Ri-labeled humanized antibody

1. A conjugate of an antibody and a chelating agent chelated with a radionuclide,

wherein the radionuclide is Zr-89;

wherein the antibody is a humanized antibody specifically binding to MUC5AC, which having a heavy chain variable region 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) or

(4) the amino acid sequence shown in SKI ID NO: 4 (H04) and a light chain variable region 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) or

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

wherein the chelating agent site-specifically modifies an Fc region of the antibody via a linker;

wherein the linker comprises a peptide consisting of not less than 13 and not more than 17 amino acid residues, is formed by a crosslinking reaction between the peptide modified with a crosslinking agent and the antibody, 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

one is an amino acid residue derived from an amino acid having a thiol group in the side

chain and the other is an amino add residue derived from an amino acid having a haloacetyl group in the side chain, and Xaa1 and Xaa3 are linked, and

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

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

wherein in the formula (A), R 11 , R 13 and R 14 are each independently a 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, one of R 12 and R 15 is a hydrogen atom, a carboxyl group, or a carboxyalkyl group having 2 or 3 carbon atoms, the other is a substituent for conjugating with the aforementioned antibody, p is an integer of not less than 0 and not more than 3, R 15 is a hydrogen atom when R 12 is a substituent for conjugating with the aforementioned antibody, and R 15 is a substituent for conjugating with the aforementioned antibody when R 12 is not a substituent for conjugating with the aforementioned antibody.

2. The conjugate according to claim 1 , wherein the antibody is a humanized antibody having

(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 peptide has any one of the following amino acid sequences;

(SEQ ID NO: 9)

(1) DCAYH(Xaa2)GELVWCT,

(SEQ ID NO: 10)

(2) GPDCAYH(Xaa2)GELVWCTFH,

(SEQ ID NO: 11)

(3) RCAYH(Xaa2)GELVWCS,

(SEQ ID NO: 12)

(4) GPRCAYH(Xaa2)GELVWCSFH,

(SEQ ID NO: 13)

(5) SPDCAYH(Xaa2)GELVWCTFH,

(SEQ ID NO: 14)

(6) GDDCAYH(Xaa2)GELVWCTFH,

(SEQ ID NO: 15)

(7) GPSCAYH(Xaa2)GELVWCTFH,

(SEQ ID NO: 16)

(8) GPDCAYH(Xaa2)GELVWCSFH,

(SEQ ID NO: 17)

(9) GPDCAYH(Xaa2)GELVWCTHH,

(SEQ ID NO: 18)

(10) GPDCAYH(Xaa2)GELVWCTFY,

(SEQ ID NO: 19)

(11) SPDCAYH(Xaa2)GELVWCTFY,

(SEQ ID NO: 20)

(12) SDDCAYH(Xaa2)GELVWCTFY

and

(SEQ ID NO: 21)

(13) RGNCAYH(Xaa2)GQLVWCTYH,

wherein Xaa2 is a lysine residue.

4. The conjugate according to claim 3 , wherein the

peptide has any one of the following amino acid sequences;

(SEQ ID NO: 10)

(2) GPDCAYH(Xaa2)GELVWCTFH,

(SEQ ID NO: 16)

(8) GPDCAYH(Xaa2)GELVWCSFH,

(SEQ ID NO: 17)

(9) GPDCAYH(Xaa2)GELVWCTHH

and

(SEQ ID NO: 18)

(10) GPDCAYH(Xaa2)GELVWCTFY,

wherein Xaa2 is a lysine residue.

5. The conjugate according to claim 1 , in the formula in the formula (A), R 11 , R 13 and R 14 are each independently a group consisting of —(CH 2 ) p COOH, or —(CHCOOH)(CH 2 ) p COOH, p is 1 R 12 and is a substituent for conjugating with the antibody and R 15 is a hydrogen atom.

6. The conjugate according to claim 5 , wherein a linkage site between the chelate site and the substituent for conjugating with the antibody comprises an amide bond or a thiourea bond, and the linkage site is derived from the amide bond formed by the reaction of an N-hydroxysuccinimidoester (NHS) group, or a 2,6-dioxo tetrahydro-2H-pyranyl group with primary amine, or thiourea bond formed by the reaction of an isothiocyanate group with primary amine or a maleimide group.

7. The conjugate according to claim 1 , wherein the chelating agent has a structure derived from a compound represented by the following formula (A-9) or a salt thereof:

8. The conjugate according to claim 1 , wherein the linker has a chelate linker connecting to a chelating agent, a first atomic group connecting to the linker, a second atomic group that can perform click reaction with the first atomic group, and an antibody-modification linker connecting to the second atomic group, which includes the antibody-modification peptide, and

wherein the linker has a chemical structure represented by the following formula (10a), (10b) or (10c) as a chemical structure derived from the first atomic group and the second atomic group:

wherein in the formula (10a) and the formula (10b), R 1A , is a binding site with a chelate linker, and R 2A is a binding site with an antibody-modification linker, and wherein in the formula (10c), one of R 3A and R 4A is a hydrogen atom, a methyl group, a phenyl group or a pyridyl group, and the other is a binding site with a chelate linker, and R 5A is a binding site with an antibody-modification linker.

9. The conjugate according to claim 1 ,

wherein the antibody is a humanized antibody having

(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);

wherein the peptide has the following amino acid sequence,

2) GPDCAYH(Xaa2)GELVWCTFH (SEQ ID NO: 10),

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 is a humanized antibody having

(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);

wherein the peptide has the following amino acid sequence,

(8) GPDCAYH(Xaa2)GELVWCSFH (SEQ ID NO: 16),

wherein Xaa2 is a Iysine residue;

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

11. The conjugate according to claim 1 ,

wherein the antibody is a humanized antibody having

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

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

wherein the peptide has the following amino acid sequence,

(9) GPDCAYH(Xaa2)GELVWCSFH (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:

12. The conjugate according to claim 1 ,

wherein the antibody is a humanized antibody having

(I) 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);

wherein the peptide has the following amino acid sequence,

(10) GPDCAYH(Xaa2)GELVWCSFH (SEQ ID NO: 1$),

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:

13. A method for diagnosing cancer using the conjugate according to claim 1 .

14. A kit for producing a conjugate according to claim 1 , comprising a chelating agent capable of chelating a radionuclide and an anti-MUC5AC antibody.

15. The kit according to claim 14 , further comprising a first atomic group capable of click reaction and a second atomic group capable of click reaction.

16. The kit according to claim 15 , wherein the first atomic group capable of click reaction and the second atomic group capable of click reaction comprise any one of alkyne, azide, 1,2,4,5-tetrazine and alkene, respectively.

17. The kit according to claim 14 , further comprising a radionuclide capable of chelating with the chelating agent.

18. A modified antibody with an Fc region of the antibody specifically modified by an antibody-modification linker provided with an antibody-modification peptide, wherein the antibody is a humanized antibody specifically binding to MUC5AC, which having a heavy chain variable region 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 NO: (H03), or

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

a light chain variable region 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), or

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

wherein the antibody-modification linker has an atomic group to connect to a chelate linker of a chelating agent chelated with a radionuclide by a click reaction.