ES2533992T3 - Procedimiento para preparar conjugados de anticuerpo maitansinoide - Google Patents

Procedimiento para preparar conjugados de anticuerpo maitansinoide Download PDF

Info

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
linkers
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
ES11004940.0T
Other languages
English (en)
Inventor
Yong Dai
Yong Wang
Shengjin Jin
Deborah H. Meshulam
Godfrey W. Amphlett
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Immunogen Inc
Original Assignee
Immunogen Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=37666423&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=ES2533992(T3) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Immunogen Inc filed Critical Immunogen Inc
Application granted granted Critical
Publication of ES2533992T3 publication Critical patent/ES2533992T3/es
Anticipated expiration legal-status Critical
Active legal-status Critical Current

Links

Classifications

    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • 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
    • A61K47/68033—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a maytansine
    • 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
    • A61K47/6867—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2896—Immunoglobulins [IG], 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2839—Immunoglobulins [IG], 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2884—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against CD44
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/40—Immunoglobulins specific features characterized by post-translational modification

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Cell Biology (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Oncology (AREA)
  • Hematology (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • 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

imagen1
imagen2
imagen3
imagen4
imagen5
imagen6
imagen7
imagen8
imagen9
imagen10
5
10
15
20
25
30
35
40
45
50 E11004940
26-03-2015
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
imagen11
imagen12
imagen13
imagen14
5
10
15
20
25
30 E11004940
26-03-2015
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.
17
imagen15

Claims (1)

  1. imagen1
    imagen2
ES11004940.0T 2005-08-24 2006-08-14 Procedimiento para preparar conjugados de anticuerpo maitansinoide Active ES2533992T3 (es)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US71085805P 2005-08-24 2005-08-24
US710858P 2005-08-24
US79771306P 2006-05-04 2006-05-04
US797713P 2006-05-04

Publications (1)

Publication Number Publication Date
ES2533992T3 true ES2533992T3 (es) 2015-04-16

Family

ID=37666423

Family Applications (2)

Application Number Title Priority Date Filing Date
ES11004940.0T Active ES2533992T3 (es) 2005-08-24 2006-08-14 Procedimiento para preparar conjugados de anticuerpo maitansinoide
ES06801436T Active ES2390826T3 (es) 2005-08-24 2006-08-14 Procedimiento para preparar conjugados de fármaco purificados

Family Applications After (1)

Application Number Title Priority Date Filing Date
ES06801436T Active ES2390826T3 (es) 2005-08-24 2006-08-14 Procedimiento para preparar conjugados de fármaco purificados

Country Status (24)

Country Link
US (7) US7811572B2 (es)
EP (4) EP3539572A1 (es)
JP (3) JP5350792B2 (es)
KR (1) KR101301011B1 (es)
CN (2) CN101267841B (es)
AU (1) AU2006283726C1 (es)
BR (1) BRPI0615049B1 (es)
CA (6) CA2893252C (es)
CR (2) CR9742A (es)
CY (1) CY1113206T1 (es)
DK (1) DK1928503T3 (es)
EA (1) EA013327B1 (es)
EC (1) ECSP088212A (es)
ES (2) ES2533992T3 (es)
HR (1) HRP20120794T1 (es)
IL (6) IL282138B2 (es)
MX (1) MX2008002597A (es)
NZ (4) NZ565964A (es)
PL (1) PL1928503T3 (es)
PT (1) PT1928503E (es)
RS (1) RS52470B (es)
SI (1) SI1928503T1 (es)
WO (1) WO2007024536A2 (es)
ZA (1) ZA200801564B (es)

