Granted Patent B2

US 12,569,578 · App. 17/825,430 · Granted Mar 10, 2026

Inventors: Norihito Nakata (Tokyo, JP); Nobuya Kobashi (Tokyo, JP); Yoshinari Shoyama (Tokyo, JP); Mitsuhiro Matono (Osaka, JP); Yasushi Ochiai (Tokyo, JP); Takayuki Murakami (Mie, JP)

Assignee: NIHON MEDI-PHYSICS CO., LTD.

A61K51/1045A61K51/0482C07K16/3092C07K2317/24

Abstract

Claims (132)

1 . A conjugate comprising

an antibody,

a peptide linker,

and a chelating agent comprising a chelate linker and a chelate site; wherein the chelate site is chelated with a radionuclide comprising an α (alpha) particle emitting metallic nuclide:

wherein the antibody is a humanized antibody specifically binding to MUC5AC, comprising a heavy chain variable region selected from the group consisting of

(1) the amino acid sequence shown in SEQ ID NO: 1 (HO1),

(2) the amino acid sequence shown in SEQ ID NO: 2 (H02),

(3) the amino acid sequence shown in SEQ ID NO: 3 (H03), and

(4) the amino acid sequence shown in SEQ ID NO: 4 (H04), and

a light chain variable region selected from the group consisting of

(5) the amino acid sequence shown in SEQ ID NO: 5 (L01),

(6) the amino acid sequence shown in SEQ ID NO: 6 (L02),

(7) the amino acid sequence shown in SEQ ID NO: 7 (L03), and

(8) the amino acid sequence shown in SEQ ID NO: 8 (L04);

wherein the chelating site specifically modifies an Fc region of the antibody via the peptide linker;

wherein the peptide linker comprises an antibody-modification peptide and a antibody-modification linker;

wherein the antibody-modification peptide consists of not less than 13 and not more than 17 amino acid residues and is represented by the following formula (i):

(Xa)-Xaa1-(Xb)-Xaa2-(Xc)-Xaa3-(Xd)   (i)

wherein Xa, Xb, Xc and Xd are each continuous X in the number of a, continuous X in the number of b, continuous X in the number of c, and continuous X in the number of d, respectively,

X is an amino acid residue having neither a thiol group nor a haloacetyl group in the side chain,

a, b, c and d are each independently an integer of not less than one and not more than 5, and satisfy a+b+c+d≤14,

Xaa1 and Xaa3 are each independently an amino acid residue derived from an amino acid having a thiol group in the side chain, or

Xaa1 is an amino acid residue derived from an amino acid having a thiol group in the side chain and the Xaa3 is an amino acid residue derived from an amino acid having a haloacetyl group in the side chain, or

Xaa3 is amino acid residue derived from an amino acid having a thiol group in the side chain and the Xaa1 is an amino residue derived from an amino acide having a haloacetyl group in the side chain,

and Xaa1 and Xaa3 are linked through their side chains, and

Xaa2 is a lysine residue, arginine residue, cysteine residue, aspartic acid residue, glutamic acid residue, 2-aminosuberic acid, or diamino propionic acid, wherein Xaa2 modified with the crosslinking agent with a structure of

wherein the Fc region is bound to the crosslinking agent at the position of A*, and is the binding site with Xaa2; and

wherein the antibody-modification linker is derived from a structure of:

wherein:

the antidody-modification peptide is bound to the antibody-modification linker at ; and n is 2 to 10

wherein the chelate site is represented by the following formula (A) or a salt thereof:

wherein:

R 11 , R 13 , and R 14 are each independently selected from the group consisting of —(CH 2 ) p COOH, —(CH 2 ) p C 5 H 5 N, —(CH 2 ) p PO 3 H 2 , —(CH 2 ) p CONH 2 or —(CHCOOH)(CH 2 ) p COOH; and p is an integer of not less than 0 and not more than 3;

R 15 is a hydrogen atom; and

R 12 is a binding site derived from a substituent having the structure of:

wherein, C* is the binding site with the chelate linker after ring opening;

wherein the chelate linker has a structure derived from:

wherein:

is the binding site with the chelate site; and

wherein the peptide linker and the chelating agent are linked via a triazole moiety derived from the azide group in the antibody-modification linker and the dibenzocyclooctyne group in the chelate linker represented by formula ( 10 a ) and ( 10 b ):

wherein ( 10 a ) and ( 10 b ) are isomers that may be present at any ratio; and

R IA is a binding site with the remaining portion of the chelate linker, and R 2A i s a binding site with the remaining portion of the antibody-modification linker.

2 . The conjugate according to claim 1 , wherein the antibody comprises

(1) a heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 1 (H01), and

(7) a light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 7 (L03).

3 . The conjugate according to claim 1 , wherein the antibody-modification peptide comprises the amino acid sequence of

SEQ ID NO: 9,

SEQ ID NO: 10,

SEQ ID NO: 11,

SEQ ID NO: 12,

SEQ ID NO: 13,

SEQ ID NO: 14,

SEQ ID NO: 15,

SEQ ID NO: 16,

SEQ ID NO: 17,

SEQ ID NO: 18,

SEQ ID NO: 19,

SEQ ID NO: 20, or

SEQ ID NO: 21

wherein Xaa2 is a lysine residue.

