CN101248075A - 作为选择性吸附IG的色谱吸附剂的[1,2,4]三唑并[I,5-a]嘧啶衍生物 - Google Patents
作为选择性吸附IG的色谱吸附剂的[1,2,4]三唑并[I,5-a]嘧啶衍生物 Download PDFInfo
- Publication number
- CN101248075A CN101248075A CNA2006800244283A CN200680024428A CN101248075A CN 101248075 A CN101248075 A CN 101248075A CN A2006800244283 A CNA2006800244283 A CN A2006800244283A CN 200680024428 A CN200680024428 A CN 200680024428A CN 101248075 A CN101248075 A CN 101248075A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- expression
- carrier
- igg
- halogen
- 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.)
- Pending
Links
- 239000003463 adsorbent Substances 0.000 title claims abstract description 20
- 238000001179 sorption measurement Methods 0.000 title description 5
- SRNKZYRMFBGSGE-UHFFFAOYSA-N [1,2,4]triazolo[1,5-a]pyrimidine Chemical class N1=CC=CN2N=CN=C21 SRNKZYRMFBGSGE-UHFFFAOYSA-N 0.000 title description 2
- 238000000034 method Methods 0.000 claims abstract description 20
- 239000000126 substance Substances 0.000 claims abstract description 9
- 238000001042 affinity chromatography Methods 0.000 claims abstract description 6
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 5
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- 239000000463 material Substances 0.000 claims description 15
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 14
- 239000002594 sorbent Substances 0.000 claims description 13
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- NAQMVNRVTILPCV-UHFFFAOYSA-N hexane-1,6-diamine Chemical compound NCCCCCCN NAQMVNRVTILPCV-UHFFFAOYSA-N 0.000 claims description 12
- 229920000936 Agarose Polymers 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 230000008878 coupling Effects 0.000 claims description 8
- 238000010168 coupling process Methods 0.000 claims description 8
- 238000005859 coupling reaction Methods 0.000 claims description 8
- 125000002587 enol group Chemical group 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 6
- 239000011707 mineral Substances 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 239000012634 fragment Substances 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 239000007787 solid Substances 0.000 claims description 5
- 125000006850 spacer group Chemical group 0.000 claims description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000012876 carrier material Substances 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 239000011159 matrix material Substances 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 claims description 2
