# US 10,864,279 B2 · Linker-drug and antibody-drug conjugate (ADC) employing the same

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- Number: US 10,864,279 B2
- Document ID: US10864279B2
- Status: Granted
- Kind: B2
- Application number: 15/830,272
- Filed: 2017-12-04
- Published: 2018-06-21
- Granted: 2020-12-15
- Earliest claimed: 2016-12-16
- Assignees: Industrial Technology Research Institute
- Applicants: Industrial Technology Research Institute
- Inventors: Maggie Lu; May-Hua Chang; Jenn-Tsang Hwang; Ping-Fu Cheng; Li-Wen Chang; Yi-Ju Ko; Chi-Y Hung; Chun-Min Liu; Chia-Yu Fan
- Web page: https://patentgrep.com/patent/US10864279B2

## CPC

- 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}
- A61K 31/4745: condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48)
- A61K 47/64: Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent (peptidic linkers A61K47/65)
- A61K 47/68031: {the drug being an auristatin}
- A61K 47/6817: {Toxins}
- A61K 47/6851: {the antibody targeting a determinant of a tumour cell}
- A61K 47/6855: {the tumour determinant being from breast cancer cell}
- A61P 35/00: Antineoplastic agents
- C07K 16/30: from tumour cells
- A61K 47/65: Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
- 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

A linker-drug represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof is provided. In formula (I), C is a conjugator, L is a linker unit, D is a toxin unit, and n is an integer ranging from 1 to 4. The structure of the conjugator is represented by formula (II). In formula (II), X is a leaving group, each of R1 and R2 is independently a single bond or —NH—, and Z is substituted aryl, heteroaryl, linear alkyl, cycloalkyl, heterocycloalkyl, or a combination thereof. The antibody is conjugated to the linker unit through a cysteine residue of the antibody. An antibody-drug conjugate (ADC) employing the above linker-drug is also provided.

## Claims

### Claim 1

A linker-drug represented by formula (IA) or formula (IA′):
wherein C is a conjugating linker; L is a linker unit; Do, Dp and Dq are drug units; and m is an integer of 1; o is an integer ranging from 1 to 4; p is an integer ranging from 1 to 4; and q is an integer ranging from 1 to 4;
wherein the structure of the conjugating linker is represented by formula (IIa), formula (IIb), or formula (IIc):
wherein X is a leaving group,
wherein the wave line of formula (IIa), formula (IIb), or formula (IIc) indicates the covalent attachment site to L.

### Claim 2 (depends on 1)

The linker-drug as claimed in claim 1, wherein the linker unit is a cleavable linker or a noncleavable linker.

### Claim 3 (depends on 2)

The linker-drug as claimed in claim 2, wherein the cleavable linker comprises a peptide unit (-AAs-) selected from a group consisting of -valline-citruline-(-Val-Cit-), -valline-lysine-(-Val-Lys-), -valline-arginine-(-Val-Arg-), -phenylalanine-citruline-(-Phe-Cit-), -phenylalanine -lysine-(-Phe-Lys-), and -phenylalanine-arginine-(-Phe-Arg-).

### Claim 4 (depends on 1)

The linker-drug as claimed in claim 1,
wherein L is linear alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, poly(ethylene glycol) chain, or a combination thereof; and Do, Dp and Dq are independently cytotoxic drugs, anti-autoimmune disease drugs, or anti-inflammation drugs.

### Claim 5 (depends on 1)

The linker-drug as claimed in claim 1, wherein the drug unit is amanitins, anthracyclines, auristatins, baccatins, calicheamicins, camptothecins, cemadotins, colchicines, colcimids, combretastatins, cryptophycins, discodermolides, docetaxel, doxorubicin, duocarmycins, echinomycins, eleutherobins, epothilones, estramustines, lexitropsins, maytansines, maytansinoids, methotrexate, netropsins, pyrrolo[2,1-c][1,4]benzodi-azepines (PBDs), puromycins, rhizoxins, SN-38, taxanes, tubulysins, or vinca alkaloids.

### Claim 6 (depends on 1)

The linker-drug as claimed in claim 1, wherein the leaving group is —Cl, —Br, —I, —F, —OTs, —OMs, —OTf or —OBs.

