Charged linkers and their uses for conjugation

Patent metadata

Field	Value
Publication number	US-10696699-B2
Application number	US-201816228130-A
Country	US
Kind code	B2
Filing date	Dec 20, 2018
Priority date	Feb 28, 2014
Publication date	Jun 30, 2020
Grant date	Jun 30, 2020

Abstract

Cell binding agent-drug conjugates comprising phosphinate-based charged linkers and methods of using such linkers and conjugates are provided.

First claim

What is claimed is:

1. A cell-binding agent-drug conjugate of formula (II)

wherein:
Cb represents a cell-binding agent which is an antibody, or a fragment thereof;
Drug represents a drug;
n is an integer from 1 to 20; and
the cell-binding agent-drug conjugate of formula (II) is formed by reacting a functional group on the drug with Z in a compound of formula (I), and reacting a functional group on the cell-binding agent with Y:

wherein Y is selected from the group consisting of an unsubstituted or substituted N-hydroxysuccinimide ester, hydrazide, p-nitrophenyl ester, dinitrophenyl ester, pentafluorophenyl ester, pyridyldisulfide, nitropyridyldisulfide, unsubstituted or substituted maleimido, β-maleimidopropionamido, haloacetate and carboxylic acid halide;
Z is a thiol, disulfide, pyridyldisulfide, —ONH 2 , carboxy, aldehyde, ketone, azide, unsubstituted or substituted maleimido, N-hydroxy succinimide ester, haloacetyl, halogen, hydrazine or hydroxy group;
M is H, Na, K, N + R 1 R 2 R 3 or a pharmaceutical salt thereof;
R 1 and R 2 are the same or different and are a linear alkyl having from 1 to 6 carbon atoms, branched or cyclic alkyl having from 3 to 6 carbon atoms, a linear, branched or cyclic alkenyl or alkynyl having from 2 to 6 carbon atoms, a polyethyleneoxy unit of formula (OCH 2 CH 2 ) p , wherein p is an integer from 1 to about 1000, or a combination thereof;
R 3 is absent, a linear alkyl having from 1 to 6 carbon atoms, branched or cyclic alkyl having from 3 to 6 carbon atoms, a linear, branched or cyclic alkenyl or alkynyl having from 2 to 6 carbon atoms, a polyethyleneoxy unit of formula (OCH 2 CH 2 ) p , wherein p is an integer from 1 to about 1000, or a combination thereof;
and
R 4 , and R 5 , are the same or different and are absent, H, a linear alkyl having from 1 to 6 carbon atoms, branched or cyclic alkyl having from 3 to 6 carbon atoms, linear, branched or cyclic alkenyl or alkynyl having from 2 to 6 carbon atoms, or polyethyleneoxy unit of formula (OCH 2 CH 2 ) p-1 OCH 2 CH 3 , wherein p−1 is an integer from 1 to about 1000, or a combination thereof.

2. The cell-binding agent-drug conjugate of claim 1 , wherein the Drug is selected from the group consisting of
1). chemotherapeutic agents:
a). alkylating agents selected from the group consisting of Nitrogen mustards selected from the group consisting of chlorambucil, chlornaphazine, cyclophosphamide, dacarbazine, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, mannomustine, mitobronitol, melphalan, mitolactol, pipobroman, novembichin, phenesterine, prednimustine, thiotepa, trofosfamide, and uracil mustard; CC-1065 and adozelesin, carzelesin and bizelesin compounds thereof; duocarmycin; benzodiazepine dimers selected from the group consisting of dimers of pyrrolobenzodiazepine, tomaymycin, indolinobenzodiazepines, imidazobenzothiadiazepines, and oxazolidinobenzodiazepines; nitrosoureas selected from the group consisting of carmustine, lomustine, chlorozotocin, fotemustine, nimustine, and ranimustine; alkylsulphonates selected from the group consisting of busulfan, treosulfan, improsulfan and piposulfan; triazenes (dacarbazine); platinum containing compounds selected from the group consisting of carboplatin, cisplatin, and oxaliplatin; aziridines selected from the group consisting of benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines selected from the group consisting of altretamine, triethylenemelamine, trietylenephosphoramide, triethylenethiophosphaoramide and trimethylolomelamine;

