ES2533992T3 - Procedimiento para preparar conjugados de anticuerpo maitansinoide - Google Patents
Procedimiento para preparar conjugados de anticuerpo maitansinoide Download PDFInfo
- Publication number
- ES2533992T3 ES2533992T3 ES11004940.0T ES11004940T ES2533992T3 ES 2533992 T3 ES2533992 T3 ES 2533992T3 ES 11004940 T ES11004940 T ES 11004940T ES 2533992 T3 ES2533992 T3 ES 2533992T3
- Authority
- ES
- Spain
- Prior art keywords
- maitansinoid
- antibody
- mixture
- antibodies
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- Prior art date
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- 238000000034 method Methods 0.000 title abstract description 5
- 239000003431 cross linking reagent Substances 0.000 abstract description 5
- 238000006243 chemical reaction Methods 0.000 abstract description 3
- 238000004587 chromatography analysis Methods 0.000 abstract description 3
- 239000000203 mixture Substances 0.000 abstract 8
- 230000000274 adsorptive effect Effects 0.000 abstract 1
- 230000001588 bifunctional effect Effects 0.000 abstract 1
- 239000006227 byproduct Substances 0.000 abstract 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 16
- 239000011347 resin Substances 0.000 description 8
- 229920005989 resin Polymers 0.000 description 8
- 239000011780 sodium chloride Substances 0.000 description 8
- 229940079593 drug Drugs 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 150000002148 esters Chemical class 0.000 description 6
- 239000008057 potassium phosphate buffer Substances 0.000 description 4
- 239000001488 sodium phosphate Substances 0.000 description 4
- 229910000162 sodium phosphate Inorganic materials 0.000 description 4
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 4
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- 239000012507 Sephadex™ Substances 0.000 description 3
- 102220589754 YjeF N-terminal domain-containing protein 3_G25F_mutation Human genes 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 230000021615 conjugation Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 239000000178 monomer Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- TYKASZBHFXBROF-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 2-(2,5-dioxopyrrol-1-yl)acetate Chemical compound O=C1CCC(=O)N1OC(=O)CN1C(=O)C=CC1=O TYKASZBHFXBROF-UHFFFAOYSA-N 0.000 description 2
- NKUZQMZWTZAPSN-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 2-bromoacetate Chemical compound BrCC(=O)ON1C(=O)CCC1=O NKUZQMZWTZAPSN-UHFFFAOYSA-N 0.000 description 2
- VRDGQQTWSGDXCU-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 2-iodoacetate Chemical compound ICC(=O)ON1C(=O)CCC1=O VRDGQQTWSGDXCU-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000008033 biological extinction Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 2
- 125000005179 haloacetyl group Chemical group 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- -1 maleimidomethyl Chemical group 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000003998 size exclusion chromatography high performance liquid chromatography Methods 0.000 description 2
- 239000001509 sodium citrate Substances 0.000 description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- PVGATNRYUYNBHO-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 4-(2,5-dioxopyrrol-1-yl)butanoate Chemical compound O=C1CCC(=O)N1OC(=O)CCCN1C(=O)C=CC1=O PVGATNRYUYNBHO-UHFFFAOYSA-N 0.000 description 1
- JSHOVKSMJRQOGY-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 4-(pyridin-2-yldisulfanyl)butanoate Chemical compound O=C1CCC(=O)N1OC(=O)CCCSSC1=CC=CC=N1 JSHOVKSMJRQOGY-UHFFFAOYSA-N 0.000 description 1
- BQWBEDSJTMWJAE-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 4-[(2-iodoacetyl)amino]benzoate Chemical compound C1=CC(NC(=O)CI)=CC=C1C(=O)ON1C(=O)CCC1=O BQWBEDSJTMWJAE-UHFFFAOYSA-N 0.000 description 1
- PMJWDPGOWBRILU-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 4-[4-(2,5-dioxopyrrol-1-yl)phenyl]butanoate Chemical compound O=C1CCC(=O)N1OC(=O)CCCC(C=C1)=CC=C1N1C(=O)C=CC1=O PMJWDPGOWBRILU-UHFFFAOYSA-N 0.000 description 1
- VLARLSIGSPVYHX-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 6-(2,5-dioxopyrrol-1-yl)hexanoate Chemical compound O=C1CCC(=O)N1OC(=O)CCCCCN1C(=O)C=CC1=O VLARLSIGSPVYHX-UHFFFAOYSA-N 0.000 description 1
- WCMOHMXWOOBVMZ-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 6-[3-(2,5-dioxopyrrol-1-yl)propanoylamino]hexanoate Chemical compound O=C1CCC(=O)N1OC(=O)CCCCCNC(=O)CCN1C(=O)C=CC1=O WCMOHMXWOOBVMZ-UHFFFAOYSA-N 0.000 description 1
- IUHSWGCULPLRNA-UHFFFAOYSA-N (3-hydroxy-2,5-dioxopyrrolidin-1-yl) 6-(2,5-dioxopyrrol-1-yl)hexanoate Chemical compound C1C(C(=O)N(C1=O)OC(=O)CCCCCN2C(=O)C=CC2=O)O IUHSWGCULPLRNA-UHFFFAOYSA-N 0.000 description 1
- OJQSISYVGFJJBY-UHFFFAOYSA-N 1-(4-isocyanatophenyl)pyrrole-2,5-dione Chemical compound C1=CC(N=C=O)=CC=C1N1C(=O)C=CC1=O OJQSISYVGFJJBY-UHFFFAOYSA-N 0.000 description 1
- YCTIVQHRJIAMKZ-UHFFFAOYSA-N 2-amino-4-(2-iodoacetyl)benzoic acid Chemical compound NC1=CC(C(=O)CI)=CC=C1C(O)=O YCTIVQHRJIAMKZ-UHFFFAOYSA-N 0.000 description 1