Families Citing this family (105)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100056762A1 (en) 2001-05-11 2010-03-04 Old Lloyd J Specific binding proteins and uses thereof
US7589180B2 (en) 2001-05-11 2009-09-15 Abbott Laboratories Inc. Specific binding proteins and uses thereof
JP5149620B2 (ja) 2004-07-23 2013-02-20 エンドサイト，インコーポレイテッド ２価リンカーおよびその結合体
US20110166319A1 (en) * 2005-02-11 2011-07-07 Immunogen, Inc. Process for preparing purified drug conjugates
EP3539572A1 (en) 2005-08-24 2019-09-18 ImmunoGen, Inc. Process for preparing maytansinoid antibody conjugates
EP2126127B1 (en) * 2007-01-25 2016-09-28 Dana-Farber Cancer Institute, Inc. Use of anti-egfr antibodies in treatment of egfr mutant mediated disease
NZ580132A (en) 2007-03-14 2012-11-30 Endocyte Inc Binding ligand linked drug delivery conjugates of tubulysins to vitamins
CA2680854C (en) 2007-03-15 2017-02-14 Ludwig Institute For Cancer Research Treatment method using egfr antibodies and src inhibitors and related formulations
US9877965B2 (en) 2007-06-25 2018-01-30 Endocyte, Inc. Vitamin receptor drug delivery conjugates for treating inflammation
CN104383553A (zh) 2007-06-25 2015-03-04 恩多塞特公司 含有亲水性间隔区接头的共轭物
US9283276B2 (en) 2007-08-14 2016-03-15 Ludwig Institute For Cancer Research Ltd. Monoclonal antibody 175 targeting the EGF receptor and derivatives and uses thereof
EP2281006B1 (en) 2008-04-30 2017-08-02 Immunogen, Inc. Cross-linkers and their uses
US20100092495A1 (en) * 2008-04-30 2010-04-15 Immunogen Inc. Potent cell-binding agent drug conjugates
JP5863640B2 (ja) * 2009-04-29 2016-02-16 バイオ−ラッド ラボラトリーズ インコーポレーティッド 免疫複合体の精製
EP2437790B1 (en) 2009-06-03 2019-02-20 Immunogen, Inc. Conjugation methods
US20110076232A1 (en) * 2009-09-29 2011-03-31 Ludwig Institute For Cancer Research Specific binding proteins and uses thereof
UY32913A (es) * 2009-10-02 2011-04-29 Sanofi Aventis Nuevos maitansinoides y el uso de dichos maitansinoides para preparar conjugados con un anticuero
US9173961B2 (en) 2010-02-10 2015-11-03 Immunogen, Inc. CD20 antibodies and uses thereof
WO2012075037A1 (en) 2010-11-30 2012-06-07 Genentech, Inc. Low affinity blood brain barrier receptor antibodies and uses therefor
KR20140010076A (ko) 2011-02-15 2014-01-23 이뮤노젠 아이엔씨 세포독성 벤조다이아제핀 유도체
WO2012135517A2 (en) 2011-03-29 2012-10-04 Immunogen, Inc. Preparation of maytansinoid antibody conjugates by a one-step process
TR201902180T4 (tr) * 2011-03-29 2019-03-21 Immunogen Inc Tek adimli bi̇r i̇şlem i̇le maytansi̇noi̇d anti̇kor konjugatlarinin hazirlanmasi
CN103619357A (zh) * 2011-03-29 2014-03-05 伊缪诺金公司 用于制造具有改善的同质性的缀合物的方法
EP3501546A3 (de) 2011-04-21 2019-09-18 Seattle Genetics, Inc. Cystein-wirkstoff konjugate und ihre verwendung
MX350954B (es) 2011-06-21 2017-09-26 Immunogen Inc Derivados de maitansinoides novedosos con enlazador de peptido y conjugados de estos.
AU2012352210A1 (en) * 2011-12-13 2014-07-24 Immunogen, Inc. Use of N-hydroxysuccinimide to improve conjugate stability
US10080805B2 (en) 2012-02-24 2018-09-25 Purdue Research Foundation Cholecystokinin B receptor targeting for imaging and therapy
US20140080175A1 (en) 2012-03-29 2014-03-20 Endocyte, Inc. Processes for preparing tubulysin derivatives and conjugates thereof
CA2869704A1 (en) * 2012-04-04 2013-10-10 Perseus Proteomics Inc. Drug conjugate comprising anti-cdh3 (pcadherin) antibody
WO2013151649A1 (en) 2012-04-04 2013-10-10 Sialix Inc Glycan-interacting compounds
HK1211208A1 (zh) 2012-08-22 2016-05-20 Immunogen, Inc. 細胞毒性苯並二氮呯衍生物
WO2014055842A1 (en) * 2012-10-04 2014-04-10 Immunogen, Inc. Process for preparing stable antibody maytansinoid conjugates
CN105208876A (zh) * 2012-10-04 2015-12-30 伊缪诺金公司 离子交换膜的从细胞结合剂细胞毒性剂缀合物中去除杂质的用途
RU2661083C2 (ru) * 2012-10-04 2018-07-11 Иммуноджен, Инк. Использование пвдф-мембраны для очистки конъюгатов клеточно-связывающий агент - цитотоксический агент
WO2014058947A1 (en) 2012-10-12 2014-04-17 Sanofi Compositions and methods for treating cancer using pi3k inhibitor and anti-cd19 maytansinoid immunoconjugate
JP2015536323A (ja) 2012-10-16 2015-12-21 エンドサイト・インコーポレイテッドＥｎｄｏｃｙｔｅ， Ｉｎｃ． 非天然アミノ酸を含む薬物送達結合体および使用方法
WO2014089177A2 (en) 2012-12-04 2014-06-12 Massachusetts Institute Of Technology Compounds, conjugates and compositions of epipolythiodiketopiperazines and polythiodiketopiperazines
HK1219422A1 (zh) 2013-02-28 2017-04-07 Immunogen, Inc. 包含细胞结合剂及细胞毒素剂的轭合物
EP2961435B1 (en) 2013-02-28 2019-05-01 ImmunoGen, Inc. Conjugates comprising cell-binding agents and cytotoxic agents
US9498532B2 (en) 2013-03-13 2016-11-22 Novartis Ag Antibody drug conjugates
EP3964237B1 (en) * 2013-03-15 2026-02-18 Regeneron Pharmaceuticals, Inc. Biologically active molecules, conjugates thereof, and therapeutic uses
BR112015021134A2 (pt) 2013-03-15 2017-10-10 Novartis Ag conjugados de fármaco e anticorpo
AU2014262566A1 (en) * 2013-05-08 2015-11-12 Zymeworks Inc. Bispecific HER2 and HER3 antigen binding constructs
WO2014194030A2 (en) 2013-05-31 2014-12-04 Immunogen, Inc. Conjugates comprising cell-binding agents and cytotoxic agents
US10208125B2 (en) 2013-07-15 2019-02-19 University of Pittsburgh—of the Commonwealth System of Higher Education Anti-mucin 1 binding agents and uses thereof
WO2015038984A2 (en) 2013-09-12 2015-03-19 Halozyme, Inc. Modified anti-epidermal growth factor receptor antibodies and methods of use thereof
TWI541022B (zh) 2013-12-18 2016-07-11 應克隆公司 針對纖維母細胞生長因子受體－３（ｆｇｆｒ３）之化合物及治療方法
CA2934617A1 (en) 2013-12-23 2015-07-02 Bayer Pharma Aktiengesellschaft Antibody drug conjugates (adcs) with kinesin spindle protein (ksp)
EP3160513B1 (en) 2014-06-30 2020-02-12 Glykos Finland Oy Saccharide derivative of a toxic payload and antibody conjugates thereof
WO2016004048A2 (en) 2014-06-30 2016-01-07 Blend Therapeutics, Inc. Targeted conjugates and particles and formulations thereof
PE20170903A1 (es) 2014-08-12 2017-07-12 Novartis Ag Conjugados de farmacos con anticuerpos anti-cdh6
AU2015311951B2 (en) * 2014-09-02 2021-04-08 Immunogen, Inc. Methods for formulating antibody drug conjugate compositions
PT3189056T (pt) 2014-09-03 2020-09-04 Immunogen Inc Derivados citotóxicos de benzodiazepina