b). plant alkaloids selected from the group consisting of Vinca alkaloids selected from the group consisting of vincristine, vinblastine, vindesine, vinorelbine, and navelbin; Taxoids selected from the group consisting of paclitaxel, and docetaxol; maytansinoids selected from the group consisting of DM1, DM2, DM3, DM4, DM5, DM6, DM7, maytansine and ansamitocins; cryptophycins selected from the group consisting of cryptophycin 1 and cryptophycin 8; epothilones, eleutherobin, discodermolide, bryostatins, dolostatins, auristatins, tubulysins, cephalostatins; pancratistatin; a sarcodictyin; and spongistatin;
c). DNA topoisomerase inhibitors selected from the group consisting of Epipodophyllins selected from the group consisting of 9-aminocamptothecin, camptothecin, crisnatol, daunomycin, etoposide, etoposide phosphate, irinotecan, mitoxantrone, novantrone, retinoic acids (retinols), teniposide, topotecan, and 9-nitrocamptothecin; and mitomycins (mitomycin C);
d). anti-metabolites selected from the group consisting of anti-folate which is selected from the group consisting of DHFR inhibitors selected from the group consisting of methotrexate, trimetrexate, denopterin, pteropterin, and aminopterin; IMP dehydrogenase inhibitors selected from the group consisting of mycophenolic acid, tiazofurin, ribavirin, and EICAR; ribonucleotide reductase inhibitors selected from the group consisting of hydroxyurea, and deferoxamine; pyrimidine compounds selected from the group consisting of uracil compounds selected from the group consisting of ancitabine, azacitidine, 6-azauridine, capecitabine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, 5-fluorouracil, floxuridine, and ratitrexed; cytosine compounds selected from the group consisting of cytarabine, cytosine arabinoside, and fludarabine; purine compounds selected from the group consisting of azathioprine, fludarabine, mercaptopurine, thiamiprine, and thioguanine; and folic acid replenisher (frolinic acid);
e). hormonal therapies selected from the group consisting of receptor antagonists selected from the group consisting of anti-estrogen selected from the group consisting of megestrol, raloxifene, and tamoxifen; LHRH agonists selected from the group consisting of goscrclin, and leuprolide acetate; anti-androgens selected from the group consisting of bicalutamide, flutamide, calusterone, dromostanolone propionate, epitiostanol, goserelin, leuprolide, mepitiostane, nilutamide, testolactone, and trilostane; retinoids/deltoids which is selected from the group consisting of Vitamin D3 compounds selected from the group consisting of CB 1093, EB 1089 KH 1060, cholecalciferol, and ergocalciferol; photodynamic therapies selected from the group consisting of verteporfin, phthalocyanine, photosensitizer Pc4, and demethoxy-hypocrellin A; cytokines selected from the group consisting of Interferon-alpha, Interferon-gamma, tumor necrosis factor (TNFs), and human proteins containing a TNF domain;
f). kinase inhibitors selected from the group consisting of BMW 2992 (anti-EGFR/Erb2), imatinib, gefitinib, pegaptanib, sorafenib, dasatinib, sunitinib, erlotinib, nilotinib, lapatinib, axitinib, pazopanib, vandetanib, E7080 (anti-VEGFR2), mubritinib, ponatinib, bafetinib, bosutinib, cabozantinib, vismodegib, iniparib, ruxolitinib, CYT387, axitinib, tivozanib, sorafenib, bevacizumab, cetuximab, trastuzumab, ranibizumab, panitumumab, and ispinesib;
g). antibiotics selected from the group consisting of enediyne antibiotics selected from the group consisting of calicheamicins, calicheamicin γ1, γ1, α1 and β1; dynemicin selected from the group consisting of dynemicin A and deoxydynemicin; esperamicin, kedarcidin, C-1027, maduropeptin, neocarzinostatin chromophore and related chromoprotein enediyne antiobiotic chromomophores, aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin; chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin,

Assignees

• Hangzhou Dac Biotech Co Ltd

Inventors

• Zhao Robert Yongxin
• Li Xing
• Huang Yuangyuang
• Yang Qingliang

Classifications

• A61K47/6803

  Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title

• A61K47/6807

  the drug or compound being a sugar, nucleoside, nucleotide, nucleic acid, e.g. RNA antisense · CPC title

• C07F9/65583

  each of the hetero rings containing nitrogen as ring hetero atom · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title