- NCPQROHLJFARLL-UHFFFAOYSA-N 4-(2,5-dioxopyrrol-1-yl)butanoic acid Chemical compound OC(=O)CCCN1C(=O)C=CC1=O NCPQROHLJFARLL-UHFFFAOYSA-N 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- 101001099381 Homo sapiens Peroxisomal biogenesis factor 19 Proteins 0.000 description 1
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 102100038883 Peroxisomal biogenesis factor 19 Human genes 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 229920005654 Sephadex Polymers 0.000 description 1
- 229920002684 Sepharose Polymers 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 235000019897 UltracelTM Nutrition 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 150000001991 dicarboxylic acids Chemical class 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 229920000889 poly(m-phenylene isophthalamide) Polymers 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- WHMDPDGBKYUEMW-UHFFFAOYSA-N pyridine-2-thiol Chemical compound SC1=CC=CC=N1 WHMDPDGBKYUEMW-UHFFFAOYSA-N 0.000 description 1
- 239000004627 regenerated cellulose Substances 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
Classifications
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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
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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
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/20—Interleukins [IL]
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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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
- A61K47/6835—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
- A61K47/6867—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 a cell of a blood cancer
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- A—HUMAN NECESSITIES
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- A61P35/00—Antineoplastic agents
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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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
- C07K16/2896—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against molecules with a "CD"-designation, not provided for elsewhere
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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
- A61K47/6807—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug or compound being a sugar, nucleoside, nucleotide, nucleic acid, e.g. RNA antisense
- A61K47/6809—Antibiotics, e.g. antitumor antibiotics anthracyclins, adriamycin, doxorubicin or daunomycin
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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
- C07K16/2839—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the integrin superfamily
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- 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
- C07K16/2884—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against CD44
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07K2317/40—Immunoglobulins specific features characterized by post-translational modification
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- General Health & Medical Sciences (AREA)
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- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
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- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Cell Biology (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Peptides Or Proteins (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Cephalosporin Compounds (AREA)
Abstract
Un procedimiento para preparar un conjugado anticuerpo-maitansinoide, que comprende las etapas de: (a) poner en contacto un anticuerpo con un reactivo de reticulación bifuncional para unir covalentemente un enlazador al anticuerpo y preparar de este modo una primera mezcla que comprende anticuerpos que tienen enlazadores unidos a los mismos, (b) someter la primera mezcla a cromatografía adsortiva y preparar de este modo una primera mezcla purificada de anticuerpos que tienen enlazadores unidos a los mismos, (c) conjugar un maitansinoide con los anticuerpos que tienen enlazadores unidos a los mismos en la primera mezcla purificada haciendo reaccionar los anticuerpos que tienen enlazadores unidos a los mismos con un maitansinoide en una solución que tiene un pH de 4 a 9 para preparar una segunda mezcla que comprende (i) anticuerpo acoplado químicamente mediante el enlazador al maitansinoide, (ii) maitansinoides libres y (iii) subproductos de reacción, y (d) someter la segunda mezcla a cromatografía adsortiva para purificar los anticuerpos acoplados químicamente mediante los enlazadores al maitansinoide de los otros componentes de la segunda mezcla y preparar de este modo una segunda mezcla purificada de anticuerpos acoplados químicamente mediante los enlazadores al maitansinoide.