TW201613930A (en) 2014-09-03 2016-04-16 Immunogen Inc Cytotoxic benzodiazepine derivatives
CN104208719B (zh) * 2014-09-24 2017-05-03 北京天广实生物技术股份有限公司 一种抗体偶联药物的阳离子交换层析纯化方法
US20170306046A1 (en) 2014-11-12 2017-10-26 Siamab Therapeutics, Inc. Glycan-interacting compounds and methods of use
EP3217962A4 (en) * 2014-11-13 2018-06-27 The Curators of the University of Missouri Multiple human antibody-nanoparticle conjugates and methods of formation
TW201711702A (zh) 2015-06-04 2017-04-01 應克隆公司 使用針對纖維母細胞生長因子受體３（ｆｇｆｒ３）之化合物的療法
WO2016203432A1 (en) 2015-06-17 2016-12-22 Novartis Ag Antibody drug conjugates
AU2016282723B2 (en) 2015-06-22 2021-09-23 Bayer Pharma Aktiengesellschaft Antibody drug conjugates (ADCs) and antibody prodrug conjugates (APDCs) with enzymatically cleavable groups
WO2017060322A2 (en) 2015-10-10 2017-04-13 Bayer Pharma Aktiengesellschaft Ptefb-inhibitor-adc
HK1259311A1 (zh) * 2015-10-28 2019-11-29 Tva (Abc), Llc Sstr靶向綴合物及其顆粒和製劑
CN108463248B (zh) 2015-11-12 2022-10-21 西雅图基因公司 聚糖相互作用化合物及使用方法
FR3045058B1 (fr) * 2015-12-11 2017-12-29 Ifp Energies Now Nouvelles polyamines, leur procede de synthese et leur utilisation pour l'elimination selective de l'h2s d'un effluent gazeux comprenant du co2
WO2017161206A1 (en) 2016-03-16 2017-09-21 Halozyme, Inc. Conjugates containing conditionally active antibodies or antigen-binding fragments thereof, and methods of use
JP7251981B2 (ja) 2016-03-24 2023-04-04 バイエル ファーマ アクチエンゲゼルシャフト 酵素開裂基を有する細胞毒性活性剤のプロドラッグ
US10918627B2 (en) 2016-05-11 2021-02-16 Massachusetts Institute Of Technology Convergent and enantioselective total synthesis of Communesin analogs
WO2017216028A1 (en) 2016-06-15 2017-12-21 Bayer Pharma Aktiengesellschaft Specific antibody-drug-conjugates (adcs) with ksp inhibitors and anti-cd123-antibodies
EP3541847A4 (en) 2016-11-17 2020-07-08 Seattle Genetics, Inc. COMPOUNDS INTERACTING WITH GLYCANE AND METHODS OF USE
JP7350313B2 (ja) 2016-12-16 2023-09-26 ブルーフィン バイオメディシン， インコーポレイテッド 抗ｃｕｂドメイン含有タンパク質１（ｃｄｃｐ１）抗体、抗体薬物コンジュゲート、およびその使用方法
WO2018114804A1 (de) 2016-12-21 2018-06-28 Bayer Pharma Aktiengesellschaft Spezifische antikörper-wirkstoff-konjugate (adcs) mit ksp-inhibitoren
KR102556826B1 (ko) 2016-12-21 2023-07-18 바이엘 파마 악티엔게젤샤프트 효소적으로 절단가능한 기를 갖는 항체 약물 접합체 (adc)
CA3047491A1 (en) 2016-12-21 2018-06-28 Bayer Aktiengesellschaft Prodrugs of cytotoxic active agents having enzymatically cleavable groups
JOP20190187A1 (ar) 2017-02-03 2019-08-01 Novartis Ag مترافقات عقار جسم مضاد لـ ccr7
EP3589319A4 (en) 2017-03-03 2021-07-14 Seagen Inc. GLYCAN INTERACTING COMPOUNDS AND METHOD OF USE
EP3603663A4 (en) * 2017-03-30 2020-04-08 Jiangsu Hengrui Medicine Co., Ltd. PROCESS FOR THE PREPARATION OF ANTIBODY CONJUGATE
WO2018185618A1 (en) 2017-04-03 2018-10-11 Novartis Ag Anti-cdh6 antibody drug conjugates and anti-gitr antibody combinations and methods of treatment
TW201839001A (zh) 2017-04-20 2018-11-01 美商伊繆諾金公司 細胞毒性苯并二氮平衍生物及其綴合物
US20180311375A1 (en) * 2017-04-27 2018-11-01 Cadila Healthcare Limited Process of preparing antibody-drug conjugate
US11932650B2 (en) 2017-05-11 2024-03-19 Massachusetts Institute Of Technology Potent agelastatin derivatives as modulators for cancer invasion and metastasis
US10640508B2 (en) 2017-10-13 2020-05-05 Massachusetts Institute Of Technology Diazene directed modular synthesis of compounds with quaternary carbon centers
WO2019105835A1 (en) 2017-11-29 2019-06-06 Bayer Consumer Care Ag Combinations of copanlisib and anetumab ravtansine
EP3732178A1 (en) 2017-12-28 2020-11-04 ImmunoGen, Inc. Benzodiazepine derivatives
CA3087993A1 (en) * 2018-01-12 2019-07-18 Immunogen, Inc. Methods for antibody drug conjugation, purification, and formulation
EP3552631A1 (en) 2018-04-10 2019-10-16 Inatherys Antibody-drug conjugates and their uses for the treatment of cancer
BR112021001194A2 (pt) 2018-07-25 2021-04-27 Daiichi Sankyo Company, Limited métodos para produzir um conjugado anticorpo-fármaco e para produzir uma composição farmacêutica
TWI824043B (zh) 2018-10-25 2023-12-01 西班牙商瑪製藥股份有限公司 藥物抗體共軛物
EP3947395A1 (en) 2019-03-29 2022-02-09 ImmunoGen, Inc. Cytotoxic bis-benzodiazepine derivatives and conjugates thereof with cell-binding agents for inhibiting abnormal cell growth or for treating proliferative diseases
HUE065484T2 (hu) 2019-04-26 2024-05-28 Immunogen Inc Camptothecin-származékok
WO2020234114A1 (en) 2019-05-21 2020-11-26 Bayer Aktiengesellschaft A novel stable high concentration formulation for anetumab ravtansine
US11535634B2 (en) 2019-06-05 2022-12-27 Massachusetts Institute Of Technology Compounds, conjugates, and compositions of epipolythiodiketopiperazines and polythiodiketopiperazines and uses thereof
PH12022550037A1 (en) 2019-07-10 2023-04-12 Cybrexa 3 Inc Peptide conjugates of microtubule-targeting agents as therapeutics
KR20220052918A (ko) 2019-07-10 2022-04-28 싸이브렉사 2, 인크. 치료제로서의 사이토톡신의 펩티드 접합체
EP4025253B1 (en) 2019-09-05 2024-03-20 Pharma Mar, S.A. Drug antibody conjugates
CN113125732B (zh) * 2019-12-31 2023-08-08 科美博阳诊断技术(上海)有限公司 一种白介素6的均相检测试剂盒及其应用
CA3175426A1 (en) 2020-04-21 2021-10-28 Alfonso Latorre Lozano Drug antibody conjugates
US20230181756A1 (en) 2020-04-30 2023-06-15 Novartis Ag Ccr7 antibody drug conjugates for treating cancer
US12030888B2 (en) 2021-02-24 2024-07-09 Massachusetts Institute Of Technology Himastatin derivatives, and processes of preparation thereof, and uses thereof
WO2023157989A1 (ko) 2022-02-17 2023-08-24 주식회사 노벨티노빌리티 항체-약물 접합체
WO2024246657A1 (en) * 2023-05-29 2024-12-05 Intas Pharmaceuticals Ltd. Method for conjugation and purification of antibody drug conjugate
WO2025005240A1 (ja) 2023-06-30 2025-01-02 第一三共株式会社 活性炭材料を使用する精製工程を含む抗体－薬物コンジュゲートの製造方法
WO2025019790A1 (en) 2023-07-19 2025-01-23 Iovance Biotherapeutics, Inc. Treatment of cancer patients with tumor infiltrating lymphocyte therapies in combination with trop-2 targeting adc
WO2025027529A1 (en) 2023-07-31 2025-02-06 Advesya Anti-il-1rap antibody drug conjugates and methods of use thereof
WO2025126157A1 (en) 2023-12-15 2025-06-19 Advesya Anti-il-1rap binding domains and antibody-drug conjugates thereof
WO2025192691A1 (ja) * 2024-03-14 2025-09-18 東レ株式会社 癌の治療及び／又は予防用医薬組成物

