Antibody-drug conjugate (adc) and method for forming the same

Patent metadata

Field	Value
Publication number	US-2017119902-A1
Application number	US-201615341834-A
Country	US
Kind code	A1
Filing date	Nov 2, 2016
Priority date	Nov 3, 2015
Publication date	May 4, 2017
Grant date	—

Abstract

An antibody-drug conjugate (ADC) of formula (I) or a pharmaceutically acceptable salt or solvate thereof is provided. In formula (I), p is an integer ranging from 1 to 26, A is an antibody, and -(L-D) is a linker-drug unit. L is a linker unit having a glycopeptide, and D is a drug unit. The antibody is conjugated to the linker unit through a cysteine residue of the antibody. A method for forming an antibody-drug conjugate (ADC) is also provided.
A-(L-D) p   (I)

First claim

What is claimed is:

1 . An antibody-drug conjugate (ADC) of formula (I) or a pharmaceutically acceptable salt or solvate thereof:
A-(L-D) p   (I)
wherein p is an integer ranging from 1 to 26; A is an antibody; and -(L-D) is a linker-drug unit, wherein L is a linker unit having a glycopeptide, and D is a drug unit, wherein the antibody is conjugated to the linker unit through a cysteine residue of the antibody.

2 . The antibody-drug conjugate (ADC) as claimed in claim 1 , wherein the antibody is a full-length antibody or an antibody fragment.

3 . The antibody-drug conjugate (ADC) as claimed in claim 1 , 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, 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

4 . The antibody-drug conjugate (ADC) as claimed in claim 1 , wherein the antibody is a therapeutic antibody used for the treatment of tumor, chronic lymphocytic leukemia (CLL), or acute myeloid leukemia (AML).

5 . The antibody-drug conjugate (ADC) as claimed in claim 1 , wherein the antibody comprises Herceptin, Erbitux, HLX-07, EG12014, anti-EpCAM Ab and IgG1, Rituximab, Ibritumomab tiuxetan, Tositumomab, Brentuximab vedotin, Alemtuzumab, IGN101, Adecatumumab, Labetuzumab, huA33, Pemtumomab, Oregovomab, CC49 (minretumomab), cG250, J591, MOv18, MORAb-003 (farletuzumab), 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), HGS-ETR2, CS-1008, Denosumab, Sibrotuzumab, F19, 8106, humanized anti HER2 mAb, OvaRex, Panorex, Cetuximab Erbitux, Vitaxin, Campath I/H, Smart MI95, LymphoCide, Smart ID10, Oncolym, Allomune, Avastin, Epratuzamab, or CEAcide.

6 . The antibody-drug conjugate (ADC) as claimed in claim 1 , wherein the linker unit is —C-SAAs-AAs-, wherein
C— is a conjugating unit selected from a group consisting of

wherein R7 is selected from a group consisting of —C1-C10 alkylene-, —C3-C8 carbocyclo-, —O—(C1-C8 alkyl)-, -arylene-, —C1-C10 alkylene-arylene-, -arylene-C1-C10 alkylene-, —C1-C10 alkylene-(C3-C8 carbocyclo)-, —(C3-C8 carbocyclo)-C1-C10 alkylene-, —C3-C8 heterocyclo-, —C1-C10 alkylene-(C3-C8 heterocyclo)-, —(C3-C8 heterocyclo)-C1-C10 alkylene-, —(CH 2 CH 2 O)r- and —(CH 2 CH 2 O)r-CH 2 —, and r is an integer ranging from 1 to 10;
-SAAs- is a sugar amino acid unit of formula (II):

wherein x is an integer ranging from 1 to 8, y is an integer ranging from 1 to 4,

is a tetrahydrofuran, dihydrofuran, tetrahydropyran or dihydropyran ring, R8 and R10 are each, independently, a single bond, methylene, hydroxymethylene, ethylene, ethylidene, hydroxyethylene, hydroxyethylidene, dihydroxyethylene, dihydroxyethylidene, vinylene, vinylidene, propylene, propylidene, trimethylene, hydroxypropylene, hydroxypropylidene, hydroxytrimethylene, dihydroxypropylene, dihydroxypropylidene, dihydroxytrimethylene, trihydroxypropylene, trihydroxypropylidene or trihydroxytrimethylene, each R9 is, independently, hydroxyl, methyl, hydroxymethyl, ethyl, hydroxyethyl, dihydroxyethyl, propyl, hydroxypropyl, dihydroxypropyl or trihydroxypropyl or any two R9 in the same ring carbon together with the carbon to which they are attached form a carbonyl group, or any two R9, R8 and any one R9, or R10 and any one R9 form a second tetrahydrofuran, dihydrofuran, tetrahydropyran or dihydropyran ring that fuses to the original tetrahydrofuran, dihydrofuran, tetrahydropyran or dihydropyran ring, or any two R9, R8 and any one R9, or R10 and any one R9 together with a methylene, ethylidene, 1-propylidene, 2-propylidene or benzylidene group form a cyclic acetal or ketal ring that fuses to the original tetrahydrofuran, dihydrofuran, tetrahydropyran or dihydropyran ring; and
-AAs- is a peptide unit of formula (III):