Description
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Los reactivos de reticulación adecuados que forman enlazadores no escindibles entre un fármaco y el agente de unión a células son bien conocidos en la técnica. Los ejemplos de enlazadores no escindibles incluyen enlazadores que tienen un resto éster de N-succinimidilo o éster de N-sulfosuccinimidilo para la reacción con el agente que se une a la célula, así como un resto basado en maleimido o haloacetilo para la reacción con el fármaco. Los reactivos de reticulación que comprenden un resto basado en maleimido incluyen 4-(maleimidometil)ciclohexanocarboxilato de N-succinimidilo (SMCC), 4-(maleimidometil)-ciclohexano-1-carboxi-(6-amidocaproato) de N-succinimidilo, que es un análogo de “cadena larga” del SMCC (LC-SMCC), éster de N-succinimidilo del ácido κ-maleimidoundecanoico (KMUA), éster de N-succinimidilo del ácido γ-maleimidobutírico (GMBS), éster de hidroxisuccinimidilo del ácido εmaleimidocaproico (EMCS), éster de m-maleidobenzoil-N-hidroxisuccinimida (MBS), éster de N-(αmaleimidoacetoxi)-succinimida (AMAS), 6-(β-maleimidopropionamido)hexanoato de N-succinimidilo (SMPH), 4-(pmaleimidofenil)-butirato de N-succinimidilo (SMPB), e isocianato de N-(p-maleimidofenilo) (PMPI). Los reactivos de reticulación que comprenden un resto basado en haloacetilo incluyen 4-(yodoacetil)-aminobenzoato de Nsuccinimidilo (SIAB), yodoacetato de N-succinimidilo (SIA), bromoacetato de N-succinimidilo (SBA) y 3(bromoacetamido)propionato de N-succinimidilo (SBAP).
También se pueden usar en el método inventivo otros reactivos de reticulación que carecen de un átomo de azufre y que forman enlazadores no escindibles. Tales enlazadores pueden derivar de restos basados en ácidos dicarboxílicos. Los restos basados en ácidos dicarboxílicos adecuados incluyen, pero no se limitan a, ácidos α,ωdicarboxílicos de la fórmula general (IX):
HOOC-X1-Yn-Zm-COOH
(IX),
en la que X es un grupo alquilo, alquenilo o alquinilo lineal o ramificado que tiene 2 a 20 átomos de carbono, Y es un grupo cicloalquilo o cicloalquenilo que lleva 3 a 10 átomos de carbono, Z es un grupo aromático sustituido o no sustituido que lleva 6 a 10 átomos de carbono, o un grupo heterocíclico sustituido o no sustituido en el que el heteroátomo se selecciona de N, O o S, y en donde cada uno de l, m y n son cero o 1, a condición de que l, m y n no son todos cero al mismo tiempo.
Muchos de los enlazadores no escindibles descritos en la presente memoria se describen en detalle en la solicitud de patente de EE.UU. Nº 10/960.602, que corresponde a la publicación de solicitud de patente de EE.UU. Nº 2005/0169933 A1.
Se describe información adicional relativa a maitansinoides, agentes citotóxicos que comprenden los mismos, conjugados de fármacos y métodos de preparación relacionados en la solicitud de patente de EE.UU. Nº 11/352.121 y la solicitud de patente de EE.UU. Nº 10/849.136, que corresponde a la publicación de solicitud de patente de EE.UU. Nº 2004/0235840 A1.
Los siguientes ejemplos ilustran adicionalmente la invención.
Ejemplo comparativo 1
Este ejemplo demuestra la purificación de un anticuerpo modificado con un reactivo de modificación heterobifuncional usando TFF.
Se incubó el anticuerpo monoclonal huN901 (concentración final de 8 mg/ml) con 4-(2-piridilditio)pentanoato de Nsuccinimidilo (SPP, exceso molar de 5,6 veces) durante aproximadamente 180 minutos a 20º C en tampón fosfato de potasio 50 mM (pH 7,5) que contenía NaCl 50 mM, EDTA 2 mM y etanol al 5%. En un primer grupo, la mezcla de reacción se purificó usando una columna de resina SephadexTM G25F equilibrada y eluida en tampón fosfato de potasio 50 mM (pH 6,5) que contenía NaCl 50 mM y EDTA 2 mM. En un segundo grupo, la mezcla de reacción se purificó usando un sistema Pellicon XL TFF (Millipore, Billerica, MA), y el anticuerpo fue diafiltrado (5 volúmenes) en fosfato de potasio 50 mM, NaCl 50 mM (pH 6,5) y EDTA 2 mM usando una membrana de corte de peso molecular de 10.000 (membrana de celulosa regenerada UltracelTM , Millipore, Billerica, MA). Ambas muestras fueron conjugadas con DM1 (exceso molar de 1,7 veces sobre el enlazador no unido) durante 18 horas a pH 6,5 en tampón fosfato de potasio que contenía NaCl 50 mM y una concentración final de 3% de DMA.