- 229920001817 Agar Polymers 0.000 claims description 2
- 229920002307 Dextran Polymers 0.000 claims description 2
- 239000004793 Polystyrene Substances 0.000 claims description 2
- 229920002472 Starch Polymers 0.000 claims description 2
- MCMNRKCIXSYSNV-UHFFFAOYSA-N Zirconium dioxide Chemical compound O=[Zr]=O MCMNRKCIXSYSNV-UHFFFAOYSA-N 0.000 claims description 2
- 239000008272 agar Substances 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- 239000001913 cellulose Substances 0.000 claims description 2
- 229920002678 cellulose Polymers 0.000 claims description 2
- 239000000835 fiber Substances 0.000 claims description 2
- 239000010408 film Substances 0.000 claims description 2
- 229920001477 hydrophilic polymer Polymers 0.000 claims description 2
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 claims description 2
- 239000002245 particle Substances 0.000 claims description 2
- 229920002492 poly(sulfone) Polymers 0.000 claims description 2
- 229920002401 polyacrylamide Polymers 0.000 claims description 2
- 229920002223 polystyrene Polymers 0.000 claims description 2
- 239000000377 silicon dioxide Substances 0.000 claims description 2
- 229960001866 silicon dioxide Drugs 0.000 claims description 2
- 235000012239 silicon dioxide Nutrition 0.000 claims description 2
- 239000008107 starch Substances 0.000 claims description 2
- 235000019698 starch Nutrition 0.000 claims description 2
- 239000004408 titanium dioxide Substances 0.000 claims description 2
- 229920002554 vinyl polymer Polymers 0.000 claims description 2
- 229920001059 synthetic polymer Polymers 0.000 claims 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 3
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 abstract 2
- 125000001475 halogen functional group Chemical group 0.000 abstract 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 23
- 238000012216 screening Methods 0.000 description 13
- 235000018102 proteins Nutrition 0.000 description 12
- 102000004169 proteins and genes Human genes 0.000 description 12
- 108090000623 proteins and genes Proteins 0.000 description 12
- 239000003446 ligand Substances 0.000 description 11
- 238000002198 surface plasmon resonance spectroscopy Methods 0.000 description 10
- 238000005481 NMR spectroscopy Methods 0.000 description 7
