Anti-Human Transferrin Receptor Antibody Permeating Blood-Brain Barrier

Patent metadata

Field	Value
Publication number	US-2022064288-A1
Application number	US-202117530587-A
Country	US
Kind code	A1
Filing date	Nov 19, 2021
Priority date	Jun 24, 2015
Publication date	Mar 3, 2022
Grant date	—

Abstract

Disclosed are a means to convert compounds having physiological or pharmacological activity and unable to pass through the blood-brain barrier into a form that allows them to pass through the blood-brain barrier, and compounds converted thereby. The means is an anti-human transferrin receptor antibody and the converted compounds are molecular conjugates between physiologically active protein or pharmacologically active low-molecular-weight compounds and an anti-human transferrin receptor antibody.

First claim

1 - 69 . (canceled)

70 . A fusion protein comprising the amino acid sequences of a humanized anti-human transferrin receptor antibody and iduronate 2-sulfatase,
wherein the amino acid sequence of iduronate 2-sulfatase is linked to the light chain of the antibody on the C-terminal side or the N-terminal side of the light chain, or linked to the heavy chain of the antibody on the C-terminal side or the N-terminal side of the heavy chain, and wherein the light chain variable region and the heavy chain variable region of the antibody are selected from (1) or (2) below: (1) the light chain variable region comprising the amino acid sequence having an identity not lower than 90% to the amino acid sequence set forth as SEQ ID NO: 191, and comprising the amino acid sequence set forth as SEQ ID NO:16 as CDR1, the amino acid sequence set forth as SEQ ID NO:18 as CDR2, and the amino acid sequence set forth as SEQ ID NO:20 as CDR3, and the heavy chain variable region comprising the amino acid sequence having an identity not lower than 90% to the amino acid sequence set forth as SEQ ID NO: 205, and comprising the amino acid sequence set forth as SEQ ID NO:88 as CDR1, the amino acid sequence set forth as SEQ ID NO:90 as CDR2, and the amino acid sequence set forth as SEQ ID NO:92 as CDR3; (2) the light chain variable region comprising the amino acid sequence having an identity not lower than 90% to the amino acid sequence set forth as SEQ ID NO: 191, and comprising the amino acid sequence set forth as SEQ ID NO:16 as CDR1, the amino acid sequence set forth as SEQ ID NO:18 as CDR2, and the amino acid sequence set forth as SEQ ID NO:20 as CDR3, and the heavy chain variable region comprising the amino acid sequence having an identity not lower than 90% to the amino acid sequence set forth as SEQ ID NO: 205, and comprising the amino acid sequence set forth as SEQ ID NO:89 as CDR1, the amino acid sequence set forth as SEQ ID NO:90 as CDR2, and the amino acid sequence set forth as SEQ ID NO:92 as CDR3.

71 . A fusion protein comprising the amino acid sequences of a humanized anti-human transferrin receptor antibody and iduronate 2-sulfatase, wherein the amino acid sequence of the antibody is selected from the group consisting of (1) to (4) below:
(1) the light chain variable region of the antibody comprises the amino acid sequence set forth as SEQ ID NO:191, and the heavy chain variable region of the antibody comprises the amino acid sequence set forth as SEQ ID NO:205; (2) the light chain variable region of the antibody comprises the amino acid sequence set forth as SEQ ID NO:193, and the heavy chain variable region of the antibody comprises the amino acid sequence set forth as SEQ ID NO:205; (3) the light chain variable region of the antibody comprises the amino acid sequence set forth as SEQ ID NO:194, and the heavy chain variable region of the antibody comprises the amino acid sequence set forth as SEQ ID NO:205; and (4) the light chain variable region of the antibody comprises the amino acid sequence set forth as SEQ ID NO:195, and the heavy chain variable region of the antibody comprises the amino acid sequence set forth as SEQ ID NO:205.

