NZ766984B2 - Antibody-drug conjugate having acidic self-stabilization junction - Google Patents

Antibody-drug conjugate having acidic self-stabilization junction Download PDF

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Publication number
NZ766984B2
NZ766984B2 NZ766984A NZ76698418A NZ766984B2 NZ 766984 B2 NZ766984 B2 NZ 766984B2 NZ 766984 A NZ766984 A NZ 766984A NZ 76698418 A NZ76698418 A NZ 76698418A NZ 766984 B2 NZ766984 B2 NZ 766984B2
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New Zealand
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group
antibody
drug
acceptable salt
pharmaceutically acceptable
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NZ766984A
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NZ766984A (en
Inventor
Jie Li
Weili Wan
Yiqian Wang
Yi Zhu
Shi Zhuo
Original Assignee
Sichuan Baili Pharm Co Ltd
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Publication date
Application filed by Sichuan Baili Pharm Co Ltd filed Critical Sichuan Baili Pharm Co Ltd
Priority claimed from PCT/CN2018/091621 external-priority patent/WO2018233571A1/en
Publication of NZ766984A publication Critical patent/NZ766984A/en
Publication of NZ766984B2 publication Critical patent/NZ766984B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/07—Tetrapeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/545—Heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/65—Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A—HUMAN NECESSITIES
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    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/68031—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being an auristatin
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    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6849—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6859—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from liver or pancreas cancer cell
    • A—HUMAN NECESSITIES
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    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6889—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C07K16/303—Liver or Pancreas

Abstract

The present invention provides a special drug conjugate having a hydrophilic acidic stabilization junction. Compared with a conjugate having a lower drug loading, due to the introduction of the acidic stabilization junction, the conjugate in the present invention can also have a higher drug loading (that is, each targeted reagent has more hydrophilic drug junctions), keeps a desired PK property and has a same or better activity in a body.