- 101710153593 Albumin A Proteins 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 5
- 102000018071 Immunoglobulin Fc Fragments Human genes 0.000 description 4
- 108010091135 Immunoglobulin Fc Fragments Proteins 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 230000027455 binding Effects 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- -1 amino benzoglyoxaline Chemical compound 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 238000003041 virtual screening Methods 0.000 description 3
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical group CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 2
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000012539 chromatography resin Substances 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 150000004715 keto acids Chemical class 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 230000009871 nonspecific binding Effects 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000010926 purge Methods 0.000 description 2
- 230000008521 reorganization Effects 0.000 description 2
- 150000003384 small molecules Chemical group 0.000 description 2
- OXFSTTJBVAAALW-UHFFFAOYSA-N 1,3-dihydroimidazole-2-thione Chemical compound SC1=NC=CN1 OXFSTTJBVAAALW-UHFFFAOYSA-N 0.000 description 1
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 1
- LUBJCRLGQSPQNN-UHFFFAOYSA-N 1-Phenylurea Chemical group NC(=O)NC1=CC=CC=C1 LUBJCRLGQSPQNN-UHFFFAOYSA-N 0.000 description 1
- PXFBZOLANLWPMH-UHFFFAOYSA-N 16-Epiaffinine Natural products C1C(C2=CC=CC=C2N2)=C2C(=O)CC2C(=CC)CN(C)C1C2CO PXFBZOLANLWPMH-UHFFFAOYSA-N 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- MSWZFWKMSRAUBD-UHFFFAOYSA-N 2-Amino-2-Deoxy-Hexose Chemical compound NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 1
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- 238000005004 MAS NMR spectroscopy Methods 0.000 description 1
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 208000034809 Product contamination Diseases 0.000 description 1
- 238000004741 STD-NMR spectroscopy Methods 0.000 description 1
- 229920002684 Sepharose Polymers 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
- 150000001263 acyl chlorides Chemical group 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 239000012504 chromatography matrix Substances 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 1
