WO2004035199A1 - Adsorbants a affinite pour immunoglobulines - Google Patents

Adsorbants a affinite pour immunoglobulines Download PDF

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Publication number
WO2004035199A1
WO2004035199A1 PCT/GB2003/004524 GB0304524W WO2004035199A1 WO 2004035199 A1 WO2004035199 A1 WO 2004035199A1 GB 0304524 W GB0304524 W GB 0304524W WO 2004035199 A1 WO2004035199 A1 WO 2004035199A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
compound
affinity
aryl
compound according
Prior art date
Application number
PCT/GB2003/004524
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English (en)
Inventor
Christopher Robin Lowe
Maria Angela Cabral Garcia Taipa MENESE DE OLIVEIRA
Ana Cecilia Afonso Roque
Original Assignee
Cambridge University Technical Services Limited
Instituto Superior Tecnico
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Publication date
Application filed by Cambridge University Technical Services Limited, Instituto Superior Tecnico filed Critical Cambridge University Technical Services Limited
Priority to AU2003274335A priority Critical patent/AU2003274335A1/en
Publication of WO2004035199A1 publication Critical patent/WO2004035199A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/06—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies from serum
    • C07K16/065—Purification, fragmentation
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D15/00—Separating processes involving the treatment of liquids with solid sorbents; Apparatus therefor
    • B01D15/08—Selective adsorption, e.g. chromatography
    • B01D15/26—Selective adsorption, e.g. chromatography characterised by the separation mechanism
    • B01D15/38—Selective adsorption, e.g. chromatography characterised by the separation mechanism involving specific interaction not covered by one or more of groups B01D15/265 - B01D15/36
    • B01D15/3804—Affinity chromatography
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/281—Sorbents specially adapted for preparative, analytical or investigative chromatography
    • B01J20/286—Phases chemically bonded to a substrate, e.g. to silica or to polymers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/281—Sorbents specially adapted for preparative, analytical or investigative chromatography
    • B01J20/286—Phases chemically bonded to a substrate, e.g. to silica or to polymers
    • B01J20/289—Phases chemically bonded to a substrate, e.g. to silica or to polymers bonded via a spacer
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/30—Processes for preparing, regenerating, or reactivating
    • B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
    • B01J20/3202—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the carrier, support or substrate used for impregnation or coating
    • B01J20/3206—Organic carriers, supports or substrates
    • B01J20/3208—Polymeric carriers, supports or substrates
    • B01J20/3212—Polymeric carriers, supports or substrates consisting of a polymer obtained by reactions otherwise than involving only carbon to carbon unsaturated bonds
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/30—Processes for preparing, regenerating, or reactivating
    • B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
    • B01J20/3214—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the method for obtaining this coating or impregnating
    • B01J20/3217—Resulting in a chemical bond between the coating or impregnating layer and the carrier, support or substrate, e.g. a covalent bond
    • B01J20/3219—Resulting in a chemical bond between the coating or impregnating layer and the carrier, support or substrate, e.g. a covalent bond involving a particular spacer or linking group, e.g. for attaching an active group
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/30—Processes for preparing, regenerating, or reactivating
    • B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
    • B01J20/3231—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the coating or impregnating layer
    • B01J20/3242—Layers with a functional group, e.g. an affinity material, a ligand, a reactant or a complexing group
    • B01J20/3244—Non-macromolecular compounds
    • B01J20/3246—Non-macromolecular compounds having a well defined chemical structure
    • B01J20/3248—Non-macromolecular compounds having a well defined chemical structure the functional group or the linking, spacer or anchoring group as a whole comprising at least one type of heteroatom selected from a nitrogen, oxygen or sulfur, these atoms not being part of the carrier as such
    • B01J20/3255—Non-macromolecular compounds having a well defined chemical structure the functional group or the linking, spacer or anchoring group as a whole comprising at least one type of heteroatom selected from a nitrogen, oxygen or sulfur, these atoms not being part of the carrier as such comprising a cyclic structure containing at least one of the heteroatoms nitrogen, oxygen or sulfur, e.g. heterocyclic or heteroaromatic structures
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
    • C07D251/40—Nitrogen atoms
    • C07D251/42—One nitrogen atom
    • C07D251/44—One nitrogen atom with halogen atoms attached to the two other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
    • C07D251/40—Nitrogen atoms
    • C07D251/48—Two nitrogen atoms
    • C07D251/50—Two nitrogen atoms with a halogen atom attached to the third ring carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
    • C07D251/40—Nitrogen atoms
    • C07D251/54—Three nitrogen atoms