Family Cites Families (163)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US585499A (en) * 1897-06-29 Oil-can
US585089A (en) * 1897-06-22 durey
US552293A (en) * 1895-12-31 ktjhn
SE430062B (sv) 1977-03-04 1983-10-17 Pharmacia Fine Chemicals Ab Kopplings- eller tioleringsreagens
US4137230A (en) 1977-11-14 1979-01-30 Takeda Chemical Industries, Ltd. Method for the production of maytansinoids
US4307016A (en) 1978-03-24 1981-12-22 Takeda Chemical Industries, Ltd. Demethyl maytansinoids
US4256746A (en) 1978-11-14 1981-03-17 Takeda Chemical Industries Dechloromaytansinoids, their pharmaceutical compositions and method of use
JPS55102583A (en) 1979-01-31 1980-08-05 Takeda Chem Ind Ltd 20-acyloxy-20-demethylmaytansinoid compound
JPS55162791A (en) * 1979-06-05 1980-12-18 Takeda Chem Ind Ltd Antibiotic c-15003pnd and its preparation
JPS5645483A (en) 1979-09-19 1981-04-25 Takeda Chem Ind Ltd C-15003phm and its preparation
EP0028683A1 (en) 1979-09-21 1981-05-20 Takeda Chemical Industries, Ltd. Antibiotic C-15003 PHO and production thereof
JPS5645485A (en) 1979-09-21 1981-04-25 Takeda Chem Ind Ltd Production of c-15003pnd
WO1982001188A1 (en) * 1980-10-08 1982-04-15 Takeda Chemical Industries Ltd 4,5-deoxymaytansinoide compounds and process for preparing same
US4450254A (en) 1980-11-03 1984-05-22 Standard Oil Company Impact improvement of high nitrile resins
US4315929A (en) * 1981-01-27 1982-02-16 The United States Of America As Represented By The Secretary Of Agriculture Method of controlling the European corn borer with trewiasine
US4313946A (en) 1981-01-27 1982-02-02 The United States Of America As Represented By The Secretary Of Agriculture Chemotherapeutically active maytansinoids from Trewia nudiflora
US4563304A (en) 1981-02-27 1986-01-07 Pharmacia Fine Chemicals Ab Pyridine compounds modifying proteins, polypeptides or polysaccharides
JPS57192389A (en) * 1981-05-20 1982-11-26 Takeda Chem Ind Ltd Novel maytansinoid
US4664911A (en) * 1983-06-21 1987-05-12 Board Of Regents, University Of Texas System Immunotoxin conjugates employing toxin B chain moieties
DE3584012D1 (de) 1985-01-22 1991-10-10 Saint Gobain Vitrage Verfahren zur herstellung eines pulvers auf basis von indium-formiat zur herstellung einer duennen beschichtung auf einem substrat, insbesondere auf glas.
GB8600582D0 (en) * 1986-01-10 1986-02-19 Ca Minister Nat Defence Purifying biological materials
US5225539A (en) * 1986-03-27 1993-07-06 Medical Research Council Recombinant altered antibodies and methods of making altered antibodies
GB8607679D0 (en) 1986-03-27 1986-04-30 Winter G P Recombinant dna product
US4859449A (en) 1987-09-14 1989-08-22 Center For Molecular Medicine And Immunology Modified antibodies for enhanced hepatocyte clearance
US5241078A (en) * 1988-06-14 1993-08-31 Cetus Oncology Coupling agents and sterically hindered disulfide linked conjugates prepared therefrom
US5024834A (en) * 1988-07-12 1991-06-18 Cetus Corporation Thioether linked immunotoxin conjugates
CA2006408A1 (en) 1988-12-27 1990-06-27 Susumu Iwasa Bispecific monoclonal antibody, its production and use
US5530101A (en) 1988-12-28 1996-06-25 Protein Design Labs, Inc. Humanized immunoglobulins
US5714149A (en) 1989-02-10 1998-02-03 Celltech Therapeutics Limited Crosslinked antibodies and processes for their preparation
CA2026147C (en) 1989-10-25 2006-02-07 Ravi J. Chari Cytotoxic agents comprising maytansinoids and their therapeutic use
US5208020A (en) 1989-10-25 1993-05-04 Immunogen Inc. Cytotoxic agents comprising maytansinoids and their therapeutic use
US6316003B1 (en) 1989-12-21 2001-11-13 Whitehead Institute For Biomedical Research Tat-derived transport polypeptides
US5137877B1 (en) 1990-05-14 1996-01-30 Bristol Myers Squibb Co Bifunctional linking compounds conjugates and methods for their production
GB9015198D0 (en) 1990-07-10 1990-08-29 Brien Caroline J O Binding substance
US5545806A (en) * 1990-08-29 1996-08-13 Genpharm International, Inc. Ransgenic non-human animals for producing heterologous antibodies
AU8507191A (en) * 1990-08-29 1992-03-30 Genpharm International, Inc. Transgenic non-human animals capable of producing heterologous antibodies
US5256294A (en) 1990-09-17 1993-10-26 Genentech, Inc. Tangential flow filtration process and apparatus
CA2048078A1 (en) 1990-11-15 1992-05-16 Wolfgang A. Wrasidlo Chemical modification of antibodies for creation of immunoconjugates
US5252714A (en) 1990-11-28 1993-10-12 The University Of Alabama In Huntsville Preparation and use of polyethylene glycol propionaldehyde
SE9102074D0 (sv) 1991-07-03 1991-07-03 Kabi Pharmacia Ab Tomour antigen specific antibody
SE470006B (sv) 1991-09-26 1993-10-25 Corline Systems Ab Nytt konjugat, dess framställning och användning samt substrat preparerat med konjugatet
