JP2015536329A - 薬物−タンパク質コンジュゲート - Google Patents
薬物−タンパク質コンジュゲート Download PDFInfo
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- JP2015536329A JP2015536329A JP2015538561A JP2015538561A JP2015536329A JP 2015536329 A JP2015536329 A JP 2015536329A JP 2015538561 A JP2015538561 A JP 2015538561A JP 2015538561 A JP2015538561 A JP 2015538561A JP 2015536329 A JP2015536329 A JP 2015536329A
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- 201000011281 bladder sarcoma Diseases 0.000 description 1
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 1
- 229910010277 boron hydride Inorganic materials 0.000 description 1
- 229960000455 brentuximab vedotin Drugs 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000006037 cell lysis Effects 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 238000003570 cell viability assay Methods 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- GTZCVFVGUGFEME-HNQUOIGGSA-N cis-Aconitic acid Natural products OC(=O)C\C(C(O)=O)=C/C(O)=O GTZCVFVGUGFEME-HNQUOIGGSA-N 0.000 description 1
- GTZCVFVGUGFEME-IWQZZHSRSA-N cis-aconitic acid Chemical compound OC(=O)C\C(C(O)=O)=C\C(O)=O GTZCVFVGUGFEME-IWQZZHSRSA-N 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- DTPCFIHYWYONMD-UHFFFAOYSA-N decaethylene glycol Chemical compound OCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO DTPCFIHYWYONMD-UHFFFAOYSA-N 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000000326 densiometry Methods 0.000 description 1
- 238000011033 desalting Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011026 diafiltration Methods 0.000 description 1
- 239000000032 diagnostic agent Substances 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 210000001163 endosome Anatomy 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 238000009650 gentamicin protection assay Methods 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 229940022353 herceptin Drugs 0.000 description 1
- 239000008241 heterogeneous mixture Substances 0.000 description 1
- 150000007857 hydrazones Chemical class 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 239000002523 lectin Substances 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 230000002132 lysosomal effect Effects 0.000 description 1
- 210000003712 lysosome Anatomy 0.000 description 1
- 230000001868 lysosomic effect Effects 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 210000004688 microtubule Anatomy 0.000 description 1
- 230000011278 mitosis Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 150000002905 orthoesters Chemical class 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 235000019834 papain Nutrition 0.000 description 1
