# US 11,998,613 B2 · Antibody-drug conjugates containing an anti-mesothelin antibody and uses thereof

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- Number: US 11,998,613 B2
- Document ID: US11998613B2
- Status: Granted
- Kind: B2
- Application number: 17/339,747
- Filed: 2021-06-04
- Published: 2021-12-16
- Granted: 2024-06-04
- Earliest claimed: 2020-06-05
- Assignees: Development Center for Biotechnology
- Applicants: Development Center for Biotechnology
- Inventors: Shih-Hsien Chuang; Wei-Ting Sun; Ying-Shuan Lailee; Chun-Liang Lai; Wun-Huei Lin; Win-Yin Wei; Shih-Chong Tsai; Cheng-Chou Yu; Chao-Yang Huang
- Web page: https://patentgrep.com/patent/US11998613B2

## CPC

- A61K 47/6851: {the antibody targeting a determinant of a tumour cell}
- A61K 47/545: {Heterocyclic compounds (A61K47/558 takes precedence)}
- A61K 47/68031: {the drug being an auristatin}
- A61K 47/68033: {the drug being a maytansine}
- A61K 47/68037: {the drug being a camptothecin [CPT] or derivatives}
- A61K 47/6817: {Toxins}
- A61K 47/6889: {Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment}
- A61P 35/00: Antineoplastic agents
- Y02P 20/55: Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
- 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
- Y02P: CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS

## Abstract

The present disclosure provides an immunoconjugate includes an antibody comprising an antigen-binding fragment that specifically binds to an epitope in mesothelin, N-glycan binding domain and an N-glycan; a linker linking to the N-glycan; and a payload A and a payload B conjugated to the linker, respectively; wherein the payload A and the payload B are the same or different. A pharmaceutical composition comprises the immunoconjugate and a method for treating cancer are also provided in the disclosure.

## Claims

### Claim 1

An immunoconjugate, comprising:
an antibody comprising an antigen-binding fragment that specifically binds to an epitope in mesothelin, an N-glycan binding domain and an N-glycan having a structure of formula (1);
wherein “*” represents a bond or a protecting group;
a linker linking to each of the “*” in the N-glycan when “*” presents the bond; and
a payload A and a payload B independently conjugated to the linkers; wherein the payload A and the payload B are the same or different;
wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 11, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 12.

### Claim 2 (depends on 1)

The immunoconjugate according to claim 1, wherein the antibody is a monoclonal antibody, a humanized antibody, an antibody Fab fragment, F(ab′)2, Fv fragment or Fc fragment from a cleaved antibody, a scFv-Fc fragment, a minibody, a diabody, or a scFv.

### Claim 3 (depends on 1)

The immunoconjugate according to claim 1, wherein the antibody comprises a heavy chain constant region, and the N-glycan binding domain is located in the heavy chain constant region.

### Claim 4 (depends on 1)

The immunoconjugate according to claim 1, wherein the antibody comprises two N-glycans.