Description

Specification Title of the Invention: dy-drug conjugate having acidic self-stabilization junction Technical Field The present invention relates to the application of an antibody-drug conjugate for the treatment of cancer or other diseases, and in particular to the ation of a l hydrophilic acidic stabilization junction in the preparation of antibody-drug conjugate to increase drug stability in plasma while at the same time significantly improving pharmacokinetics (PK).
Background Art Antibody-drug conjugates (ADCs) are a class of novel targeted drugs which generally consist of three components: an antibody or antibody-like ligand, a smallmolecule drug, and a linker that couples the antibody to the drug. Antibody-drug ates make use of the specific recognition of certain antigens by antibodies to transport drug molecules to the vicinity of target cells and release them effectively in order to provide a therapeutic effect.
In August 2011, the U.S. Food and Drug Administration (FDA) approved Seattle Genetics' new ADC, isTM, for the ent of Hodgkin's lymphoma as well as anaplastic large cell ma (ALCL), and clinical application has demonstrated the safety and efficacy of this class of drugs.
For antibody-drug conjugates, in order to ensure the efficient attachment of the drug molecule to the antibody, conjugates currently entering clinical trials are typically attached via linkers to lysine residues on the e of the ligand or to cysteine residues (obtained by partial reduction of hain disulfide bonds) in the hinge region of the antibody. However, the presence of a large number of lysine residues (more than 1003412317 12 889 5 7 345674 5 35 !"#$ % ! & % ' "# $ % "(& ) & " % # "* # $ % "(& )! ! !+ , % "# & ! & %- $ * ) #") % .") !/ 0"&$ # & 1 % "(& ) % $$ % ' & * ) (# & * $ ( # (# "% 2" & % ! ! % + * & * ! #' ) ! & - # % # ( & ) & ! & % ' & $ #* # (# "% ! , !"&$ # & )# "(! " # * & 4 , ' #+ %# ! ) "* # $ ! " ! ' ! , $ !"%% * , !"&$ # & ! # ' #! & (# % !! 5 ' #! 6 % & + , 31 (# "% #! (& !* + 7% ) $ (# "% , & "* !"&$ # & )# "(+ # !"& ) ! ) $ #") * & %"& + % %& #& ! #' ' (# ! % $ & #) "* # $ (# ! % ) $# !"&$ # & )# "(! (& !* / 8 ! ) $ #") * & %"& (# "% ! 7 % ! $$ % ! , & # # "% ) $$ % % $ #") % .") / 50 0 + 9: ; .") ! * "& ' ' ! & # ( " % % ' $ #") % .") != ? "# 1 @ % 5 3 A B3 C 3 DE @ & , F G %-+ @ % ./ > * 33+ + 3DCH 3D1AE I&& + 9: ; */ + 3D+ J1D JH1/ 6 ' ! ) #! ' % ## " (" & ! ! " ! , ) & $ *(# ' ) ! & $ A #") % .") ! (& !