- 229940055729 papain Drugs 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000006320 pegylation Effects 0.000 description 1
- 125000001151 peptidyl group Chemical group 0.000 description 1
- 108010073101 phenylalanylleucine Proteins 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920002704 polyhistidine Polymers 0.000 description 1
- 102000040430 polynucleotide Human genes 0.000 description 1
- 108091033319 polynucleotide Proteins 0.000 description 1
- 239000002157 polynucleotide Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000008057 potassium phosphate buffer Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 235000019833 protease Nutrition 0.000 description 1
- 235000019419 proteases Nutrition 0.000 description 1
- 239000012474 protein marker Substances 0.000 description 1
- 239000001990 protein-drug conjugate Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000010188 recombinant method Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 208000015347 renal cell adenocarcinoma Diseases 0.000 description 1
- 125000006853 reporter group Chemical group 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000012146 running buffer Substances 0.000 description 1
- 150000003839 salts Chemical group 0.000 description 1
- 150000007659 semicarbazones Chemical class 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 238000001542 size-exclusion chromatography Methods 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 125000006850 spacer group Chemical group 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000004354 sulfur functional group Chemical group 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 231100000057 systemic toxicity Toxicity 0.000 description 1
- GISRSYIQHFGCMC-UHFFFAOYSA-N tert-butyl n-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCN GISRSYIQHFGCMC-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- SRVJKTDHMYAMHA-WUXMJOGZSA-N thioacetazone Chemical compound CC(=O)NC1=CC=C(\C=N\NC(N)=S)C=C1 SRVJKTDHMYAMHA-WUXMJOGZSA-N 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- GTZCVFVGUGFEME-UHFFFAOYSA-N trans-aconitic acid Natural products OC(=O)CC(C(O)=O)=CC(O)=O GTZCVFVGUGFEME-UHFFFAOYSA-N 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000010304 tumor cell viability Effects 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
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- 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