- 238000013016 damping Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000003118 drug derivative Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 238000000126 in silico method Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 238000000302 molecular modelling Methods 0.000 description 1
- 150000003014 phosphoric acid esters Chemical class 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000009394 selective breeding Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- QZRSVBDWRWTHMT-UHFFFAOYSA-M silver;3-carboxy-3,5-dihydroxy-5-oxopentanoate Chemical compound [Ag+].OC(=O)CC(O)(C([O-])=O)CC(O)=O QZRSVBDWRWTHMT-UHFFFAOYSA-M 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 230000004304 visual acuity Effects 0.000 description 1
Images
Classifications
-
- 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
-
- 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
- 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
-
- 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
- B01J20/30—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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
本发明涉及一种用于选择性地吸附IgG的色谱吸附剂,其包括化学式(I)及其对应的烯醇式,其中X表示O、S或NH;R1表示H、C1-6烷基、C1-6烷氧基、C1-6烷氧基-C1-6烷基、Ar、-C(O)NHR3、-C(O)-R3或卤素;R2表示H、C1-3烷基或卤素;R3表示H、C1-6烷基、C1-6烷氧基、C1-6烷氧基-C1-6烷基或Ar;n表示0、1、2或3;Y表示载体。本发明还涉及一种生产所述吸附剂的方法,以及该吸附剂用于通过亲和层析分离物质的用途。
Description
技术领域
本发明属于生物分子的色谱分离领域。进一步涉及一种包含选择性吸附IgG的新型配体的色谱吸附剂,以及生产所述色谱吸附剂的方法和该吸附剂在亲和层析中的用途。
发明背景
单克隆抗体技术的发展为科学和医学进行研究、诊断和治疗提供了巨大的机遇。单克隆抗体,例如用于体外和体内诊断以及人类疾病免疫治疗。目前,大多数正在开发的生物工程学衍生药物都是以G型单克隆抗体为基础的。
IgG通常根据标准技术在细胞表达体系中大批量地生产。应用最广泛的生产方法包括通过色谱法提纯,由于该方法对化合物的通用性和灵敏性,经常是生物分子的优选提纯方法。
在亲和层析领域,有多个专利和专利申请涉及蛋白A,一种作为配体的结合IgG的细菌金黄色葡萄球菌细胞壁蛋白质。例如,PCT/SE83/00297(Pharmacia Biotech AB)揭示了重组体型的蛋白A,其中在该蛋白A分子中添加一个半胱氨酸残基,以改善其与随后作亲和配体使用的分离基质的偶联。此外,美国专利6,197,927(转让给Genentech公司)揭示了葡萄球菌蛋白A的Z结构域变体,具有与野生型Z结构域相当的IgG结合能力,但具有显著减小的尺寸。而且,蛋白A已被证明对蛋白酶敏感。另外,基于蛋白A的亲和配体已知在酸性和碱性条件下不稳定,这就可能会在纯化过程中产生不希望的配体渗漏,而导致产品污染并损害纯化系统的性能。
在现有技术中,许多专利申请描述了小分子配体具有对IgG的亲和力。
WO 2004039765(Amersham Biosciences AB)描述了基于苯脲骨架的小分子作为含K型轻链的IgG和Fab片段的层析亲和配体的用途。
US 6610630(转让给Ciphergen Biosystems公司)描述了2-巯基咪唑及其衍生物附着于作为拟生物亲和层析培养基的固体载体,以便选择性吸附IgG的用途。
US 6117996(转让给Novo Nordisk A/S)描述了三嗪型结构的制备方法及其在提纯多种蛋白质材料中的用途。
US 20030166002(Chang等)描述了在含有适合与树脂结合的接头的三嗪结构基础上合成和筛选活性化合物。
EP 1500431(Millipore UK,Ltd,UK)涉及一种培养基,包含固体载体和吸附在其上的选自2-氨基苯并咪唑和2-氨基甲基苯并咪唑的一种或多种亲和层析配体。本发明的亲和配体用于IgG的提纯。
尽管存在与IgG结合的蛋白A的替代物,但仍然需要一种新型的更有优越性质的IgG结合配体。这种新的配体将不具备前述缺陷,并优选还具有比迄今建议的配体更优选的结合特性。
发明概述