Definitions

  • Immunoglobulins are glycoproteins consisting of Y-shaped building block having two identical light chains (of weight -25 kDa) and two identical heavy chains (of weight ⁇ 50 kDa). Each chain is composed of constant and variable regions which are divided into individual domains. Five distinct classes of immunoglobulin (corresponding to heavy chain isotypes: a (IgA), d (IgD), e (IgE), m (IgM) and g (IgG)) are recognised in higher mammals, the molecules differing in size, charge, biological properties, amino acid composition and carbohydrate content.
  • the light chains may take the form of one of two isotypes, termed kappa and lambda.
  • Immunoglobulins are widely used in diagnostic, therapeutic, preparative and analytical applications. Interest in such proteins stems from developments in hybridoma technology, alone or combined with genetic engineering, and also in the use of polyclonal preparations such as human IGIV. There is also an increasing interest in the use of immunoglobulin classes, subclasses and fragments, since they may differ both chemically and functionally from the whole polyclonal preparation or the intact molecule. For example, Fab fragments offer a number of advantages over the intact protein for imaging and therapy, since they exhibit rapid pharmacokinetics and reduced non-specific binding that is often associated with the glycosylated Fc portion of the immunoglobulin.
  • a concern in the administration of immunoglobulins in vivo is the presence of contaminants in the preparation.
  • contaminants include DNA, viruses, pyrogens and leachates from separation media.
  • High purity immunoglobulin preparations must comply with GMP procedures and strict FDA guidelines. The requirement for high purity coupled with the need for more effective biopharmaceuticals and research tools has led to the development of many new purification techniques, especially those based on affinity interactions.
  • affinity adsorbents for immunoglobulin purification are immobilised bacterial surface proteins. These natural proteins typically interact with the Fc portion of IgG (e.g. Proteins A and G) or immunoglobulin light chains (e.g. Protein L). Protein L, obtainable from Peptostreptococc ⁇ s magnus, is often used because it binds regardless of heavy chain class.
  • natural protein affinity ligands are generally poor adsorbents due to difficulties in immobilisation, high cost, leakage and poor stability.
  • the present invention is based on the discovery of a particular class of compounds which addresses the problem described supra.
  • a first aspect of the invention is the use of a compound of formula (I)
  • R 1 and R 2 are the same or different and are each optionally substituted alkyl or aryl;
  • R 3 is a solid support optionally attached via a spacer; for the affinity binding of an immunoglobulin or fragment thereof.
  • the affinity of the compound for the immunoglobulin or fragment is at least 50% of that of Protein L.
  • a second aspect of the invention is a compound of formula (I), wherein any substitutent on R 1 or R 2 is selected from aryl, alkyl, OH, NH 2 , COOH and CONH 2 , and R 3 may alternatively be a functional atom or group, optionally attached via a spacer, which is capable of reaction with a solid support.
  • Another aspect of the invention is the use of a compound of the invention as an affinity ligand.
  • Compounds of the invention may be used as affinity ligands for immunoglobulin separation, isolation, characterisation, identification, quantification and purification.
  • they may act as affinity ligands for immunoglobulins and fragments thereof, e.g. Fabs.
  • the compounds may be able to mimic the affinity and selectivity of natural ligands such as Protein L, without suffering from the limitations of such ligands.
  • the compounds may bind both kappa and lambda light chains, and may act as affinity ligands for a broader range of IgG types (e.g. mouse, bovine and human IgG) relative to Protein L. Description of the Invention
  • alkyl refers to a straight or branched chain alkyl moiety having from one to six carbon atoms, and includes, for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl and the like.
  • C 6 alkyl has the same meaning.
  • aryl refers to aromatic ring systems comprising six to ten ring atoms, and polycyclic ring systems having two or more cyclic rings at least one of which is aromatic. This term includes, for example, phenyl and naphthyl.