- A61K47/6801—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
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- 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
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- 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
- A61K47/6889—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
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
(((Dq-Lk1)m-P)p-Lk2-Lk3)n-Ab (I)
[式中、Dは、メイタンシン部分を表し;
qは、1〜10の整数を表し;
Lk1は、リンカーを表し;
mは、1〜10の整数を表し;
Pは、結合またはz価の基-P1-NH(ここでzは2〜11であり、P1は少なくとも1つのエチレン単位-CH2-CH2またはエチレングリコール単位-O-CH2-CH2-を含む基である)を表し;
pは、1〜10の整数を表し;
Lk2は、結合またはy価のリンカー(ここでyは2〜11であり、1〜9のアスパルテートおよび/もしくはグルタメート残基からなる)を表し;
Lk3は、一般式:
-CO-Ph-X-Y- (II)
{式中、Phは場合により置換されたフェニル基であり;XはCO基またはCH.OH基を表し;Yは式:
のリンカーを表し;
Abは、標的上の結合パートナーに結合することができる結合タンパク質またはペプチドを表し、前記結合タンパク質またはペプチドは、結合タンパク質またはペプチドにおけるジスルフィド結合由来の2つの硫黄原子を介してLk3に結合されており;
nは、1〜sの整数(ここでsは、Lk3にコンジュゲートする前に結合タンパク質またはペプチドに存在しているジスルフィド結合の数である)を表し;
m、n、p、q、yおよびzの値は、コンジュゲートに1〜10個のD基が含まれるように選択される]
のメイタンシン含有コンジュゲートを提供する。
を含む化合物である。
を含む。
が挙げられる。好ましい実施形態において、Lk1は、
である。
のコンジュゲートであり得る。
((Dq-Lk1)m-P)p-Lk2-Lk3a (VIII)
[式中、D、Lk1、P、Lk2ならびにm、pおよびqは一般式Iで示した意味を有し;
Lk3aは式:
-CO-Ph-Xa-Ya (IX)
{式中、Phは上記で示された意味を有し;XaはCO基を表し;Yaは基:
の基を表す]
のコンジュゲート化試薬と反応させることによって調製することができる。
が挙げられる。
が挙げられる。
((Lk1b)m-P)p-Lk2-Lk3a
[式中、m、P、L、p、Lk2およびLk3aは一般式VIIIに示される意味を有し、Lk1bはメイタンシンに存在する基と反応する基を含むように式Lk1を改変させた基である]
の化合物とを反応させることによって調製し得る。典型的な基および適切な反応は当業者にとって周知である。
O-(6-クロロベンゾトリアゾル-1-イル)-N,N,N',N'-テトラメチルウロニウムヘキサフルオロホスフェート(HCTU)(29mg)を、ビス-スルホン-PEG(24)-CO2H(75mg、NH2-PEG(24)-CO2HからNat. Prot.、1巻、4号、2006に基づく方法を使用して調製)の無水ジメチルホルムアミド(5.8mL)の撹拌溶液に添加し、20分間撹拌した。val-ala-PAB-AHX-DM1(100mg、Concortis Biosystems社)を添加し、反応混合物を30℃で撹拌した。24時間後、さらなる量のHCTU(2mg)を添加し、反応混合物を30℃で撹拌した。さらに16時間後、揮発物を真空下で除去し、固体残留物をカラムクロマトグラフィーによりジクロロメタン-メタノール(97:3v/v+5滴のAcOH/50mL溶媒、次いで96:4v/v+5滴のAcOH/50mL溶媒)で溶出して精製し、溶媒を真空下で除去し、ビス-スルホン-PEG(24)-val-ala-PAB-AHX-DM11を薄黄色の油(55mg)として単離した。m/z M+Na+ 2716;診断シグナル:
1-[ビス(ジメチルアミノ)メチレン]-1H-1,2,3-トリアゾロ[4,5-b]ピリジニウム3-オキシドヘキサフルオロホスフェート(HATU)(10mg)を、既知のビス-スルホン-PEG(5kDa)-CO2H(56mg、NH2-PEG(5kDa)-CO2HからNat. Prot.、1巻、4号、2006に基づく方法を使用して調製)の無水ジメチルホルムアミド(0.5mL)の撹拌溶液に添加し、val-ala-PAB-AHX-DM1(15.8mg、Concortis Biosystems社)のジメチルホルアミド(0.5mL)溶液を添加した後、N-メチルモルホリン(4.4μL)を添加し、反応混合物を室温で撹拌した。24時間後、さらなる量のHATU(10mg)およびN-メチルモルホリン(4.4μL)を添加し、反応物を室温で撹拌した。さらに19時間後、揮発物を真空下で除去し、固体残留物を逆相C18-カラムクロマトグラフィーによりバッファーA(v/v):水:5%アセトニトリル:0.1% TFAおよびバッファーB(v/v):0.1% TFAのアセトニトリル(100:0v/vから0:100)で溶出して精製し、有機溶媒を真空下で除去し、水性溶媒を凍結乾燥によって除去し、ビス-スルホン-PEG(5kDa)-val-ala-PAB-AHX-DM12を無色の膜(10.6mg)として単離した。m/z M+Na+ 6380。
