim 8 , wherein the linker sequence comprises 15 amino acid residues in which the amino acid sequence set forth as SEQ ID NO: 4 is consecutively repeated three times.

10 . The conjugate according to claim 1 , wherein the anti-human transferrin receptor antibody comprises the amino acid sequence set forth as SEQ ID NO: 22 in the variable region of the light chain and the amino acid sequence set forth as SEQ ID NO: 23 in the variable region of the heavy chain.

11 . The conjugate according to claim 10 , wherein the amino acid sequence of the variable region of the light chain has an identity not lower than 80% to the amino acid sequence set forth as SEQ ID NO: 22, and the amino acid sequence of the variable region of the heavy chain has an identity not lower than 80% to the amino acid sequence set forth as SEQ ID NO: 23.

12 . The conjugate according to claim 10 , wherein the amino acid sequence of the variable region of the light chain has an identity not lower than 90% to the amino acid sequence set forth as SEQ ID NO: 22, and the amino acid sequence of the variable region of the heavy chain has an identity not lower than 90% to the amino acid sequence set forth as SEQ ID NO: 23.

13 . The conjugate according to claim 10 , wherein 1 to 10 amino acids constituting the variable region of the light chain are substituted with other amino acids relative to the amino acid sequence set forth as SEQ ID NO: 22.

14 . The conjugate according to claim 10 , wherein 1 to 3 amino acids constituting the variable region of the light chain are substituted with other amino acids relative to the amino acid sequence set forth as SEQ ID NO: 22.

15 . The conjugate according to claim 10 , wherein 1 to 10 amino acids constituting the variable region of the heavy chain are substituted with other amino acids relative to the amino acid sequence set forth as SEQ ID NO: 23.

16 . The conjugate according to claim 10 , wherein 1 to 3 amino acids constituting the variable region of the heavy chain are substituted with other amino acids relative to the amino acid sequence set forth as SEQ ID NO: 23.

17 . The conjugate according to claim 10 , wherein 1 to 10 amino acids constituting the variable region of the light chain are substituted with other amino acids relative to the amino acid sequence set forth as SEQ ID NO: 22, and 1 to 10 amino acids constituting the variable region of the heavy chain are substituted with other amino acids relative to the amino acid sequence set forth as SEQ ID NO: 23.

18 . The conjugate according to claim 10 , wherein 1 to 3 amino acids constituting the variable region of the light chain are substituted with other amino acids relative to the amino acid sequence set forth as SEQ ID NO: 22, and 1 to 3 amino acids constituting the variable region of the heavy chain are substituted with other amino acids relative to the amino acid sequence set forth as SEQ ID NO: 23.

19 . The conjugate according to claim 10 , wherein the anti-human transferrin receptor antibody comprises the light chain comprising an amino acid sequence set forth as SEQ ID NO: 24 and the heavy chain comprising an amino acid sequence set forth as SEQ ID NO: 25.

20 . The conjugate according to claim 19 , wherein the amino acid sequence of the light chain has an identity not lower than 80% to the amino acid sequence set forth as SEQ ID NO: 24, and the amino acid sequence of the heavy chain has an identity not lower than 80% to the amino acid sequence set forth as SEQ ID NO: 25.

21 . The conjugate according to claim 19 , wherein the amino acid sequence of the light chain has an identity not lower than 90% to the amino acid sequence set forth as SEQ ID NO: 24, and the amino acid sequence of the heavy chain has an identity not lower than 90% to the amino acid sequence set forth as SEQ ID NO: 25.

22 . The conjugate according to claim 1 , wherein the agent is a peptide or a protein.

23 . The conjugate according to claim 22 , selected from the group consisting of (1) to (4) below:
(1) a conjugate in which the protein is linked to the C-terminal side of the light chain of the anti-human transferrin receptor antibody by a peptide bond, (2) a conjugate in which the protein is linked to the N-terminal side of the light chain of the anti-human transferrin receptor antibody by a peptide bond, (3) a conjugate in which the protein is linked to the C-terminal side of the heavy chain of the anti-human transferrin receptor antibody by a peptide bond, and (4) a conjugate in which the protein is linked to the N-terminal side of the heavy chain of the anti-human transferrin receptor antibody by a peptide bond.

24 . The conjugate according to claim 23 , wherein the protein is linked to the anti-human transferrin receptor antibody via a linker sequence.

25 . The conjugate according to claim 24 , wherein the linker sequence consists of 1 to 50 amino acid residues.

26 . The conjugate according to claim 25 , wherein the linker sequence comprises 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, and the amino acid sequence consisting of 1 to 10 amino acid sequences thereof that are linked consecutively.

27 . The conjugate according to claim 1 , wherein the anti-human transferrin receptor antibody is a humanized anti-human transferrin receptor antibody.

28 . The conjugate according to claim 22 , wherein the protein is a lysosomal enzyme.

29 . The conjugate according to claim 28 , wherein the lysosomal enzyme is human α-galactosidase A.

30 . The conjugate acco

Assignees

• Japan Chem Res

Inventors

• Takahashi Kenichi
• Sonoda Hiroyuki

Classifications

• C07K2317/77

  Internalization into the cell · CPC title

• C07K2317/33

  Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity · CPC title

• A61K2300/00

  Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 · CPC title

• A61K39/3955

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

• A61K47/6849

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