wherein z is an integer ranging from 0 to 10, R11 is —(CH 2 ) 3 NHC(═NH)NH 2 , —(CH 2 ) 3 NH 2 , —(CH 2 ) 3 NHCONH 2 , —(CH 2 ) 4 NHC(═NH)NH 2 , —(CH 2 ) 4 NH 2 or —(CH 2 ) 4 NHCONH 2 , R12 is H, methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, phenyl or benzyl, R13 is hydrogen, methyl, isopropyl, cyclopropyl, butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, cyclohexyl, phenyl, benzyl, p-hydroxybenzyl, —CH 2 OH, —CH(OH)CH 3 , —CH 2 CH 2 SCH 3 , —CH 2 CONH 2 , —CH 2 COOH, —CH 2 CH 2 CONH 2 , —CH 2 CH 2 COOH, —(CH 2 ) 3 NHC(═NH)NH 2 , —(CH 2 ) 3 NH 2 , —(CH 2 ) 3 NHCOCH 3 , —(CH 2 ) 3 NHCHO, —(CH 2 ) 4 NHC(═NH)NH 2 , —(CH 2 ) 4 NH 2 , —(CH 2 ) 4 NHCOCH 3 , —(CH 2 ) 4 NHCHO, —(CH 2 ) 3 NHCONH 2 , —(CH 2 ) 4 NHCONH 2 , —CH 2 CH 2 CH(OH)CH 2 NH 2 , 2-pyridylmethyl, 3-pyridylmethyl or 4-pyridylmethyl.

7 . The antibody-drug conjugate (ADC) as claimed in claim 6 , wherein C— is the conjugating unit selected from a group consisting of

wherein R7 is selected from a group consisting of -1,5-pentylene-, -1,6-hexylene-, -1,4-cyclohexylene-, —(CH 2 CH 2 O)r-CH 2 — and —(CH 2 CH 2 O)r-CH 2 —CH 2 —, and r is an integer ranging from 2-5.

8 . The antibody-drug conjugate (ADC) as claimed in claim 6 , wherein -SAAs- is the sugar amino acid unit selected from a group consisting of

9 . The antibody-drug conjugate (ADC) as claimed in claim 6 , wherein -AAs- is the peptide unit selected from a group consisting of -Val-Cit-, -Val-Lys-, -Val-Arg-, -Phe-Cit-, -Phe-Lys- and -Phe-Arg-.

10 . The antibody-drug conjugate (ADC) as claimed in claim 1 , wherein the drug unit is the cytotoxic agent selected from a group consisting

wherein R1, R2, R3, R4, R5 and R6 are each, independently, hydrogen, amino, nitro, halogen, hydroxyl, methoxy, ethoxy, carboxylic acid, methoxycarbonyl, ethoxycarbonyl, methylamino, dimethylamino, ethylamino, diethylamino, 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, ethylaminocarbonyl, diethylaminocarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, 1-piperazinylcarbonyl, methyl, ethyl, propyl, isopropyl or phenyl.

11 . The antibody-drug conjugate (ADC) as claimed in claim 1 , wherein the drug unit has a cytostatic or cytotoxic activity against a target cell.

12 . The antibody-drug conjugate (ADC) as claimed in claim 1 , wherein the drug unit is a cytotoxic agent selected from a group consisting of amanitins, anthracyclines, auristatins, baccatins, calicheamicins, camptothecins, cemadotins, colchicines, colcimids, combretastatins, cryptophysins, discodermolides, duocarmycins, echinomycins, eleutherobins, epothilones, estramustines, lexitropsins, mayt

Assignees

• Ind Tech Res Inst

Inventors

• Ko Yi-Ju
• Li Jheng-Sian
• Lu Maggie
• Lee On
• Cheng Ping-Fu
• Liu Chun-Min

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07K7/02 Primary

  Linear peptides containing at least one abnormal peptide link · CPC title

• A61K47/6889 Primary

  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 · CPC title

• A61K47/551

  one of the codrug's components being a vitamin, e.g. niacinamide, vitamin B3, cobalamin, vitamin B12, folate, vitamin A or retinoic acid · CPC title