  • halogen as used herein refers to F, Cl, Br or I.
  • the groups -NHR 1 and -NHR 2 may be obtained by substitution of a triazine ring using any suitable amine compound.
  • -NHR 1 and -NHR 2 derive from amines such as alanine, 1 ,5-diaminopentane, tyramine, -xylylenediamine, phenethylamine, isoamylamine, 4-aminobutanoic acid, 4-aminobenzamide, 1 -amino-2-propanol, 2-methylbutylamine or 4-aminobutyramide,
  • R 1 and/or R 2 is preferably alkyl, -alkyl-C(0)OH, -alkyl-NH 2 , -alkyl-OH, -aryl-C(O)NH 2 , -alkyl-aryl, -alkyl-aryl-OH or -alkyl-aryl- alkyl-NH 2 .
  • R 1 and/or R 2 is 1-carboxyethyl, 5-aminopentyl, (4- hydroxyphenyl)methyl, (4-aminomethyl-phenyl)methyl, 2-phenylethyl, 3-methylbutyl, 3-carboxypropyl, 4-amidophenyl, 2-hydroxypropyl, 2-carboxyethyl, 2-methylbutyl or 3-amidopropyl.
  • R 3 is preferably halogen (e.g. Cl) or a solid substrate optionally attached via a spacer.
  • preferred compounds of the invention include those wherein R 1 is 4-amidophenyl and R 2 is 3-carboxypropyl; R 1 is 2-phenylethyl and R 2 is 2-hydroxypropyl; or R 1 is (4-hydroxyphenyl)methyl and R 2 is 3-amidopropyl.
  • R 3 is preferably halogen (e.g. Cl) or a solid substrate.
  • Compounds of the invention may be chiral. They may be in the form of a single enantiomer or diastereomer, or a racemate.
  • a compound of the invention may be in a protected amino, protected hydroxy or protected carboxy form.
  • protected amino refers to amino, hydroxy and carboxy groups which are protected in a manner familiar to those skilled in the art.
  • an amino group can be protected by a benzyloxycarbonyl, tert- butoxycarbonyl, acetyl or like group, or in the form of a phthalimido or like group.
  • a carboxyl group can be protected in the form of a readily cleavable ester such as the methyl, ethyl, benzyl or tert-butyl ester.
  • a hydroxy group can be protected by an alkyl or like group.
  • Compounds of the invention may be in the form of salts, for example, addition salts of inorganic or organic acids. Salts may also be formed with inorganic bases. Salts may be prepared by reacting the compound with a suitable acid or base in a conventional manner.
  • R 3 may be any suitable substrate known in the art, preferably agarose.
  • the substrate may be in any suitable form, for example beads, and may be linked to the ligand via a spacer.
  • the presence of a spacer may hold the ligand away from the support and reduce steric hindrance.
  • a spacer has a length of about 1 to about 10 atoms, more preferably about 6 atoms.
  • the spacer may be attached using any suitable method known in the art.
  • the substrate or spacer comprises an amine group which can substitute at the R 3 position of formula (I).
  • a compound of the invention may be prepared by any suitable method known in the art and/or by the following processes:
  • Scheme 3 depicts the synthesis of an intermediate compound, suitable for use in Scheme 4.
  • the dashed line represents a direct coupling process
  • the solid lines representing a semi-solution process.
  • R, and R 2 represent -NHR 1 and -NHR 2 of formula (I) respectively.
  • Any mixtures of final products or intermediates obtained can be separated on the basis of the physico-chemical differences of the constituents, in a known manner, into the pure final products or intermediates, for example by chromatography, distillation, fractional crystallisation, or by the formation of a salt if appropriate or possible under the circumstances.
  • F(ab') 2 and human Fc 95% pure were obtained from Calbiochem.
  • Protein L immobilised on agarose was obtained from Pierce.
  • Anti-human IgG Fab and
  • anti-human lambda light chains both alkaline phosphatase conjugates
  • anti-human kappa light chains anti-human kappa light chains
  • Silica gel 60 (0.040-0.063mm) was obtained from Merck. TLC assays were performed using Polygram SilG/UV 254 silica plates (obtained from Macherey-Nagel) and Silica gel 60 F254 (obtained from Merck).
  • Example 1 4-r4-f4-Carbamoyl-phenylamino)-6-chloro-ri.3.51triazin-2- ylaminolbutyric acid (B in Scheme 1) 4-(4,6-Dichloro-[1,3,5]triazin-2-ylamino)benzamide (A)
  • the white solid was dissolved in an aqueous solution K 2 CO 3 5%(w/v) and washed four times with ethylacetate.
  • the aqueous phase was neutralised with HCI (5M) and the resultant white precipitate filtered, washed with water and dried in vacuo over solid P 2 0 5 . Yield: 36% (0.87g, 2.5mmol).