5mg/mLの抗体(2.25mg)(ハーセプチン(登録商標)の、pH7.5の20mMリン酸ナトリウム、150mM NaClおよび20mM EDTAの溶液に、5mM TCEP溶液(18μL)を添加し、得られた混合物を40℃で1時間インキュベートした。還元抗体溶液(0.468mL、4.8mg/mLにて)を、pH7.5の20mMリン酸ナトリウムバッファー、150mM NaClおよび20mM EDTAで3.33mg/mLに希釈した。還元抗体に、ビス-スルホン-PEG(24)-val-ala-PAB-AHX-DM1試薬1のDMF溶液(75μL、3.23mg/mLにて)を添加し、得られた溶液を混合し、22℃で22時間インキュベートした。反応物を50mMのN-アセチル-L-システイン(36μL)の添加によってクエンチし、22℃でさらに1時間インキュベートした。最終反応混合物(786μL)を、5mLのZeba(商標)スピンカラム(Pierce社)を使用して、PBS×1にバッファー交換した。反応混合物を、TOSOH TSK-ゲル ブチル-NPRカラムを使用して、疎水性相互作用クロマトグラフィー(HIC)により分析した。方法は、30分で100%バッファーA(pH7.0の50mMリン酸ナトリウム、1.5M硫酸アンモニウム)から100%バッファーB(pH7.0の50mMリン酸ナトリウム、20%イソプロパノール)への直線勾配で構成した。検出は248nmおよび280nmでのUV吸収に従って実施した。付加された薬物に従って化学種を分離し、248nmおよび280nmでの最大UV吸収度の比によって特徴づけした。DAR変異体それぞれについての面積を測定し、棒グラフとしてプロットした。結果を図1に示す。主生成物はDAR=4コンジュゲートであった(65%)。
Fab(5mg、トラスツズマブのパパイン消化物由来)の2.59mg/mLでのPBS溶液に、19.3μLの1M DTTを添加した。還元混合物を、22℃で1時間インキュベートした。インキュベーション後、混合物を、5mL Zeba(商標)スピン脱塩カラムを使用して、pH7.4の20mMリン酸ナトリウム、150mM NaClおよび20mM EDTAへのバッファー交換を行った。還元Fab溶液(1.9mL、2.58mg/mLにて)を、pH7.4の20mMリン酸ナトリウムバッファー、150mM NaClおよび20mM EDTAで2.22mg/mLに希釈した。還元Fab(2.12mL、2.22mg/mLにて)に、ビス-スルホン-PEG(24)-val-ala- PAB-AHX-DM1試薬1の50% DMSOおよび50% 20mMリン酸ナトリウムバッファー(pH7.4)、150mM NaClならびに20mM EDTA(235μL、1.62mg/mLにて)を添加し、得られた溶液を混合し、22℃で18時間インキュベートした。次いで、反応混合物をSDS-PAGEによって分析した。その後、コンジュゲーション混合物を、5mLのHiTrap(商標)フェニルHP HICカラムを使用して分取HICによって精製した。精製されたFab-試薬1コンジュゲートをRP-HPLC(図2)およびSDS-PAGE(図3)により分析した。RP-HPLC分析をVariTide RPC 250×4.6mmカラム(Agilent Technologies社)で実施し、図2に示すようにFab-AHX-DM1コンジュゲート生成物を走らせると単一の主ピークとなり(面積で92%)、コンジュゲートが非常に均質であることが示された。SDS-PAGE分析に関しては、サンプルを4-12% Bis-TrisゲルでMESランニングバッファー中にて200Vで35分間走らせた。Novex(登録商標)Sharp Pre-stained Standardをタンパク質マーカーとして使用した。NuPAGE(登録商標)LDS Sample Buffer(4×)をサンプルバッファーとして使用し、ゲルをInstantBlue(商標)タンパク質ステインで染色した。各レーンについての純粋な読取値を得るためにデンシトメトリーをImageQuant LAS 4000で分析し、ゲルに対する百分率として図4に示している。1μgのサンプル(Fabに基づく)を各レーンに、すなわちサンプル毎に充填した。図4において、Mとラベルしたレーンはタンパク質標準であり、1とラベルしたレーンは初発のFabであり、2とラベルしたレーンはDTT処理後の初発のFabであり、3とラベルしたレーンは精製済みFab-AHX-DM1コンジュゲートであり、4とラベルしたレーンはDTT処理後の精製済みFab-AHX-DM1コンジュゲートである。Fabおよびコンジュゲートの両方を、DTTを用いて同様の方法により、すなわち最終濃度10mMのDTTで1時間、室温で処理した。
実施例3および4において、それぞれ調製した抗体およびFabコンジュゲートのインビトロ効果をHER-2受容体過剰発現がん細胞株の細胞増殖に対する阻害効果を測定することによって求めた。
Claims (19)
- 一般式:
(((Dq-Lk1)m-P)p-Lk2-Lk3)n-Ab (I)
[式中、Dは、メイタンシン部分を表し;
qは、1〜10の整数を表し;
Lk1は、リンカーを表し;
mは、1〜10の整数を表し;
Pは、結合またはz価の基-P1-NH(ここでzは2〜11であり、P1は少なくとも1つのエチレン単位-CH2-CH2-またはエチレングリコール単位-O-CH2-CH2-を含む基である)を表し;
pは、1〜10の整数を表し;
Lk2は、結合またはy価のリンカー(ここでyは2〜11であり、1〜9のアスパルテートおよび/もしくはグルタメート残基からなる)を表し;
Lk3は、一般式:
-CO-Ph-X-Y- (II)
{式中、Phは場合により置換されたフェニル基であり;XはCO基またはCH.OH基を表し;Yは式:
のリンカーを表し;