本发明发现了一种基于与嘌呤相关的结构的小有机分子,当其附着于色谱树脂时,会与IgG发生普通的结合。该有机分子也可以作为IgG纯化过程的亲和配体。
第一方面,本发明涉及一种用于选择性吸附IgG的色谱吸附剂,包含以下化学式
及其对应的烯醇式,
其中
X表示O、S或NH;
R1表示H、C1-6烷基、C1-6烷氧基、C1-6烷氧基-C1-6烷基、Ar、-C(O)NHR3、-C(O)-R3或卤素;
R2表示H、C1-3烷基或卤素;
R3表示H、C1-6烷基、C1-6烷氧基、C1-6烷氧基-C1-6烷基或Ar;
n表示0、1、2或3;
Y表示载体;
Ar表示C6-10芳基,该基团任选地被选自羟基、氰基、卤素、硝基、C1-6烷基和烷氧基的一个或多个取代。
本文所用术语“卤素”包括氟、氯、溴、碘。
除非另作说明,本文所定义的烷基以及烷氧基和烷氧烷基的烷基部分,可以为直链的,或当碳原子数足够时(即最少为3)可以为支链的和/或环状的。此外,当碳原子数足够时(即最少为4),该基团还可以为部分环状的/非环状的。所述烷基,以及烷氧基和烷氧基烷基的烷基部分可以为饱和的,或当碳原子数足够时(即最少为2),可以为不饱和的。除非另作说明,该基团还可以被一个或多个卤素,特别是氟原子取代。
为了避免引起疑问,烷氧基通过烷氧基中的氧原子与该分子的其它基团连接。
在该方面中,本发明的化合物可显示出互变异构现象。所有互变异构体及其混合物被包括在本发明的范围内。
在上述结构式中,载体Y选自纤维素、淀粉、右旋糖酐、琼脂、琼脂糖、聚丙烯酰胺、聚(甲基)丙烯酸酯、聚乙烯基亲水聚合物、聚苯乙烯和聚砜、二氧化硅、氧化铝、二氧化钛、氧化锆、多糖-合成的聚合物、多糖-矿物结构或合成的聚合物-矿物结构。
在根据本发明的优选方案中,在上述结构式中,R1表示H,n表示0,X表示NH,Y表示琼脂糖。
任选地,在上述结构式中,X和Y之间含有间隔分子,例如六亚甲基二胺或氨基己酸。
在更优选的方案中,R1表示H,n表示0,X表示NH ,Y表示HP-琼脂糖,如果存在间隔分子则是六亚甲基二胺。
载体材料Y是任何形状的色谱载体材料,可以是珠子、不规则形状粒子、纤维、膜、扁平结构或多孔矿物材料形式。
第二方面,本发明涉及一种制备上述色谱吸附剂的方法,包括以下步骤:
a)提供色谱载体材料Y;和
b)在所述载体材料的表面偶联一种配体,以产生下述结构式的吸附剂
及其对应的烯醇式,
其中
X表示O、S或NH;
R1表示H、C1-6烷基、C1-6烷氧基、C1-6烷氧基-C1-6烷基、Ar、-C(O)NHR3、-C(O)-R3或卤素;
R2表示H、C1-3烷基或卤素;
R3表示H、C1-6烷基、C1-6烷氧基、C1-6烷氧基-C1-6烷基或Ar;
n表示0、1、2或3;
Y表示载体。
Ar表示C6-10芳基,该基团任选地被一个或多个选自羟基、氰基、卤素、硝基、C1-6烷基和烷氧基的取代基取代;
载体Y被X取代,X=NH2或SH或OH。
优选,载体Y是含胺的基质。该载体还可以为含硫醇的基质或含羟基的基质
更优选地,载体Y是采用六亚甲基二胺延伸的表氯醇活化的HP-琼脂糖。
第三方面,本发明涉及上述吸附剂用于在亲和层析中分离物质的用途。优选的用途是用于分离IgG、其片段和/或包括IgG或其片段的复合物。所述IgG可以为单克隆IgG、多克隆IgG或重组的IgG或其片段。所述复合物可以是涉及IgG的免疫复合物或融合蛋白。该吸附剂可用于分离IgG的全部亚类及其片段。分离出来的IgG可以用于治疗、诊断、研究与开发目的或用于例如色谱法的亲和处理。
计算机技术被用于识别IgG Fc部分上的合适的保守且普通的结合的裂缝。
随后,对市售物质进行实质筛选,以便鉴定出该裂缝的潜在结合剂。对潜在的结合结构进行排序,并通过基于STD-NMR和细胞质基因组表面共振(SPR)分析的体外方法测定结合和选择性。该方法鉴定出一种具有感兴趣的色谱特性的结构。将已鉴定的结合结构连接到色谱树脂上,评价对IgG的结合力。发现该配体显示了对IgG的普通的结合。
IgG的普通的结合表示结合所有的IgG亚类,即、IgG1、IgG2、IgG3、IgG4。
附图简述
图1显示在本发明的吸附剂上注入多克隆IgG的洗脱蛋白图谱。虚线表示洗脱液中的pH值。
发明详述
现在,通过与计算机(in silico)和湿式实验相关联,对本发明进行进一步地描述。
识别适合的IgG结合位点
通过利用具有代码1dn2的蛋白质数据库(pdb)结构,使用分子模型技术筛选蛋白表面,识别出人IgG的Fc片段上的一个裂缝为小有机分子的假定目标停靠位点(Delano等,2000)。
识别出两个与对称性相关的槽,其由该与对称性相关的分子间界面处的深层裂缝产生。在这些裂缝表面上包含极性基团而使其更加亲水。这两个与对称性相关的裂缝均可用作(相等的)虚拟筛选位点。该识别位点在获自人源的IgG家族成员之间基本上是保守的。
停靠模拟
将来自数据库的用于虚拟筛选的化合物停靠到已鉴定的裂缝内,产生总共119个不同的化合物,鉴定上述化合物为推定的结合剂。由于具有较高的分辨率,用于停靠模拟的蛋白结构是1.65的与Z34C络合的Fc结构(pdb代码116x;Idusogie等。2000)。该二聚体是采用程序O由晶体学对称性产生的(Jones等。1991)。每个分子都保存了最有序构象及其FlexX值(Rarey等。1996)。
停靠分子(配体分子)的选择
目测结合自由能估值比-20千焦/摩尔更负的能产生停靠构象的所有化合物,针对与裂缝表面的互补性就疏水性、氢键模式、电荷和构象方面来说。此外,刚性则被认为是优点,而短接触和有张力的几何学被认为是不利的。
潜在配体的NMR和SPR筛选