### Claim 7

An antibody-drug conjugate (ADC) represented by formula (IVA) or formula (IVA′):
wherein A is a full-length antibody, or an antibody fragment; C′-(L-Do)m and
are linker-drugs, wherein C′ is a conjugating linker; L is a linker unit; Do, Dp and Dq are drug units; and m is an integer of 1; o is an integer ranging from 1 to 4; p is an integer ranging from 1 to 4; and q is an integer ranging from 1 to 4;
wherein A is conjugated to the linker-drug through two thiol groups respectively present in two cysteine residues of A;
A-C′ is the following structure represented by formula (Va), formula (Vb), or formula (Vc):
wherein the wave line of formula (Va), formula (Vb), or formula (Vc) indicates the covalent attachment site to L; A′ indicates the remaining part of A which conjugated to the linker-drug through two thiol groups respectively present in two cysteine residues of A.

### Claim 8 (depends on 7)

The antibody-drug conjugate (ADC) as claimed in claim 7, wherein A targets cell surface receptors or tumor-related antigens.

### Claim 9 (depends on 7)

The antibody-drug conjugate (ADC) as claimed in claim 7, wherein the antibody is a chimeric antibody or a functionally active fragment thereof, a humanized antibody or a functionally active fragment thereof, a human antibody or a functionally active fragment thereof, a mouse antibody or a functionally active fragment thereof, a rat antibody or a functionally active fragment thereof, a goat antibody or a functionally active fragment thereof, or a rabbit antibody or a functionally active fragment thereof.

### Claim 10 (depends on 7)

The antibody-drug conjugate (ADC) as claimed in claim 7, wherein the antibody is an IgG1 antibody or a functionally active fragment thereof, an IgG4 antibody or a functionally active fragment thereof.

### Claim 11 (depends on 7)

The antibody-drug conjugate (ADC) as claimed in claim 7, wherein the antibody is HLX-07, EG12014, anti-EpCAM Ab and IgG1, Rituximab, Ibritumomab tiuxetan, Tositumomab, Brentuximab, Alemtuzumab, IGN101, Adecatumumab, Labetuzumab, huA33, Pemtumomab, Oregovomab, CC49 (minretumomab), cG250, J591, MOv18, Farletuzumab (MORAb-003), 3F8, ch14.18, KW-2871, hu3S193, IgN311, Bevacizumab, IM-2C6, CDP791, Etaracizumab, Volociximab, Cetuximab, Panitumumab, Nimotuzumab, 806, Trastuzumab, Pertuzumab, MM-121, AMG 102, METMAB, SCH 900105, AVE1642, IMC-A12, MK-0646, R1507, CP 751871, KB004, IIIA4, Mapatumumab (HGS-ETR1), Lexatumumab (HGS-ETR2), CS-1008, Denosumab, Sibrotuzumab, F19, 8106, humanized anti HER2 mAb, Edrecolomab, Cetuximab, Smart MI95, LymphoCide, Smart ID10, Oncolym, Allomune, or Epratuzamab.

### Claim 12 (depends on 7)

The antibody-drug conjugate (ADC) as claimed in claim 7, wherein the linker unit is a cleavable linker or a noncleavable linker.

### Claim 13 (depends on 12)

The antibody-drug conjugate (ADC) as claimed in claim 12, wherein the cleavable linker comprises a peptide unit (-AAs-) selected from a group consisting of -valline-citruline-(-Val-Cit-), -valline-lysine-(-Val-Lys-), -valline-arginine-(-Val-Arg-), -phenylalanine-citruline-(-Phe-Cit-), -phenylalanine-lysine-(-Phe-Lys-), and -phenylalanine-arginine-(-Phe-Arg-).

### Claim 14 (depends on 7)

The antibody-drug conjugate (ADC) as claimed in claim 7,
wherein L is linear alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, poly(ethylene glycol) chain, or a combination thereof; and Do, Dp and Dq are independently cytotoxic drugs, anti-autoimmune disease drugs, or anti-inflammation drugs.

### Claim 15 (depends on 7)

The antibody-drug conjugate (ADC) as claimed in claim 7, wherein the drug unit is amanitins, anthracyclines, auristatins, baccatins, calicheamicins, camptothecins, cemadotins, colchicines, colcimids, combretastatins, cryptophycins, discodermolides, docetaxel, doxorubicin, duocarmycins, echinomycins, eleutherobins, epothilones, estramustines, lexitropsins, maytansines, maytansinoids, methotrexate, netropsins, pyrrolo[2,1-c][1,4]benzodi-azepines (PBDs), puromycins, rhizoxins, SN-38, taxanes, tubulysins, or vinca alkaloids.

### Claim 16

The antibody-drug conjugate (ADC) as claimed in claim , wherein the average DAR of the antibody-drug conjugate is about 3-8.