4 . The conjugate according to claim 3 , wherein the antibody-modification peptide comprises the amino acid sequence of;

SEQ ID NO: 10,

SEQ ID NO: 16,

SEQ ID NO: 17, or

SEQ ID NO: 18;

wherein Xaa2 is a lysine residue.

5 . The conjugate according to claim 1 , wherein R 11 , R 13 and R 14 are each independently a group consisting of —(CH 2 ) p COOH or —(CHCOOH)(CH 2 ) p COOH, and p is 1.

6 . The conjugate according to claim 1 , wherein the chelating agent has a structure derived from a compound represented by the following formula or a salt thereof:

7 . The conjugate according to claim 1 ,

wherein the antibody comprises

(1) the heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 1 (H01), and

(7) the light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 7 (L03);

wherein the antibody-modification peptide has comprises the amino acid sequence of

SEQ ID NO: 10,

wherein Xaa2 is a lysine residue;

and wherein the chelating agent has a structure derived from a compound represented by the following formula or a salt thereof:

8 . The conjugate according to claim 1 ,

wherein the antibody comprises,

(1) the heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 1 (H01), and

(7) the light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 7 (L03);

wherein the antibody-modification peptide comprises the amino acid sequence of

SEQ ID NO: 16,

wherein Xaa2 is a lysine residue;

and wherein the chelating agent has a structure derived from a compound represented by the following formula or a salt thereof:

9 . The conjugate according to claim 1 ,

wherein the antibody comprises,

(1) the heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 1 (H01), and

(7) the light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 7 (L03);

wherein the antibody-modification comprises the amino acid sequence of

SEQ ID NO: 17,

wherein Xaa2 is a lysine residue;

wherein the chelating agent has a structure derived from a compound represented by the following formula (A-9) or a salt thereof:

10 . The conjugate according to claim 1 ,

wherein the antibody comprises,

(1) the heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 1 (H01), and

(7) the light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 7 (L03);

wherein the antibody-modification peptide comprises the amino acid sequence of

SEQ ID NO: 18,

wherein Xaa2 is a lysine residue;

wherein the chelating agent has a structure derived from a compound represented by the following formula or a salt thereof:

11 . The conjugate of claim 1 , wherein the radionuclide comprising an α (alpha) particle emitting metallic is Actinium 225 Ac.

12 . The conjugate of claim 1 wherein the radionuclide comprising an α (alpha) particle emitting metallic nuclide is selected from the group consisting of 212 Bi, 213 Bi, and 227 Th and 225 Ac.

13 . The conjugate according to claim 1 , wherein the chelate site has a structure derived from a compound represented by the following formula (A-12) or a salt thereof:

wherein the chelate site is chelated with a radionuclide comprising an α (alpha) particle emitting metallic nuclide.

14 . The conjugate according to claim 2 , wherein the antibody comprises:

a heavy chain constant region consisting of the amino acid sequence shown in SEQ ID NO: 25, and

a light chain constant region consisting of the amino acid sequence shown in SEQ ID NO: 26.

15 . The conjugate according to claim 1 , wherein the peptide linker comprises the structure of formula (L):

wherein the Lys252 of the Fc region of the antibody by EU numbering is bound through Fc* and the chelating agent is bound via a triazole derived from the azide group.

16 . The conjugate of claim 1 , wherein the antibody-modification linker is bound at the N-terminus of the antibody-modification peptide.

17 . A conjugate comprising an antibody,

wherein the antibody is a humanized antibody specifically binding to MUC5AC, comprising a heavy chain variable region selected from the group consisting of

(1) the amino acid sequence shown in SEQ ID NO: 1 (H01),

(2) the amino acid sequence shown in SEQ ID NO: 2 (H02),

(3) the amino acid sequence shown in SEQ ID NO: 3 (H03), and

(4) the amino acid sequence shown in SEQ ID NO: 4 (H04), and

a light chain variable region selected from the group consisting of

(5) the amino acid sequence shown in SEQ ID NO: 5 (L01),

(6) the amino acid sequence shown in SEQ ID NO: 6 (L02),

(7) the amino acid sequence shown in SEQ ID NO: 7 (L03), and

(8) the amino acid sequence shown in SEQ ID NO: 8 (L04); and

a compound comprising a peptide and a chelating agent, or a pharmaceutically acceptable salt thereof, having the structure of:

wherein the chelating agent is chelated with an a (alpha) particle emitting metallic nuclide; and

the Lys252 of the Fc region of the antibody by EU numbering is bound through Fc*.

18 . The conjugate of claim 17 , wherein the compound comprising a peptide and a chelating agent, or a pharmaceutically acceptable salt thereof, has the structure of:

19 . The conjugate of claim 17 , wherein the compound comprising a peptide and a chelating agent, or a pharmaceutically acceptable salt thereof, has the structure of:

20 . The conjugate of claim 17 , wherein the antibody comprises:

(1) the heavy chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 1 (H01), and

(7) the light chain variable region consisting of the amino acid sequence shown in SEQ ID NO: 7 (L03).

21 . The conjugate according to claim 20 , wherein the antibody comprises:

a heavy chain constant region consisting of the amino acid sequence shown in SEQ ID NO: 25, and a light chain constant region consisting of the amino acid sequence shown in SEQ ID NO: 26 .

22 . The conjugate of claim 20 wherein the conjugate further comprises an α (alpha) particle emitting metallic nuclide comprising Actinium-225 ( 225 Ac).

Assignments (4)

Priority Claims (1)

Continuity (3)

References Cited (42)