  • the white solid product was dried in vacuo over solid P 2 0 5 and further purified by column chromatography (silica, solvent system EtOAc/Heptane 1:1 to separate the contaminants and acetone for elution of purified product). The solvent was evaporated and the white solid dried in vacuo over solid P 2 0 5 . Yield: 83% (1.8g, 5.8mmol). R, 0.2 (EtOAc/Hexane 1 :1).
  • Aminated agarose (1g, 24mmol/g) or aminated agarose with a -OCH 2 CH(OH)CH 2 NH 2 spacer (1g, 20mmol/g) was added to a solution of DMF:H 2 050%(v/v) (5ml) containing 2 molar equivalent (48mmol or 40mmol) of compounds A, C or H and 2 molar equivalent (48mmol or 40 mmol) of NaHC0 3 . The reaction was carried out at 30°C for 24h. At the end of the reaction the agarose beads were sequentially washed with DMF:water (1:1; 1:0, 1:1, 0:1).
  • the second chloride (R 2 in Scheme 3) was displaced by reaction with solutions containing, respectively, 4- aminobutanoic acid and NaHCO 3 (0.12mmol/0.1 mmol, 5eq. of each) or 1 -amino-
  • the H-substituted resin (1g) was reacted at 85°C for 72h with different compounds in order to replace the second chloride.
  • a 5 molar equivalent of an aqueous solution (5ml) of the one of the following reagents was used:
  • the ligand densities of the resins of Examples 4 and 5 were determined by solubilisation of the immobilised ligands. Immobilised ligands (30mg of moist gel) were hydrolysed in HCI 5M (0.3ml) at 60°C for 10min.
  • Example 7 Assessment of binding to human IgG and its fragments, by affinity chromatography
  • the derivatised resins of Example 5 were assessed for their affinity for human Fab and Fc fragments using affinity chromatography. The affinities were compared with that of Protein L.
  • Protein (human IgG, hFab, hF(ab') 2 or hFc) was reconstituted to 0.5mg/ml in equilibration buffer and the absorbance at 280nm (A 280nm ) measured. Protein solution (1 ml) was loaded on to each column. The columns were washed with equilibration buffer until the absorbance of the samples at 280nm was less than or equal to 0.005. Bound protein was eluted using elution buffer (Glycine-HCI 0.1M, pH 2.0) and neutralized by addition of 90ml of 1 M Tris.HCI, pH9.
  • elution buffer Glycine-HCI 0.1M, pH 2.0
  • Immobilised Protein L was regenerated using elution buffer and stored in an aqueous sodium azide solution (0.02% (w/v)).
  • Immobilised ligands 8/7, 5/9, 3/12 and (for comparison) Protein L were packed into 4ml columns (0.8x 6cm) to a final volume of about 0.2ml.
  • the resulting matrices were washed with 1 ml regeneration buffer and then distilled water, to bring the pH value to neutral.
  • the resins were then equilibrated with 10ml of equilibration buffer 0.2ml of a solution containing either human myeloma IgG ! kappa or lambda light chain was loaded on to each column.
  • the columns were washed with a total of 17 column volumes of equilibration buffer (2x500ml; 4x250ml; 3x500ml) and fractions collected.
  • Bound protein was eluted using elution buffer and two fractions collected (1x650ml; 1x500ml) to which 65 and 50ml of Tris.HCI (1M, pH9.0) were added, respectively. After elution, the columns were washed with regeneration buffer, followed by distilled water and stored at 0-4° C in 20%(v/v) ethanol. Quantitative ELISA
  • the amount of each protein collected from was determined using a quantitative ELISA.
  • Antibody anti-human kappa light chain was diluted 1 : 1 ,000 in PBS-Tween and anti-human lambda light chain diluted 1 :6,500 in PBS-Tween.
  • the substrate solution for the kappa chain was an oPD solution (1.85mM oPD, 5mM NaH 2 P0 4 ,
  • Calibration curves to correlate hlgG., kappa (mg/ml) with A 4g0nm were constructed using hlgG, kappa standard solutions from 5-0.5ng/ml. The reactions were stopped by the addition of 2M sulphuric acid (50ml). The absorbance was read at 490nm. Calibration curves to correlate hlgG, lambda (mg/ml) with A 405nm were constructed using hlgG., lambda standard solutions from 10-1 ng/rril.
  • the ligands of the invention bind with high affinity to human IgG from both kappa and lambda light chains. Protein L, effectively only binds to kappa light chains.
  • Example 7 The procedure described in Example 7 was followed except that 0.5mg/ml solutions of human, bovine or mouse IgG were loaded on to each column.
  • the results are shown in Figure 5.
  • the ligands of the invention bind have a high affinity for bovine, mouse and human IgG.
  • Protein L does not bind bovine IgG.