* # "% ) !"&$ # & )# "( # ' #! 6 % & / K ! # ( # % %& % # (# "% $ #* * & * !"&$ # & % " #) # & ! ! 12 889 5 7 345674 5 35 ! ! " # $ # $ % & ' ( ) %*%( % ( $ $$ # $ % + ( $ " # $ # $ % ,( #( $ ( " -%! " $ . ! ! ( !*$ *( " # & /! + 0 ! -%! " ( !*$ *( " # % , % (* $ $ (( , $* $ " % 1 " % $ " # $ % , ! , $*& 23 /! # $ $$ " # " % ( % $ ,* * % %( $ " ! #4 $ # ! % . (( ! % ,1 % ! % $ $ ! * , $ #4 $ # + # $ " # " #4 $ # ! ! , $* % ( , %! $ ,* # 5 " ! ( ) % & 6 78932:390;09 $ %( ! $ .! ,* " ( % % " " # $ % $ $ ! %% $ "+ .! $ ! $ ( " ( % 93 , , % $ % ! -%! " ! ! $$ # $ % . ! (, < ! . + # % (* , % ! # % $ ( % , , " " # ! ! %% $ $ $ " ( ) " $ % ( # $ ( % $ $ %% $ , " " 90 ( % % " " # ! "!(* % # ,( " !*$ (* .! %! ( " ,( $ " ! $$ . ! ! ! & 3 = ( > % ?'=@ 6 A & '=932 3 3B90: $ %( ( ) ! $ % , % " # $ 12 345673889 5 7 345674 5 35 ! " # $ % &! ! ' # ! ( ! $$ $ ' (( ) * $ $ $ ! (( ( ! ' " % " ( * # ) " ' * "# + ," / " * - & % ! . ( ! # "# " & - * ' " $ ! ! ! ( ' " " # ! " # $ % # ) ! !*$ ! * ( ! # ' # " # $ (( + 0! " ! # " & ( # $ 87 " '" 1 2 3 " % 45678/7/9:;;+ ,( " ' < = ' ' " # % ! ) " ( ! " ) $ " ) $ ! ' $* $ = # & " " $ * $ $ $ # 8/ ! ! $ $" $ !*$ ! ' * >" ? @ + 7/9:;;% ? 66/A% $ # ) ! ' ) " % ! ) " & ( $ $ # * !* * " ! " $ ! ( ! # # ) ! ( ! 67 # >" ? @ + 45678/7/9:;;A+ B $$ $ ' # ! $ # ) "# " ' *% ! # ( ! # " ' " $ $ ' $* $ = $ " " ! # ( $ ! ' $ ) $ 6/ > + +% ! 1 * ( * ! $ ! > + +% ! ' $*AA% &! ! " ( $ " ! $ $+ B ! " ' !* ! " < $ ! ! ! $ $" $ ' (( * ! & $ $" > + +% C $ "! $ ! ' ' J7 DE FDFG $ DE FDHIG (( * # $ $A+ 0! ( ! " ! * " ! = " & ! ! ! $ $" & $ ) # $ > * A "+ K " " ' $ DE FDHIG ! ) " ( # $ ! = " & ! ! ! $ $" J/ ! ' ! ! ) * " " DE FDHIG+ . & ) % " '" 1 " $ " ! ) ) $ ! ! " !* ! " " ! " * ' " # * ( # $ DE FDFG 12 889 5 7 345674 5 35 ! ! "# " $" % &$' ( ) $ * $ "$' + $" # $ ,- % . " % # . $" / ' " ++ % %. ( ! "# $ " * $ "$' 0 1 ! / 23 45 / 6 % 6 % " 7 89: ;9<= ;9 >?99)@ 1 ! " # " + " ! # ,- " - +$" " " - " ' " AB6 " % " +" % "%$ " C$ %D . E + " 89 % " % % %. + " ' " % &$' # " $ ! FG % - " ( " % &$' / ' " % &$' , ! ( " HEB % $ # "" ( " " - $ % , % " / AB6 ( + ( 8 " + % . + % ! . ( " " - " # " ! " FG -" - " " - $ % % + $" $ AB6 0 " - " -$! !. I$ $ $ / 23 45 / 6 % 6 % " 7 8<: );?989@ ?9 %" ' "$' " % . %" $ + "$' % "" !. ' ! .
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Claims (17)