72 . A fusion protein comprising the amino acid sequences of a humanized anti-human transferrin receptor antibody and iduronate 2-sulfatase, wherein the amino acid sequence of the antibody is selected from the group consisting of (1) to (8) below:
(1) the light chain of the antibody comprises the amino acid sequence set forth as SEQ ID NO:196, and the heavy chain of the antibody comprises the amino acid sequence set forth as SEQ ID NO:210; (2) the light chain of the antibody comprises the amino acid sequence set forth as SEQ ID NO:198, and the heavy chain of the antibody comprises the amino acid sequence set forth as SEQ ID NO:210; (3) the light chain of the antibody comprises the amino acid sequence set forth as SEQ ID NO:200, and the heavy chain of the antibody comprises the amino acid sequence set forth as SEQ ID NO:210; (4) the light chain of the antibody comprises the amino acid sequence set forth as SEQ ID NO:202, and the heavy chain of the antibody comprises the amino acid sequence set forth as SEQ ID NO:210; (5) the light chain of the antibody comprises the amino acid sequence set forth as SEQ ID NO:196, and the heavy chain of the antibody comprises the amino acid sequence set forth as SEQ ID NO:212; (6) the light chain of the antibody comprises the amino acid sequence set forth as SEQ ID NO:198, and the heavy chain of the antibody comprises the amino acid sequence set forth as SEQ ID NO:212; (7) the light chain of the antibody comprises the amino acid sequence set forth as SEQ ID NO:200, and the heavy chain of the antibody comprises the amino acid sequence set forth as SEQ ID NO:212; and (8) the light chain of the antibody comprises the amino acid sequence set forth as SEQ ID NO:202, and the heavy chain of the antibody comprises the amino acid sequence set forth as SEQ ID NO:212.

73 . The fusion protein according to claim 70 , wherein the antibody has an affinity to both the extracellular region of human transferrin receptor and the extracellular region of monkey transferrin receptor.

74 . The fusion protein according to claim 73 , wherein the dissociation constant of the antibody's complex with the extracellular region of human transferrin receptor is not greater than 1×10 −8 M, and the dissociation constant of the antibody's complex with the extracellular region of monkey transferrin receptor is not greater than 5×10 −8 M.

75 . The fusion protein according to claim 70 , wherein the antibody is Fab antibody, F(ab′)2 antibody, or F(ab′) antibody.

76 . The fusion protein according to claim 70 , wherein the antibody is a single-chain antibody selected from the group consisting of scFab, scF(ab′), scF(ab′)2 and scFv.

77 . The fusion protein according to claim 76 , wherein the light chain and the heavy chain thereof are linked via a linker sequence.

78 . The fusion protein according to claim 76 , wherein the heavy chain is linked, via a linker sequence, to the light chain on the C-terminal side of the light chain.

79 . The fusion protein according to claim 76 , wherein the light chain is linked, via a linker sequence, to the heavy chain on the C-terminal side of the heavy chain.

80 . The fusion protein according to claim 77 , wherein the linker sequence consists of 8 to 50 amino acid residues.

81 . The fusion protein according to claim 80 , 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, and the amino acid sequence consisting of three consecutively linked amino acid sequences each set forth as SEQ ID NO:3.

82 . The fusion protein according to claim 70 , wherein the iduronate 2-sulfatase is linked, via a linker sequence, to the light chain on the C-terminal side or the N-terminal side of the light chain, or to the heavy chain on the C-terminal side or the N-terminal side of the heavy chain.

83 : The fusion protein according to claim 81 , wherein the linker sequence consists of 1 to 50 amino acid residues.

84 . The fusion protein according to claim 81 , 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 N

Assignees

• Japan Chem Res

Inventors

• Sonoda Hiroyuki
• Takahashi Kenichi

Classifications

• C07K2317/92

  Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value · CPC title

• C07K2317/24

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

• C12Y301/06013

  Iduronate-2-sulfatase (3.1.6.13) · CPC title

• A61P25/00 Primary

  Drugs for disorders of the nervous system · CPC title

• C12N15/63

  Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression · CPC title