### Claim 5 (depends on 1)

The immunoconjugate according to claim 1, wherein the linker is selected from the group consisting of a linear or branched alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, alkoxy, acyl, alkylamine, arylamine group having 2 to 20 carbon atoms, ether, ester, amide, carbamate, carbonate, formula (3) to formula (7), disulfide containing linker, acid labile linker, photolabile linker, peptidase labile linker, and esterase labile linker, or combinations thereof;
wherein in formula (3) and formula (4):
R1 is independently selected from the group consisting of hydrogen, halogen, —OR5, —NO2, —CN, —S(O)2R5, a C1-C24 alkyl group, a C6-C24 (hetero)aryl group, a C7-C24 alkyl(hetero)aryl group and a C7-C24 (hetero)arylalkyl group, and
wherein the alkyl group, (hetero)aryl group, alkyl(hetero)aryl group and (hetero)arylalkyl group are optionally substituted,
two substituents R1 may be linked together to form an annelated cycloalkyl or an annelated (hetero)arene substituent, and
R5 is independently selected from the group consisting of hydrogen, halogen, a C1-C24 alkyl group, a C6-C24 (hetero)aryl group, a C7-C24 alkyl(hetero)aryl group, and a C7-C24 (hetero)arylalkyl group;
X is C(R1)2, O, S or NR2, wherein R2 is R1; a is 0, 1, 2, 3, 4, 5, 6, 7 or 8; a′ is 0, 1, 2, 3, 4, 5, 6, 7 or 8; and a+a′<10; and
L is selected from the group consisting of a linear or branched alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, alkoxy, acyl, alkylamine, arylamine group having 2 to 20 carbon atoms, ether, ester, amide, carbamate, carbonate, disulfide containing linker, acid labile linker, photolabile linker, peptidase labile linker, and esterase labile linker, or combinations thereof;
wherein in formula (5),
R1 is independently selected from the group consisting of hydrogen, halogen, —OR5, —NO2, —CN, —S(O)2R5, a C1-C24 alkyl group, a C6-C24 (hetero)aryl group, a C7-C24 alkyl(hetero)aryl group and a C7-C24 (hetero)arylalkyl group, and
wherein the alkyl group, (hetero)aryl group, alkyl(hetero)aryl group and (hetero)arylalkyl group are optionally substituted,
two substituents R1 may be linked together to form an annelated cycloalkyl or an annelated (hetero)arene substituent, and
R5 is independently selected from the group consisting of hydrogen, halogen, a C1-C24 alkyl group, a C6-C24 (hetero)aryl groups, C7-C24 alkyl(hetero)aryl groups and C7-C24 (hetero)arylalkyl groups;
L is selected from the group consisting of a linear or branched alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, alkoxy, acyl, alkylamine, arylamine group having 2 to 20 carbon atoms, ether, ester, amide, carbamate, carbonate, disulfide containing linker, acid labile linker, photolabile linker, peptidase labile linker, and esterase labile linker, or combinations thereof;
R3 is independently selected from the group consisting of hydrogen, halogen, C1-C24 alkyl groups, C6-C24 (hetero)aryl groups, C7-C24 alkyl(hetero)aryl groups and C7-C24 (hetero)arylalkyl groups; and
R4 is selected from the group consisting of hydrogen, halogen, a C1-C24 alkyl group, a C6-C24 (hetero)aryl group, a C7-C24 alkyl(hetero)aryl group, a C7-C24 (hetero)arylalkyl group, the alkyl group optionally being interrupted by one of more hetero-atoms selected from the group consisting of O, N and S, wherein the alkyl group, (hetero)aryl group, alkyl(hetero)aryl group and (hetero)arylalkyl group are independently optionally substituted; and
wherein in formula (6) and formula (7),
L is selected from the group consisting of a linear or branched alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, alkoxy, acyl, alkylamine, arylamine group having 2 to 20 carbon atoms, ether, ester, amide, carbamate, carbonate, disulfide containing linker, acid labile linker, photolabile linker, peptidase labile linker, and esterase labile linker, or combinations thereof.

### Claim 6 (depends on 1)

The immunoconjugate according to claim 1, wherein the payload A and the payload B are independently a therapeutic agent, or a label.

### Claim 7 (depends on 6)

The immunoconjugate according to claim 6, wherein the therapeutic agent is antimetabolites, alkylating agents, alkylating-like agents, DNA minor groove alkylating agents, anthracyclines, antibiotics, calicheamicins, antimitotic agents, topoisomerase inhibitors, proteasome inhibitors, radioisotopes, or isotope-chelating agents.

### Claim 8 (depends on 6)

The immunoconjugate according to claim 6, wherein the therapeutic agent is monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), maytansinoids, duocarmycin-hydroxy benzamide azaindole (DUBA), diethylenetriamine-N,N,N′,N″,N″-pentaacetate (DTPA), exatecan, or Dxd2.

### Claim 9 (depends on 6)

The immunoconjugate according to claim 6, wherein the label is a fluorescent label, a chromophoric label, an electron-dense label, a chemiluminescent label, a radioactive label, an enzymatic label, or a positron emitter.

### Claim 10 (depends on 1)

The immunoconjugate according to claim 1, wherein the protecting group is azide.

### Claim 11 (depends on 1)

A pharmaceutical composition comprising the immunoconjugate according to claim 1 and a pharmaceutically acceptable carrier.

### Claim 12 (depends on 1)

A method for treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the immunoconjugate according to claim 1.

### Claim 13 (depends on 12)

The method according to claim 12, wherein the cancer is a mesothelin-expressing cancer.

### Claim 14 (depends on 12)

The method according to claim 12, wherein the cancer is ovarian cancer, mesothelioma, pancreatic cancer, non-small-cell lung cancer, esophageal cancer, gastric cancer, biliary cancer, colorectal cancer, endometrial cancer, or breast cancer.

### Claim 15 (depends on 12)

The method according to claim 12, wherein the cancer is ovarian cancer.