# US 2024/0189461 A1 · Humanised antibodies labelled with radionuclides that emit beta-rays

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- Number: US 2024/0189461 A1
- Document ID: US20240189461A1
- Status: Published application
- Kind: A1
- Application number: 18/556,582
- Filed: 2022-04-21
- Published: 2024-06-13
- Earliest claimed: 2021-04-21
- Assignees: Nihon Medi-Physics Co., Ltd.; Sumitomo Pharma Co., Ltd.
- Applicants: Nihon Medi-Physics Co., Ltd.; Sumitomo Pharma Co., Ltd.
- Inventors: Masato YAMADA; Fumiaki TAKENAKA; Kotaro HARADA; Momoko OMURA; Mitsuhiro MATONO; Kumiko OTSUKI; Yasushi OCHIAI; Takayuki MURAKAMI
- Web page: https://patentgrep.com/patent/US20240189461A1

## CPC

- A61K 51/1045: {against animal or human tumor cells or tumor cell determinants}
- A61K 51/1093: {conjugates with carriers being antibodies}
- A61K 51/1057: {the tumor cell being from liver or pancreas}
- A61K 51/1087: {the immunoglobulin comprises domains from different animal species, e.g. chimeric immunoglobulins}
- A61K 51/1096: {radioimmunotoxins, i.e. conjugates being structurally as defined in A61K51/1093, and including a radioactive nucleus for use in radiotherapeutic applications}
- A61P 35/00: Antineoplastic agents
- C07K 16/30: from tumour cells
- A61K 2039/505: {comprising antibodies}
- A61K 2039/507: {Comprising a combination of two or more separate antibodies}
- C07K 2317/31: multispecific
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## Abstract

The present invention aims to provide a radionuclide-labeled anti-MUC5AC humanized antibody that is superior in the specificity for mucin subtype 5AC (MUC5AC) and accumulation in tumor. The present invention provides a conjugate of a radionuclide and an antibody, wherein the radionuclide is a nuclide that emits β-rays, and the antibody is a humanized antibody that specifically binds to mucin subtype 5AC and has a heavy chain variable region consisting of the amino acid sequence shown in any of SEQ ID NOs: 1 to 4, and a light chain variable region consisting of the amino acid sequence shown in any of SEQ ID NOs: 5 to 8.

## Claims

### Claim at position 1

1: A conjugate of a radionuclide and an antibody, wherein the radionuclide is a nuclide that emits 3-rays and the antibody is a humanized antibody that specifically binds to mucin subtype 5AC and that comprises;
a heavy chain variable region consisting of
(1) the amino acid sequence shown in SEQ ID NO: 1 (H01), or an amino acid sequence having not less than 95% sequence identity with the amino acid sequence shown in SEQ ID NO: 1;
(2) the amino acid sequence shown in SEQ ID NO: 2 (H02), or an amino acid sequence having not less than 95% sequence identity with the amino acid sequence shown in SEQ ID NO: 2;
(3) the amino acid sequence shown in SEQ ID NO: 3 (H03), or an amino acid sequence having not less than 95% sequence identity with the amino acid sequence shown in SEQ ID NO: 3; or
(4) the amino acid sequence shown in SEQ ID NO: 4 (H04), or an amino acid sequence having not less than 95% sequence identity with the amino acid sequence shown in SEQ ID NO: 4; and
a light chain variable region consisting of
(5) the amino acid sequence shown in SEQ ID NO: 5 (L01), or an amino acid sequence having not less than 95% sequence identity with the amino acid sequence shown in SEQ ID NO: 5;
(6) the amino acid sequence shown in SEQ ID NO: 6 (L02), or an amino acid sequence having not less than 95% sequence identity with the amino acid sequence shown in SEQ ID NO: 6;
(7) the amino acid sequence shown in SEQ ID NO: 7 (L03), or an amino acid sequence having not less than 95% sequence identity with the amino acid sequence shown in SEQ ID NO: 7; or
(8) the amino acid sequence shown in SEQ ID NO: 8 (L04), or an amino acid sequence having not less than 95% sequence identity with the amino acid sequence shown in SEQ ID NO: 8.