PT1696031E (pt) 1991-12-02 2010-06-25 Medical Res Council Produção de auto-anticorpos a partir de reportórios de segmentos de anticorpo e exibidos em fagos
CA2076465C (en) 1992-03-25 2002-11-26 Ravi V. J. Chari Cell binding agent conjugates of analogues and derivatives of cc-1065
US5639641A (en) * 1992-09-09 1997-06-17 Immunogen Inc. Resurfacing of rodent antibodies
US5556623A (en) 1993-03-30 1996-09-17 Eli Lilly And Company Antibody-drug conjugates
GB9320575D0 (en) 1993-10-06 1993-11-24 Amp Gmbh Coaxial connector having improved locking mechanism
IL111748A0 (en) 1993-12-03 1995-01-24 Zeneca Ltd Proteins
DE19503164A1 (de) * 1994-02-04 1995-08-10 Siemens Comp Inc Optisch gekoppelte Datenanschalteanordnung und Gabelschaltung
US5747446A (en) 1994-03-22 1998-05-05 Beth Israel Deaconess Medical Center Modified polypeptides with increased biological activity
US5580853A (en) * 1994-03-22 1996-12-03 New England Deaconess Hospital Modified polypeptides with increased biological activity
US5919758A (en) 1994-03-22 1999-07-06 Beth Israel Deaconess Medical Center Modified polypeptides with altered biological activity
US5612474A (en) 1994-06-30 1997-03-18 Eli Lilly And Company Acid labile immunoconjugate intermediates
AU5908296A (en) 1995-05-31 1996-12-24 Fred Hutchinson Cancer Research Center Compositions and methods for targeted delivery of effector m olecules
US6265150B1 (en) 1995-06-07 2001-07-24 Becton Dickinson & Company Phage antibodies
US5714352A (en) 1996-03-20 1998-02-03 Xenotech Incorporated Directed switch-mediated DNA recombination
GB9610992D0 (en) 1996-05-24 1996-07-31 Glaxo Group Ltd Concentrated antibody preparation
US6340461B1 (en) 1996-12-17 2002-01-22 David Stephen Terman Superantigen based methods and compositions for treatment of diseases
US6462070B1 (en) 1997-03-06 2002-10-08 The General Hospital Corporation Photosensitizer conjugates for pathogen targeting
US6371975B2 (en) 1998-11-06 2002-04-16 Neomend, Inc. Compositions, systems, and methods for creating in situ, chemically cross-linked, mechanical barriers
EP1012280B1 (en) 1997-06-11 2004-11-10 Borean Pharma A/S Trimerising module
US6171586B1 (en) 1997-06-13 2001-01-09 Genentech, Inc. Antibody formulation
US5958677A (en) 1997-07-28 1999-09-28 The New York Blood Center, Inc. Method for purifying viral nucleic acids
CA2297070A1 (en) 1997-08-01 1999-02-11 Morphosys Ag Novel method and phage for the identification of nucleic acid sequences encoding members of a multimeric (poly)peptide complex
US5965714A (en) * 1997-10-02 1999-10-12 Connaught Laboratories, Inc. Method for the covalent attachment of polysaccharides to protein molecules
KR100680014B1 (ko) 1997-10-03 2007-02-09 갈레니카 파마슈티칼스 인크. 이민 형성 폴리사카라이드, 이의 제조 방법 및 이것의 아쥬반트 및 면역자극제로서의 용도
US6121236A (en) 1998-03-24 2000-09-19 The Children's Medical Center Corporation Multivalent ligands which modulate angiogenesis
US5963761A (en) * 1998-04-15 1999-10-05 Xerox Corporation Area coverage sensor calibration and algorithm for seam detection noise eliminator on a seamed photoreceptor
WO1999055715A2 (en) 1998-04-28 1999-11-04 Galenica Pharmaceuticals, Inc. Polysaccharide-antigen conjugates
US5981564A (en) 1998-07-01 1999-11-09 Universite Laval Water-soluble derivatives of paclitaxel, method for producing same and uses thereof
AU750414B2 (en) 1998-07-13 2002-07-18 Board Of Regents, The University Of Texas System Cancer treatment methods using therapeutic conjugates that bind to aminophospholipids
AUPQ014799A0 (en) 1999-05-04 1999-05-27 Access Pharmaceuticals Australia Pty Limited Amplification of folate-mediated targeting to tumor cells using polymers
CA2385528C (en) * 1999-10-01 2013-12-10 Immunogen, Inc. Compositions and methods for treating cancer using immunoconjugates and chemotherapeutic agents
ES2276708T3 (es) * 1999-11-24 2007-07-01 Immunogen, Inc. Agentes citotoxicos que comprenden taxanos y su uso terapeutico.
ES2274823T3 (es) 1999-12-29 2007-06-01 Immunogen, Inc. Agentes cototoxicos que comprenden doxorrubicinas y daunorrubicinas y su utilizacion terapeutica.
EP1257289A1 (en) * 2000-02-08 2002-11-20 The Penn State Research Foundation Immunotherapy using interleukin 13 receptor subunit alpha 2
US7097840B2 (en) 2000-03-16 2006-08-29 Genentech, Inc. Methods of treatment using anti-ErbB antibody-maytansinoid conjugates
US6632979B2 (en) 2000-03-16 2003-10-14 Genentech, Inc. Rodent HER2 tumor model
EP1316119A4 (en) 2000-07-24 2009-02-11 Microcell Corp MICROCELLULAR ELECTROCHEMICAL DEVICES AND ARRANGEMENTS AND CORRESPONDING MANUFACTURING METHOD
US6596503B1 (en) 2000-08-18 2003-07-22 East Carolina University Monoclonal antibody DS6, tumor-associated antigen CA6, and methods of use thereof
US6333410B1 (en) 2000-08-18 2001-12-25 Immunogen, Inc. Process for the preparation and purification of thiol-containing maytansinoids
US20060062786A1 (en) 2000-11-08 2006-03-23 Human Genome Sciences, Inc. Antibodies that immunospecifically bind to TRAIL receptors