通过虚拟筛选,提出了166个化合物作为将要被识别的裂缝的潜在结合剂。在进一步的人工选择之后(以假定的稳定性、反应性和可用性为基础),对化合物排序进行试验。在进入该筛选程序前,最终得到69个化合物,并给它们分配各自的内部识别号。
该筛选程序以体外筛选为基础,利用两种独立的溶液分析技术,依靠饱和度差异转移核磁共振(STD NMR)和表面等离子体振子共振(SPR)法。
在NMR筛选中,测试了69种物质对两种不同的单克隆抗体(MABs)和市售Fc片段的亲和力。通过测试对α-淀粉酶的亲和力来研究非特异性蛋白结合。将对全部三个IgG相关蛋白都具有亲和力,但对α-淀粉酶没有亲和力的蛋白归属为对IgG-Fc部分的亲和配体的潜在候选物。
在SPR筛选中,对53个化合物(不溶性物质除外)进行了对单克隆抗体和市售Fc片段的亲和力测试。对不同分子量进行校正,并以占理论的最大反应的百分比表示。
为了选择用于进一步研究的潜在候选物,将SPR数据以这样的方式排列,以便将对Fc片段和IgG的反应都大于10%的所有物质都选作潜在候选物。这些化合物可以与通过核磁共振筛选而指示的物质相比。结果,大多数SPR衍生的采集数都因对α-淀粉酶的非特异性结合而在NMR筛选中被拒绝。用两个方法选出了一种作为潜在亲和候选物的化合物;化合物I,如下。
为了使亲和配体候选物最佳化,在溶液中对围绕化合物I的其它结构(市售化合物)进行研究。对这些化合物进行如前面所述的相应SPR和NMR亲和性分析。但这次仅在NMR筛选中使用Fc-片段,而SPR分析就用相应的测试蛋白作为第一选择。
选定的结构应当是NMR阳性的,并且如SPR所指示的,还对IgG分子具有高级亲和力,并且至少对Fc片段具有中级亲和力。排除了对HSA显示出非特异性结合的化合物。这种选择在最终候选物,化合物II中出现。该化合物还具有直接通过(酯保护的)羧酸官能团偶联的化学性质的潜能。
从文库中命中的化合物,配体II是酮式。在溶液中筛选并且与凝胶偶联的配体以酮式和烯醇式间的平衡体存在。
酮和烯醇式之间的关系受许多参数,如溶解度、浓度和温度的影响。其所有的互变异构体和混合物都被包括在本发明的范围内。
吸附剂A 吸附剂A
色谱吸附剂的生产
现以实例描述本发明吸附剂的制备,但并非限制的方式。偶联试剂和载体的选择可以在较宽的限制内改变并为所属领域技术人员所熟知。
选择的配体(化合物II)与色谱基质(载体)的偶联
已识别的候选化合物II是市售的,并可用于偶联。化合物II通过其羧酸官能团与含胺基质或载体连接,使用任何常规的酰胺形成剂,例如O-(7-氮苯并三唑-1-基)-N,N,N’,N’-四甲基脲六氟磷酸盐(HATU)、N,N’-二环己基碳化二亚胺(DCC)、N-(3-二甲基氨基丙基)-N’-乙基碳化二亚胺(EDC)、1-羟基苯并三唑(HOBt)、酰氯形成剂或其组合在合适的碱存在下,所述合适碱例如是二异丙基乙胺、三乙基胺或碳酸钾。所用载体是采用六亚甲基二胺延伸的表氯醇活化的HP-琼脂糖珠。该偶联物将化合物II的酯官能团转变成酰胺官能团,这将会使来自溶液中测定的酯功能的空间和电子变化最小化。
吸附剂A的结构(载体+间隔区+配体II)
吸附剂A包括酮类或烯醇式,或酮类和烯醇式的混合物,如吸附剂A的上述平衡公式所描写的。使用标准MAS NMR法测定偶联结果为7μmol/mL。
使用吸附剂A的色谱法
将0.5mL吸附剂A加至Tricorn5/20柱内,并用0.1M醋酸盐,0.137M氯化钠,pH5.0平衡。
将多克隆IgG(Gammanorm)(1mL缓冲液中有1mg)注射到吸附剂A柱内,用0.1M醋酸盐,0.137M氯化钠,pH5.0,作为偶联缓冲液。
在图1中在1mL处的峰值表示注射的蛋白质绕过该柱。观察到多克隆IgG的普通的结合。将56-65%的多克隆IgG用18mLPBS,pH7.4洗脱。通过计算收集馏分中的蛋白质浓度,并通过积分计算洗脱峰面积和通过峰面积之间的比率来确定回收率。在CIP过程中,在23ml顶点处将剩余的结合的蛋白质释放出来。
虚线显示洗脱液中的pH值。
在另一个缓冲液系统中(0.1M HAC,50mM磷酸酯,pH5.0)动态结合力是24mg/mL。
图1的结果表明本发明的吸附剂可用于IgG的普通的结合。
参考文献
DeLano,W.L.,Ultsch,M.H.,De Vos,A.M.,Wells,J.A.:ConvergentSolutions to Binding at a Protein-Protein Interface Science 287 pp.1279(2000).
Idusogie,E.E.,Presta,L.G.,Santoro-Gazzano,H.,Totpal,K.,Wong,P.Y.,Ultsch,M.,Meng,Y.G.,Mullkerrin,M.G.:Mapping of the ClQ BindingSite on Rituxan,a Chimeric Antibody with a Human Iggl Fc J.Immunol.164pp.4178(2000).
Jones TA,Zou JY,和Cowan SW.1991.Improved methods for buildingprotein models in electron density maps and the location of errors in thesemethods.Acta Crystallogr.A 47:110-119.
Rarey M,Kramer B.Lengauer T和Kleve G.1996.a fst flexible dockingmethod using an incremental construction algorithm.J.MoI.Biol.261:470-489.