Abstract

L'invention concerne l'utilisation d'un composé de formule (I), dans laquelle R1 et R2 sont identiques ou différents et représentent respectivement et facultativement un alkyle ou un aryle substitué, et R3 représente un support solide facultativement attaché via un espaceur. Ledit composé est utilisé pour une liaison d'affinité d'une immunoglobuline ou d'un fragment associé.
PCT/GB2003/004524 2002-10-21 2003-10-21 Adsorbants a affinite pour immunoglobulines WO2004035199A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003274335A AU2003274335A1 (en) 2002-10-21 2003-10-21 Affinity adsorbents for immunoglobulins

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0224446.5 2002-10-21
GBGB0224446.5A GB0224446D0 (en) 2002-10-21 2002-10-21 Affinity adsorbents for immunoglobulins

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006010915A1 (fr) * 2004-07-27 2006-02-02 Prometic Biosciences Limited Triazines substitues utilises comme ligands des proteines prions, et leur utilisation pour la detection ou l'extraction des prions
WO2006024175A1 (fr) * 2004-09-03 2006-03-09 Prometic Biosciences Inc. COMPOSÉS À BASE DE 2,4,6-TRIAMINO-S-TRIAZINE RELIÉS À LA PARTIE DE QUEUE (Fc) DES IMMUNOGLOBULINES ET LEUR UTILISATION
WO2006131768A2 (fr) * 2005-06-10 2006-12-14 Prometic Biosciences Limited Ligands de liaison de proteines
WO2007004954A1 (fr) * 2005-07-05 2007-01-11 Ge Healthcare Bio-Sciences Ab Derives de [1, 2, 4] triazolo [1, 5-a] pyrimidine utilises comme adsorbants chromatographiques d'adsorption selective d'igg
WO2007099374A1 (fr) * 2006-03-02 2007-09-07 Prometic Biosciences Ltd Adsorbants pour la purification de protéines
EP1864706A1 (fr) * 2006-06-09 2007-12-12 Generon S.R.L. Appareil pour la purification de molécules organiques et procédé de fabrication correspondant
WO2009138714A1 (fr) * 2008-05-16 2009-11-19 Avecia Biologics Limited Procédé de purification pour fragments d'anticorps en utilisant comme ligands affinitaires des triazines dérivées
WO2014174316A1 (fr) 2013-04-26 2014-10-30 Adc Biotechnology Ltd Procédé de synthèse de conjugués anticorps-médicament au moyen de résines d'affinité
EP2918641A1 (fr) 2014-03-13 2015-09-16 Basf Se Procédé de purification d'anticorps, fragments d'anticorps ou leurs variants manipulés à l'aide de structures ligands colorants d'anthraquinone spécifiques
WO2016067013A1 (fr) 2014-10-28 2016-05-06 Adc Biotechnology Ltd Procédé de synthèse de cam au moyen de résines d'affinité
WO2016067016A1 (fr) 2014-10-28 2016-05-06 Adc Biotechnology Ltd Procédé de synthèse de conjugués d'anticorps à l'aide de résines d'affinité
WO2022248846A1 (fr) * 2021-05-24 2022-12-01 Astrea Uk Services Limited Échafaudage permettant d'isoler une biomolécule

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US5066307A (en) * 1987-09-29 1991-11-19 American Cyanamid Company Textile finishing agents having reduced formaldehyde emission
US5674688A (en) * 1991-04-02 1997-10-07 Terrapin Technologies, Inc. Method for analyte classification by SC profiles
WO1997010887A1 (fr) * 1995-09-20 1997-03-27 Novo Nordisk A/S Nouveaux ligands a affinite et leur utilisation
EP0818450A1 (fr) * 1996-07-08 1998-01-14 Ciba SC Holding AG Dérivés de triazine en tant que filtre UV dans des produits antisolaires
WO2003050237A2 (fr) * 2001-12-12 2003-06-19 New York University Bibliotheque de triazine avec lieurs

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