KR20030091978A (ko) 2001-01-29 2003-12-03 아이덱 파마슈티칼즈 코포레이션 변형된 항체 및 사용 방법
WO2002098885A1 (en) 2001-02-07 2002-12-12 Beth Israel Deaconess Medical Center Modified psma ligands and uses related thereto
CA2444483A1 (en) 2001-04-26 2002-11-07 Board Of Regents, The University Of Texas System Diagnostic imaging compositions, their methods of synthesis and use
WO2002092127A1 (en) 2001-05-11 2002-11-21 Board Of Regents, The University Of Texas System Anti-cd26 monoclonal antibodies as therapy for diseases associated with cells expressing cd26
EP1258255A1 (en) 2001-05-18 2002-11-20 Boehringer Ingelheim International GmbH Conjugates of an antibody to CD44 and a maytansinoid
US6441163B1 (en) * 2001-05-31 2002-08-27 Immunogen, Inc. Methods for preparation of cytotoxic conjugates of maytansinoids and cell binding agents
JP4619651B2 (ja) * 2001-06-01 2011-01-26 コーネル・リサーチ・ファンデーション・インコーポレイテッド 前立腺特異的膜抗原に対する修飾抗体およびその使用
US6576802B2 (en) 2001-06-04 2003-06-10 Shell Oil Company One-step production of 1, 3-propanediol from ethylene oxide and syngas with a catalyst with a phospholanoalkane ligand
JP2005532415A (ja) 2001-12-11 2005-10-27 メルク　エンド　カムパニー　インコーポレーテッド スタフィロコッカス・アウレウスエキソポリサッカライド及び方法
US6716821B2 (en) 2001-12-21 2004-04-06 Immunogen Inc. Cytotoxic agents bearing a reactive polyethylene glycol moiety, cytotoxic conjugates comprising polyethylene glycol linking groups, and methods of making and using the same
WO2003057163A2 (en) * 2002-01-03 2003-07-17 Smithkline Beecham Corporation Methods for preparing immunoconjugates
US7591994B2 (en) 2002-12-13 2009-09-22 Immunomedics, Inc. Camptothecin-binding moiety conjugates
US8877901B2 (en) 2002-12-13 2014-11-04 Immunomedics, Inc. Camptothecin-binding moiety conjugates
US6534660B1 (en) 2002-04-05 2003-03-18 Immunogen, Inc. CC-1065 analog synthesis
US6756397B2 (en) 2002-04-05 2004-06-29 Immunogen, Inc. Prodrugs of CC-1065 analogs
DK1501369T3 (en) 2002-04-26 2015-09-28 Genentech Inc Non-affinity purification of proteins
SG187991A1 (en) 2002-05-02 2013-03-28 Wyeth Corp Calicheamicin derivative-carrier conjugates
US20090068178A1 (en) 2002-05-08 2009-03-12 Genentech, Inc. Compositions and Methods for the Treatment of Tumor of Hematopoietic Origin
US6596757B1 (en) 2002-05-14 2003-07-22 Immunogen Inc. Cytotoxic agents comprising polyethylene glycol-containing taxanes and their therapeutic use
EP1551875A4 (en) 2002-06-21 2006-06-28 Biogen Idec Inc TAMPON PREPARATIONS FOR CONCENTRATING ANTIBODIES AND METHODS FOR USE THEREOF
US7390898B2 (en) 2002-08-02 2008-06-24 Immunogen Inc. Cytotoxic agents containing novel potent taxanes and their therapeutic use
ES2361739T3 (es) 2002-08-16 2011-06-21 Immunogen, Inc. Reticulantes con elevada reactividad y solubilidad y su uso en la preparación de conjugados para el suministro dirigido de fármacos de molécula pequeña.
ATE409048T1 (de) 2002-10-08 2008-10-15 Fresenius Kabi De Gmbh Pharmazeutisch aktive oligosaccharid-conjugate
DK3299463T3 (da) 2002-10-30 2020-12-07 Nuevolution As Enzymatisk kodning
HUE026914T2 (en) 2002-11-07 2016-08-29 Immunogen Inc Anti-CD33 antibodies and a method of treating acute myeloid leukemia
US7374762B2 (en) 2003-05-14 2008-05-20 Immunogen, Inc. Drug conjugate composition
US8088387B2 (en) 2003-10-10 2012-01-03 Immunogen Inc. Method of targeting specific cell populations using cell-binding agent maytansinoid conjugates linked via a non-cleavable linker, said conjugates, and methods of making said conjugates
US7276497B2 (en) 2003-05-20 2007-10-02 Immunogen Inc. Cytotoxic agents comprising new maytansinoids
KR101145506B1 (ko) 2003-05-20 2012-05-15 이뮤노젠 아이엔씨 새로운 메이탠시노이드를 포함하는 개선된 세포독성체
US7736644B2 (en) 2003-06-27 2010-06-15 Amgen Fremont Inc. Antibodies directed to the deletion mutants of epidermal growth factor receptor and uses thereof
US20050074425A1 (en) 2003-07-02 2005-04-07 Polycord, Inc. Method for delivering polymerized therapeutic agent compositions and compositions thereof
CN1878568A (zh) 2003-11-05 2006-12-13 盘林京有限公司 Cdim结合抗体的增强的b细胞细胞毒性
US20050175619A1 (en) * 2004-02-05 2005-08-11 Robert Duffy Methods of producing antibody conjugates
US20110064754A1 (en) 2005-03-03 2011-03-17 Center For Molecular Medicine And Immunology Immunoconjugates Comprising Poxvirus-Derived Peptides and Antibodies Against Antigen-Presenting Cells for Subunit-Based Poxvirus Vaccines
WO2005094882A1 (en) * 2004-03-03 2005-10-13 Millennium Pharmaceuticals, Inc. Modified antibodies to prostate-specific membrane antigen and uses thereof
JP2008505853A (ja) 2004-04-13 2008-02-28 クインテセンス バイオサイエンシーズ インコーポレーティッド 細胞傷害性薬剤としての非天然のリボヌクレアーゼ複合体
US20060073528A1 (en) 2004-05-14 2006-04-06 Jean-Michel Lecerf Measurement methods
US7691962B2 (en) 2004-05-19 2010-04-06 Medarex, Inc. Chemical linkers and conjugates thereof