### Claim at position 2 (depends on 1)

2: The conjugate according to claim 1, wherein the antibody is a humanized antibody 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 SEQ 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).

### Claim at position 3 (depends on 1)

3: The conjugate according to claim 1, wherein the antibody is a humanized antibody having
a heavy chain variable region consisting of
(1) the amino acid sequence shown in SEQ ID NO: 1 (H01), and
a light chain variable region consisting of (7) the amino acid sequence shown in SEQ ID NO: 7 (L03).

### Claim at position 4 (depends on 1)

4: The conjugate according to claim 1, wherein the nuclide that emits β-rays is iodine-131, yttrium-90, or lutetium-177.

### Claim at position 5 (depends on 1)

5: The conjugate according to claim 1, wherein the conjugate comprises a chelating agent chelated with a radionuclide, and the radionuclide is a metal nuclide that emits β-rays.

### Claim at position 6 (depends on 5)

6: The conjugate according to claim 5, wherein the metal nuclide that emits β-rays is yttrium-90.

### Claim at position 7 (depends on 5)

7: The conjugate according to claim 5, wherein the metal nuclide that emits β-rays is lutetium-177.

### Claim at position 8 (depends on 5)

8: The conjugate according to claim 5, comprising not less than 1 molecule and not more than 8 molecules of the chelating agent per 1 molecule of the antibody.

### Claim at position 9 (depends on 5)

9: The conjugate according to claim 5, wherein the chelating agent site-specifically modifies an Fc region of the antibody via a linker.

### Claim at position 10 (depends on 9)

10: The conjugate according to claim 9, wherein the linker comprises a peptide represented by the following formula (i) which consists of not less than 13 and not more than 17 amino acid residues, and which is formed by a crosslinking reaction of the peptide modified by a crosslinking agent and the antibody:
(Xa)-Xaa1-(Xb)-Xaa2-(Xc)-Xaa3-(Xd) (i)
wherein Xa, Xb, Xc and Xd are 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 acid 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, an arginine residue, a cysteine residue, an aspartic acid residue, a glutamic acid residue, 2-aminosuberic acid, or diamino propionic acid, and modified with the crosslinking agent.

### Claim at position 11 (depends on 5)

11: The conjugate according to claim 5, 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), R11, R13 and R14 are each independently a group consisting of —(CH2)pCOOH, —(CH2)pC5H5N, —(CH2)pPO3H2, —(CH2)pCONH2 or —(CHCOOH)(CH2)pCOOH, one of R12 and R15 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 antibody, p is an integer of not less than 0 and not more than 3, R15 is a hydrogen atom when R12 is a substituent for conjugating with the antibody, and R15 is a substituent for conjugating with the antibody when R12 is not a substituent for conjugating with the antibody.

### Claim at position 12 (depends on 1)

12: A radiopharmaceutical comprising the conjugate according to claim 1, as the active ingredient.

### Claim at position 13 (depends on 12)

13: The radiopharmaceutical according to claim 12, that is used for RI internal therapy for cancer.

### Claim at position 14 (depends on 13)

14: The radiopharmaceutical according to claim 13, that is administered to a subject at a dose of not more than 100 MBq/kg one time in the RI internal therapy, wherein the radionuclide is iodine-131.

### Claim at position 15 (depends on 13)

15: The radiopharmaceutical according to claim 13, that is administered to a subject at a dose of not more than 50 MBq/kg one time in the RI internal therapy, wherein the radionuclide is yttrium-90.

### Claim at position 16 (depends on 13)

16: The radiopharmaceutical according to claim 13, that is administered to a subject at a dose of not more than 50 MBq/kg one time in the RI internal therapy, wherein the radionuclide is lutetium-177.