En ambos grupos, los rendimientos se determinaron espectrofotométricamente (longitud de onda 280 nm) para la etapa de modificación y purificación combinada. Las relaciones enlazador/anticuerpo también se determinaron por tratamiento con ditiotreitol para liberar piridina-2-tiona, que tiene un coeficiente de extinción de 8.080 M-1cm-1 a 343 nm. Las relaciones fármaco/anticuerpo se determinaron espectrofotométricamente (longitudes de onda de 280 nm y 252 nm) para la etapa de conjugación. Además, la retirada de especies moleculares pequeñas relacionadas con el SPP se midió por HPLC Hisep.
Los datos resultantes se exponen en la Tabla 1.
12
5
10
15
20
25
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Las relaciones enlazador/anticuerpo (E/A) se determinaron por tratamiento con ditiotreitol para liberar piridina-2tiona, que tiene un coeficiente de extinción de 8.080 M-1cm-1 a 343 nm. Las relaciones fármaco/anticuerpo (D/A) y el rendimiento se determinaron espectrofotométricamente (longitudes de onda de 280 nm y 252 nm) para la etapa de conjugación. Los porcentajes de monómero fueron ensayados por SEC-HPLC. Los porcentajes de fármaco libre fueron ensayados por HPLC en una columna Hisep. Los resultados de estos análisis se exponen en la Tabla 7.
Tabla 7: Eliminación opcional de la etapa de purificación para el anticuerpo modificado
- Parámetros
- Procedimiento de 4 etapas Procedimiento de 3 etapas
- SPDB de partida
- 4,6 x 4,6 x
- E/A
- 4,1 No determinado
- D/A
- 3,9 4,0
- Rendimiento
- 79% 91%
- % de Monómero
- 95,8% 96,1%
- % de Fármaco libre
- 2,4% 1,1%
Como demuestran los resultados expuestos en la Tabla 7, la etapa para purificar el anticuerpo modificado puede ser eliminada en el contexto de la invención.
Ejemplo comparativo 7
Este ejemplo demuestra un medio mejorado para purificar un anticuerpo que ha sido modificado con un reactivo de modificación heterobifuncional y conjugado después con un maitansinoide.
El anticuerpo huN901 modificado con SPP (exceso molar de 7 veces) y purificado en resina SephadexTM G25F, como se describe en el Ejemplo 1, fue conjugado con el maitansinoide DM1 (exceso molar de 1,7 veces sobre el enlazador, disuelto en dimetilacetamida (DMA), concentración final 3%).
Una primera muestra de conjugado se purificó por cromatografía estándar en resina SephadexTM G25F en suero salino tamponado con fosfato (PBS, pH 6,5).
Una segunda muestra de conjugado se purificó por un sistema Pellicon XL TFF (Millipore, Billerica, MA), como se describe en el Ejemplo 1.
Una tercera muestra de conjugado se purificó usando una columna de resina MEP Hypercell equilibrada en Tris 50 mM (pH 8,0), y eluida con acetato de sodio 50 mM (pH 4,0).
Una cuarta muestra de conjugado se purificó usando una columna de resina UNOsphere S equilibrada en fosfato de sodio 50 mM (pH 6,5) y eluida con NaCl 0,2 M y fosfato de sodio 50 mM (pH 6,5).
Una quinta muestra de conjugado se purificó usando una columna de resina CHT (Bio-Rad Laboratories, Hercules, CA) equilibrada en fosfato de sodio 50 mM (pH 6,5) y eluida con NaCl 0,3 M y fosfato de sodio 50 mM (pH 6,5).
Una sexta muestra de conjugado se purificó usando una columna de resina SP Sefarosa equilibrada en citrato de sodio 35 mM, cloruro de sodio 10 mM (pH 5,0), y eluida con NaCl 0,25 M, citrato de sodio 35 mM (pH 5,0).
El monómero conjugado se determinó por SEC-HPLC usando una columna de resina TSKG3000SWXL equilibrada y desarrollada en tampón fosfato de potasio 0,2 M a pH 7,0, que contenía cloruro de potasio 0,2 M e isopropanol al 20%. El rendimiento de la etapa de conjugación se determinó dividiendo el rendimiento de anticuerpo conjugado por la cantidad de anticuerpo modificado que fue conjugado (determinado espectrofotométricamente a una longitud de onda de 280 nm).
Los resultados de estos análisis se exponen en la Tabla 8.
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