US7517903B2 (en) 2004-05-19 2009-04-14 Medarex, Inc. Cytotoxic compounds and conjugates
MXPA06014065A (es) 2004-06-01 2007-01-31 Genentech Inc Conjugados de droga-anticuerpo y metodos.
US7313946B2 (en) * 2004-07-15 2008-01-01 Matsuo Electric Co., Ltd. Moisture detector
SV2006002258A (es) 2004-10-08 2006-09-19 Wyeth Corp Inmunoterapia de trastornos autoinmunes
AU2005316844A1 (en) 2004-11-29 2006-06-22 Seattle Genetics, Inc. Engineered antibodies and immunoconjugates
US7408030B2 (en) * 2005-01-13 2008-08-05 North Carolina State University Purification of immunoglobulins using affinity chromatography and peptide ligands
US20110166319A1 (en) 2005-02-11 2011-07-07 Immunogen, Inc. Process for preparing purified drug conjugates
JP5165387B2 (ja) 2005-02-11 2013-03-21 イムノゲン インコーポレーティッド 安定な薬物複合体を調製するための方法
WO2006113623A2 (en) 2005-04-15 2006-10-26 Immunogen, Inc. Elimination of heterogeneous or mixed cell population in tumors
GB2427360A (en) 2005-06-22 2006-12-27 Complex Biosystems Gmbh Aliphatic prodrug linker
JP5436856B2 (ja) 2005-07-15 2014-03-05 アンジオケム インコーポレーティッド 薬学的複合体における担体としてのアプロチニンポリペプチドの使用
WO2007019232A2 (en) 2005-08-03 2007-02-15 Immunogen, Inc. Immunoconjugate formulations
EP3539572A1 (en) * 2005-08-24 2019-09-18 ImmunoGen, Inc. Process for preparing maytansinoid antibody conjugates
WO2007034495A2 (en) 2005-09-22 2007-03-29 Hadasit Medical Research Services & Development Limited Dextran and arabinogalactan conjugates of therapeutically active compounds
AU2006294554B2 (en) 2005-09-26 2013-03-21 E. R. Squibb & Sons, L.L.C. Antibody-drug conjugates and methods of use
JP5199108B2 (ja) 2005-11-14 2013-05-15 ユニヴァーシティー オブ サザン カリフォルニア インテグリン結合小分子
US7964415B2 (en) 2006-04-26 2011-06-21 Cardiogenics Inc. Stable water-soluble polyethylenimine conjugates and methods of use thereof
US7307016B1 (en) * 2006-06-07 2007-12-11 Grace Semiconductor Manufacturing Corporation Method of processing metal surface in dual damascene manufacturing
EA020324B1 (ru) 2006-07-18 2014-10-30 Санофи-Авентис АНТИТЕЛА К РЕЦЕПТОРУ ЭФРИНА EphA2 И ИХ ПРИМЕНЕНИЕ
US20080213349A1 (en) 2006-09-11 2008-09-04 Deepak Ramesh Thakker Liposome Complexes Containing Pharmaceutical Agents and Methods
US8969532B2 (en) 2006-10-03 2015-03-03 Novo Nordisk A/S Methods for the purification of polypeptide conjugates comprising polyalkylene oxide using hydrophobic interaction chromatography
SI2019104T1 (sl) 2007-07-19 2013-12-31 Sanofi Citotoksična sredstva, ki obsegajo nove tomaimicinske derivate, in njihova terapevtska uporaba
EP2281006B1 (en) 2008-04-30 2017-08-02 Immunogen, Inc. Cross-linkers and their uses
RU2487877C2 (ru) 2008-04-30 2013-07-20 Иммьюноджен, Инк. Высокоэффективные конъюгаты и гидрофильные сшивающие агенты (линкеры)
GB0811743D0 (en) 2008-06-26 2008-07-30 Hemosol Biopharma Inc Composition
CN102215820A (zh) 2008-11-17 2011-10-12 安龙制药公司 用于核酸输送系统的可释放融合脂质
CN102365021B (zh) 2009-02-05 2015-07-15 伊缪诺金公司 新型苯并二氮杂*衍生物
EP2437790B1 (en) 2009-06-03 2019-02-20 Immunogen, Inc. Conjugation methods
FR2947269B1 (fr) 2009-06-29 2013-01-18 Sanofi Aventis Nouveaux composes anticancereux
UY32914A (es) 2009-10-02 2011-04-29 Sanofi Aventis Anticuerpos que se usan específicamente al receptor epha2
AR080301A1 (es) 2010-02-24 2012-03-28 Immunogen Inc Anticuerpos e inmunoconjugados del receptor 1 de folato y sus usos
KR20110103182A (ko) 2010-03-12 2011-09-20 삼성전자주식회사 입체 영상 표시 장치
US20120149732A1 (en) 2010-12-14 2012-06-14 Alexander Chucholowski Multifunctional linkers and methods for the use thereof
KR20140010076A (ko) 2011-02-15 2014-01-23 이뮤노젠 아이엔씨 세포독성 벤조다이아제핀 유도체
WO2012135517A2 (en) 2011-03-29 2012-10-04 Immunogen, Inc. Preparation of maytansinoid antibody conjugates by a one-step process
CN103619357A (zh) 2011-03-29 2014-03-05 伊缪诺金公司 用于制造具有改善的同质性的缀合物的方法
TR201902180T4 (tr) 2011-03-29 2019-03-21 Immunogen Inc Tek adimli bi̇r i̇şlem i̇le maytansi̇noi̇d anti̇kor konjugatlarinin hazirlanmasi
PL2694106T3 (pl) 2011-04-01 2018-06-29 Immunogen, Inc. Sposoby zwiększania skuteczności terapii przeciwnowotworowej opartej na receptorze folr1
US20130071482A1 (en) 2011-09-20 2013-03-21 The University Of Kentucky Research Foundation Block copolymer cross-linked nanoassemblies as modular delivery vehicles
AU2012352210A1 (en) 2011-12-13 2014-07-24 Immunogen, Inc. Use of N-hydroxysuccinimide to improve conjugate stability
RU2661083C2 (ru) 2012-10-04 2018-07-11 Иммуноджен, Инк. Использование пвдф-мембраны для очистки конъюгатов клеточно-связывающий агент - цитотоксический агент
CN105208876A (zh) 2012-10-04 2015-12-30 伊缪诺金公司 离子交换膜的从细胞结合剂细胞毒性剂缀合物中去除杂质的用途
WO2014055842A1 (en) 2012-10-04 2014-04-10 Immunogen, Inc. Process for preparing stable antibody maytansinoid conjugates
WO2014086835A1 (en) 2012-12-05 2014-06-12 Ruprecht-Karls-Universität Heidelberg Conjugates of proteins and multivalent cell-penetrating peptides and their uses