Carredano E,Baumann H,Gronberg A,Norrman N,Glad G,Zou J-Y,Ersoy O,Steensma E,Axen A.2004.A novel and conserved pocket of human-Fab fragments:Design,synthesis,and verification of directed affinityligands.Protein.Sci.13(6):1476-1488.
Claims (11)
2.根据权利要求1所述的吸附剂,其中载体Y选自纤维素、淀粉、右旋糖酐、琼脂、琼脂糖、聚丙烯酰胺、聚(甲基)丙烯酸酯、聚乙烯基亲水聚合物、聚苯乙烯和聚砜、二氧化硅、氧化铝、二氧化钛、氧化锆、多糖-合成聚合物、多糖-矿物结构或合成的聚合物-矿物结构。
3.根据权利要求1或2所述的吸附剂,其中R1表示H,n表示0,X表示NH,并且Y表示琼脂糖。
4.根据权利要求1、2或3所述的吸附剂,其在X和Y之间包括一个间隔分子。
5.根据权利要求3或4所述的吸附剂,其中R1表示H,n表示0,X表示NH,Y表示HP-琼脂糖,并且六亚甲基二胺作为间隔分子。
6.根据上述一项或多项权利要求所述的吸附剂,其中载体材料Y呈珠子、不规则形状的粒子、纤维、膜、扁平结构或多孔矿物材料的形式。
8.根据权利要求7的方法,其中载体Y为具有胺的基质。
9.根据权利要求8的方法,其中载体Y是采用六亚甲基二胺延伸的表氯醇活化的HP-琼脂糖。
10.根据权利要求1-6的吸附剂用于通过亲和层析分离物质的用途。
11.根据权利要求10所述的用途,用于分离IgG、其片段和/或涉及IgG或其片段的复合物。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE05015607 | 2005-07-05 | ||
SE0501560 | 2005-07-05 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN101248075A true CN101248075A (zh) | 2008-08-20 |
Family
ID=37604721
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNA2006800244283A Pending CN101248075A (zh) | 2005-07-05 | 2006-06-29 | 作为选择性吸附IG的色谱吸附剂的[1,2,4]三唑并[I,5-a]嘧啶衍生物 |
Country Status (8)
Country | Link |
---|---|
US (2) | US20080220968A1 (zh) |
EP (1) | EP1899342B1 (zh) |
JP (1) | JP2009500604A (zh) |
KR (1) | KR20080027330A (zh) |
CN (1) | CN101248075A (zh) |
AU (1) | AU2006266536A1 (zh) |
CA (1) | CA2627592A1 (zh) |
WO (1) | WO2007004954A1 (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103084148A (zh) * | 2011-07-27 | 2013-05-08 | 帕尔公司 | 混合模式的配体 |
CN109847716A (zh) * | 2018-12-10 | 2019-06-07 | 哈尔滨工程大学 | 一种利用天然矿物为基的海水提铀吸附剂及其制备方法 |
Families Citing this family (22)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8349846B2 (en) * | 2008-01-11 | 2013-01-08 | Glenmark Pharmaceuticals, S.A. | Fused pyrimidine derivatives as TRPV3 modulators |
EP2918641A1 (en) | 2014-03-13 | 2015-09-16 | Basf Se | Method for purification of antibodies, antibody fragments or engineered variants thereof using specific anthraquinone dye-ligand structures |
EP3365340B1 (en) | 2015-10-19 | 2022-08-10 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
MD3377488T2 (ro) | 2015-11-19 | 2023-02-28 | Incyte Corp | Compuși heterociclici ca imunomodulatori |
SG11201805300QA (en) | 2015-12-22 | 2018-07-30 | Incyte Corp | Heterocyclic compounds as immunomodulators |
ES2906460T3 (es) | 2016-05-06 | 2022-04-18 | Incyte Corp | Compuestos heterocíclicos como inmunomoduladores |
US20170342060A1 (en) | 2016-05-26 | 2017-11-30 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
CA3028685A1 (en) | 2016-06-20 | 2017-12-28 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
US20180016260A1 (en) | 2016-07-14 | 2018-01-18 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
ES2941716T3 (es) | 2016-08-29 | 2023-05-25 | Incyte Corp | Compuestos heterocíclicos como inmunomoduladores |