Claims
1. An antibody-drug conjugate or its pharmaceutically acceptable salt thereof as shown in Formula I: wherein: the circle represents a scaffold, wherein the scaffold comprises a C1-8 alkylene group, a C1-8 heteroalkylene 10 group, a C6-10 arylidene group, or a C4-10 heteroarylidene group; L comprises an antibody or a functional antibody fragment thereof; M comprises a succinimide group or a hydrolytically ring- 15 opened succinimide group; Ac is connected to the scaffold through an amino group, wherein Ac comprises an acidic unit that serves to stabilize the antibody-drug conjugate, and wherein Ac comprises a nt consisting of at least one amino group 20 and at least one acidic group or an oligopeptide group ting of a plurality of amino acid units; D comprises a drug unit; A comprises a linker; m is an integer selected from 1 to 20; and n is 1 or 2.
2. The antibody-drug conjugate or its pharmaceutically acceptable salt thereof as described in claim 1, wherein said antibody corresponds to an antibody for a cell surface or and tumor-associated antigen.
3. The antibody-drug ate or its pharmaceutically acceptable salt thereof as described in claim 1 or 2, wherein the acidic unit of Ac is ed from a group consisting of carboxylic acid, phosphoric acid, ite, 35 and sulfonic acid . 1004805184
4. The dy-drug conjugate or its pharmaceutically acceptable salt thereof as described in any one of claims 1 to 3, wherein Ac comprises an acidic amino acid group or an acidic oligopeptide group.
5. The dy-drug conjugate or its pharmaceutically acceptable salt thereof as described in claim 4, wherein said oligopeptide group comprises 2 to 5 natural amino acid units, 2 to 5 unnatural amino acid units, or 2 to 5 10 natural and unnatural amino acid units.
6. The dy-drug conjugate or its pharmaceutically acceptable salt thereof as described in any one of claims 1 to 5, wherein the heteroalkylene group comprises one or 15 more heteroatoms selected from a group consisting of O, S,
7.N or P atoms; wherein the arylidene group is selected from a group consisting of phenyl, naphthyl or diphenyl; n the heteroarylidene group is selected from a group consisting of pyridyl, pyridazinyl, pyrazinyl, 20 pyrimidinyl, l, quinolinyl, isoquinolinyl, isothiazolyl, lyl, indazolyl, pteridyl, imidazolyl, lyl, tetrazolyl, oxazolyl, olyl, thiadiazolyl, pyrrole, thiazolyl, furanyl and thiophene. 25 7. The antibody-drug conjugate or its pharmaceutically acceptable salt thereof as described in any one of claims 1 to 6, wherein A comprises a cleavable linker or a noncleavable linker. 30
8. The antibody-drug conjugate or its pharmaceutically acceptable salt thereof as described in any one of claims 1 to 7, n said drug unit D comprises a cytotoxic drug, a drug for treating autoimmune disease, or an antiinflammatory drug.
9. The antibody-drug conjugate or its pharmaceutically acceptable salt thereof as bed in claim 8, wherein the drug unit D is selected from a group consisting of 1004805184 maitansine drugs, australin drugs, benzodipyrrole drugs, pyrrolozodiazole drugs, amantin and camptothecine compounds, their pharmaceutically able salts or derivatives thereof.
10. The antibody-drug conjugate or its pharmaceutically acceptable salt thereof as described in claim 7, wherein A has a structure as shown in the following formula: wherein C represents an extensible unit at the end, E represents a cleavable unit, F represents a spacer unit, subscripts e and f each is independently 0 or 1, the wavy line on the left represents a connection site to the 15 scaffold and the wavy line on the right represents a connection site to the drug unit.
11. The antibody-drug conjugate or its pharmaceutically acceptable salt thereof as described in claim 10, wherein 20 E is configured to be cleaved off from the drug unit D or the spacer unit F by a tumor-associated protease or under an acidic pH.
12. The antibody-drug conjugate or its ceutically 25 acceptable salt thereof as described in claim 10, n
13.F is selected from a group consisting of p-aminobenzyl alcohol, ethylenediamine units, and their derivatives thereof. 30 13. The antibody-drug conjugate or its pharmaceutically acceptable salt thereof as described in claim 6, wherein the scaffold comprises C1-8 alkylene or C1-8 heteroalkylene.
14. The antibody-drug ate or its pharmaceutically 35 acceptable salt thereof as described in claim 13, n ld ses a C1-3 alkylene. 1004805184
15. The antibody-drug conjugate or its pharmaceutically acceptable salt thereof as described in claim 1, wherein Ac is selected a group consisting of (D/L) glycine, (D/L) alanine, (D/L) leucine, (D/L) isoleucine, (D/L) valine, 5 (D/L) alanine, (D/L) proline, (D/L) tryptophan, (D/L) serine, (D/L) ne, (D/L) cysteine, (D/L) methionine, (D/L) asparagine, (D/L) glutamine, (D/L) threonine, (D/L) aspartic acid, (D/L) glutamic acid, or the following structural formulas: where a wavy line represents a linkage site to the scaffold 15 and R represents any structure between an amino group and a phosphate group.
16. A junction-drug linkage having the following wherein Ac is connected to the hydrocarbyl group through an amino group, and wherein Ac comprises a nt 25 consisting of at least one amino group and at least one acidic group or an oligopeptide consisting of a plurality of amino acid units; D comprises a drug unit; A comprises a linker; 30 q is an integer ranging from 1 to 8, and n is 1 or 2. 1004805184
17. Use of the antibody-drug conjugate or pharmaceutically acceptable salt thereof as described in any one of claims 1 through 15, in the preparation of a medicament for the treatment of cancer, immune disease or 5 mation. 1004805184 12 889 5 7 345674 5 35 12 889 5 7 345674 5 35 01 889 5 7 345674 5 35 01 889 5 7 345674 5 35 01 889 5 7 345674 5 35 01 889 5 7 345674 5 35
NZ766984A 2018-06-15 Antibody-drug conjugate having acidic self-stabilization junction NZ766984B2 (en)

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Application Number Priority Date Filing Date Title
CN201710462790 2017-06-19
PCT/CN2018/091621 WO2018233571A1 (en) 2017-06-19 2018-06-15 Antibody-drug conjugate having acidic self-stabilization junction

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NZ766984B2 true NZ766984B2 (en) 2023-11-28

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