Also Published As

Publication number Publication date
EA200800657A1 (ru) 2008-08-29
EP2399609B1 (en) 2015-03-18
IL305084A (en) 2023-10-01
US20190030177A1 (en) 2019-01-31
US7811572B2 (en) 2010-10-12
CA2620343C (en) 2013-01-08
US20110021744A1 (en) 2011-01-27
IL282138B2 (en) 2024-01-01
IL248076A0 (en) 2016-11-30
PL1928503T3 (pl) 2012-12-31
IL189461A (en) 2013-07-31
DK1928503T3 (da) 2012-10-15
IL189461A0 (en) 2008-08-07
IL226985A0 (en) 2013-07-31
NZ565964A (en) 2011-11-25
HK1120407A1 (en) 2009-04-03
CN102989000A (zh) 2013-03-27
JP2014196307A (ja) 2014-10-16
AU2006283726C1 (en) 2015-05-07
CA3000520C (en) 2023-04-04
CA3190867A1 (en) 2007-03-01
CN102989000B (zh) 2016-04-20
CA3000520A1 (en) 2007-03-01
NZ595430A (en) 2013-05-31
IL282138A (en) 2021-05-31
KR20080034476A (ko) 2008-04-21
EP1928503A2 (en) 2008-06-11
IL248076B (en) 2021-04-29
EP3539572A1 (en) 2019-09-18
CR20150350A (es) 2015-08-20
US20130281678A1 (en) 2013-10-24
CR9742A (es) 2008-09-29
CN101267841B (zh) 2012-10-10
HRP20120794T1 (hr) 2012-11-30
JP5738248B2 (ja) 2015-06-17
WO2007024536A3 (en) 2007-07-05
IL226985A (en) 2016-10-31
IL220816A0 (en) 2012-08-30
US20230158168A1 (en) 2023-05-25
EP1928503B1 (en) 2012-10-03
IL282138B1 (en) 2023-09-01
PT1928503E (pt) 2012-10-19
HK1165329A1 (en) 2012-10-05
CA2620343A1 (en) 2007-03-01
BRPI0615049B1 (pt) 2023-04-25
SI1928503T1 (sl) 2012-11-30
JP5350792B2 (ja) 2013-11-27
JP2009506032A (ja) 2009-02-12
CA3250822A1 (en) 2025-11-29
CA2794554C (en) 2015-09-22
US8933205B2 (en) 2015-01-13
AU2006283726B2 (en) 2012-06-28
JP6028001B2 (ja) 2016-11-16
ECSP088212A (es) 2008-03-26
BRPI0615049A2 (pt) 2011-04-26
US11471536B2 (en) 2022-10-18
US9789204B2 (en) 2017-10-17
MX2008002597A (es) 2008-03-14
AU2006283726A1 (en) 2007-03-01
IL220816A (en) 2014-08-31
NZ716641A (en) 2017-06-30
NZ609752A (en) 2014-08-29
CN101267841A (zh) 2008-09-17
CA2794554A1 (en) 2007-03-01
EA013327B1 (ru) 2010-04-30
ES2390826T3 (es) 2012-11-16
CA3190867C (en) 2025-04-01
CA2893252A1 (en) 2007-03-01
EP2662096A1 (en) 2013-11-13
JP2013014604A (ja) 2013-01-24
US8383122B2 (en) 2013-02-26
US20150182635A1 (en) 2015-07-02
KR101301011B1 (ko) 2013-08-30
RS52470B (sr) 2013-02-28
CA2893252C (en) 2018-05-29
US20070048314A1 (en) 2007-03-01
WO2007024536A2 (en) 2007-03-01
ZA200801564B (en) 2012-07-25
EP2399609A1 (en) 2011-12-28
CY1113206T1 (el) 2016-04-13
US20250255979A1 (en) 2025-08-14

Similar Documents

Publication Publication Date Title
ES2390826T3 (es) Procedimiento para preparar conjugados de fármaco purificados
ES2709577T3 (es) Preparación de conjugados de maitansinoides y anticuerpos mediante un proceso de una sola etapa
ES2404304T3 (es) Conjugados de maitansinoide DM1 con anticuerpo trastuzumab, unidos mediante un conector no escindible, y su uso en el tratamiento de tumores
JP6114783B2 (ja) 抱合方法
Kuijpers et al. Expedient synthesis of triazole-linked glycosyl amino acids and peptides
Grandjean et al. On the preparation of carbohydrate− protein conjugates using the traceless Staudinger ligation
Sadowsky et al. Development of efficient chemistry to generate site-specific disulfide-linked protein–and peptide–payload conjugates: application to THIOMAB antibody–drug conjugates
ES2503719T3 (es) Procedimiento para preparar conjugados de anticuerpos y de maitansinoides
ES2729643T3 (es) Métodos para la conjugación de oxima con polipéptidos modificados con cetona
CA2492803C (en) Oxime conjugates and methods for their formation and use
ES2732574T3 (es) Métodos para preparar conjugados a partir de proteínas que contienen disulfuro
RU2013125317A (ru) Конъюгированные с фолатом антитела и их применение
JP2023541637A (ja) 抗体－エクサテカンコンジュゲート
Kubler-Kielb et al. A new method for conjugation of carbohydrates to proteins using an aminooxy-thiol heterobifunctional linker
NO20231301A1 (no) Fremgangsmåte for målsøking av spesifikke cellepopulasjoner ved å benytte cellebindingsmiddel-maytansinoidkonjugater bundet via en ikke-kløyvbar linker, nevnte konjugater og fremstilling av nevnte konjugater.
YU91503A (sh) Citotoksični imunokonjugati sa antitelima specifičnim za cd44
RU2015116882A (ru) Использование пвдф-мембраны для очистки конъюгатов клеточно-связывающий агент - цитотоксический агент
JP2015504869A (ja) 複合体安定性を改善するためのｎ−ヒドロキシスクシンイミドの使用
Tarragó‐Trani et al. Shiga‐like toxin subunit B (SLTB)‐enhanced delivery of chlorin e6 (Ce6) improves cell killing
CA3186027A1 (fr) Composes capables de se lier a des proteines et conjugues obtenus a partir de ces composes
JP5479095B2 (ja) Ｃｄ４受容体由来ペプチドとその製法
Mhidia et al. Synthesis of Peptide− Protein Conjugates Using N-Succinimidyl Carbamate Chemistry
Zhong et al. Design and synthesis of lipopeptide–carbohydrate assembled multivalent vaccine candidates using native chemical ligation
JPH06239898A (ja) 免疫抱合体の調製法
CA3236102A1 (en) Pyridazinedione-based heterobicyclic covalent linkers and methods and applications thereof