Abは、標的上の結合パートナーに結合することができる結合タンパク質またはペプチドを表し、前記結合タンパク質またはペプチドは、結合タンパク質またはペプチドにおけるジスルフィド結合由来の2つの硫黄原子を介してLk3に結合されており;
nは、1〜sの整数(ここでsは、Lk3にコンジュゲートする前に結合タンパク質またはペプチドに存在しているジスルフィド結合の数である)を表し;
m、n、p、q、yおよびzの値は、コンジュゲートに1〜10個のD基が含まれるように選択される]
のメイタンシン含有コンジュゲート。 - メイタンシン部分は、
- Lk1は、分解性リンカーである、請求項1または2に記載のコンジュゲート。
- Lk1は、以下の基:
の1つを含む、請求項3に記載のコンジュゲート。 - Lk1は、
- qは、2〜10の整数であり、Lk1は、1つもしくは複数のアスパルテートまたはグルタメート残基が組み込まれた多価のリンカーである、請求項1または請求項2のいずれか一項に記載のコンジュゲート。
- Pは結合を表すか、またはPは-P1-NH-(ここでP1は2〜10のエチレングリコール単位を含む)を表す、請求項1から6のいずれか一項に記載のコンジュゲート。
- Pは、ポリエチレングリコールを表す、請求項1から6のいずれか一項に記載のコンジュゲート。
- Lk3のフェニル基Phは置換されていない、請求項1から8のいずれか一項に記載のコンジュゲート。
- Yは、式:
- Abは、完全長抗体または完全長抗体の抗原結合領域を含む抗体フラグメントを表す、請求項1から10のいずれか一項に記載のコンジュゲート。
- Abは、IgG1もしくはIgG4またはIgG1もしくはIgG4のフラグメントを表す、請求項11に記載のコンジュゲート。
- 請求項1から12のいずれか一項に記載のコンジュゲートの調製方法であって、結合タンパク質における1つまたは複数のジスルフィド結合を還元する工程と、続けて一般式:
((Dq-Lk1)m-P)p-Lk2-Lk3a (VIII)
[式中、D、Lk1、P、Lk2ならびにm、pおよびqは請求項1に規定の意味を有し;
Lk3aは式:
-CO-Ph-Xa-Ya (IX)
{式中、Phは請求項1に規定の意味を有し、XaはCO基を表し、Yaは基:
の基を表す]のコンジュゲート化試薬と反応させて、XがCOを表す式Iのコンジュゲートを生成する工程と、場合により前記最初に形成されたCO基Xを還元してCH.OH基Xを有するコンジュゲートを得る工程とを含む、方法。 - Yaは、
- 一般式:
((Dq-Lk1)m-P)p-Lk2-Lk3a (VIII)
[式中、Dは、請求項1から3のいずれか一項に規定の意味を有し;Lk1は、請求項1および4から7のいずれか一項に規定の意味を有し;Pは、請求項1、8および9のいずれか一項に規定の意味を有し;Lk2、m、pおよびqは請求項1に規定の意味を有し、Lk3aは、式:
-CO-Ph-Xa-Ya (IX)
{式中、Phは請求項1または請求項10に規定の意味を有し、XaはCO基を表し、Yaは基:
の基を表す]
の化合物。 - Yaは、
- 請求項1から12のいずれか一項に記載のコンジュゲートと、医薬的に許容される担体と、場合によりさらなる治療剤とを含む、医薬組成物。
- 治療において使用するための、請求項1から12のいずれか一項に記載のコンジュゲートまたは請求項17に記載の組成物。
- 医薬的有効量の請求項1から12のいずれか一項に記載のコンジュゲートまたは請求項17に記載の医薬組成物を患者に投与する工程を含む、患者の処置方法。
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ES2965349T3 (es) | 2016-06-06 | 2024-04-12 | Abzena Uk Ltd | Anticuerpos, usos de los mismos y conjugados de los mismos |
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EP2911696B1 (en) | 2017-09-20 |
CN104755106B (zh) | 2018-03-13 |
SG11201501955VA (en) | 2015-04-29 |
ES2652513T3 (es) | 2018-02-02 |
US20150283259A1 (en) | 2015-10-08 |
NO2789793T3 (ja) | 2018-01-27 |
WO2014064424A1 (en) | 2014-05-01 |
DK2911696T3 (en) | 2018-01-08 |
IL237673A0 (en) | 2015-04-30 |
HK1208186A1 (en) | 2016-02-26 |
IN2015DN02577A (ja) | 2015-09-11 |
EP2911696A1 (en) | 2015-09-02 |
JP6328649B2 (ja) | 2018-05-23 |
ZA201501996B (en) | 2016-01-27 |
KR20150085808A (ko) | 2015-07-24 |
BR112015008311A2 (pt) | 2017-07-04 |
MX2015005124A (es) | 2015-10-29 |
CN104755106A (zh) | 2015-07-01 |
CA2884359A1 (en) | 2014-05-01 |
RU2015119557A (ru) | 2016-12-20 |
HUE037604T2 (hu) | 2018-09-28 |
AU2013336410A1 (en) | 2015-04-09 |
AU2013336410B2 (en) | 2017-08-03 |
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