HRP20221216T1 (hr) | 2016-12-22 | 2022-12-23 | Incyte Corporation | Derivati tetrahidro imidazo[4,5-c]piridina kao induktori internalizacije pd-l1 |
US20180179201A1 (en) | 2016-12-22 | 2018-06-28 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
ES2934230T3 (es) | 2016-12-22 | 2023-02-20 | Incyte Corp | Derivados de benzooxazol como inmunomoduladores |
US20180179179A1 (en) | 2016-12-22 | 2018-06-28 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
FI3774791T3 (fi) | 2018-03-30 | 2023-03-21 | Incyte Corp | Heterosyklisiä yhdisteitä immunomodulaattoreina |
CN112752756A (zh) | 2018-05-11 | 2021-05-04 | 因赛特公司 | 作为PD-L1免疫调节剂的四氢-咪唑并[4,5-c]吡啶衍生物 |
TW202115059A (zh) | 2019-08-09 | 2021-04-16 | 美商英塞特公司 | Pd—1/pd—l1抑制劑之鹽 |
AU2020357514A1 (en) | 2019-09-30 | 2022-04-07 | Incyte Corporation | Pyrido[3,2-d]pyrimidine compounds as immunomodulators |
WO2021096849A1 (en) | 2019-11-11 | 2021-05-20 | Incyte Corporation | Salts and crystalline forms of a pd-1/pd-l1 inhibitor |
US11760756B2 (en) | 2020-11-06 | 2023-09-19 | Incyte Corporation | Crystalline form of a PD-1/PD-L1 inhibitor |
US11780836B2 (en) | 2020-11-06 | 2023-10-10 | Incyte Corporation | Process of preparing a PD-1/PD-L1 inhibitor |
IL302590A (en) | 2020-11-06 | 2023-07-01 | Incyte Corp | Process for preparing PD-1/PD-L1 inhibitor and salts and crystalline forms thereof |
Family Cites Families (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SE8204810L (sv) | 1982-08-23 | 1984-02-24 | Pharmacia Fine Chemicals Ab | Hybrid-dna-molekyl, transformerad mikroorganism och sett att framstella protein a |
CA1320718C (en) * | 1987-06-08 | 1993-07-27 | Richard Frederick Hammen | Chromatographic material |
SE464687B (sv) * | 1987-11-10 | 1991-06-03 | Biocarb Ab | Foerfarande foer framstaellning av en gelprodukt |
US5502022A (en) * | 1994-05-16 | 1996-03-26 | Biosepra, Inc. | Chromatography adsorbents utilizing mercapto heterocyclic ligands |
SE9401960L (sv) * | 1994-06-07 | 1995-12-08 | Sven Oscarsson | Alkalibeständigt proteinadsorbent |
US6117996A (en) * | 1995-09-20 | 2000-09-12 | Novo Nordisk A/S | Triazine based ligands and use thereof |
GB9519197D0 (en) * | 1995-09-20 | 1995-11-22 | Affinity Chromatography Ltd | Novel affinity ligands and their use |
US6013763A (en) * | 1996-06-04 | 2000-01-11 | Genentech, Inc. | Peptide variants of protein A |
DK1386660T3 (da) * | 1996-08-30 | 2009-12-21 | Upfront Chromatography As | Isolering af immunoglobuliner |
US6969518B2 (en) * | 1998-12-28 | 2005-11-29 | Corixa Corporation | Compositions and methods for the therapy and diagnosis of breast cancer |
AU2002340125A1 (en) * | 2001-12-12 | 2003-06-23 | New York University | Triazine library with linkers |
JP2005539223A (ja) * | 2002-09-13 | 2005-12-22 | ポール コーポレイション | クロマトグラフィーの吸着剤およびバイオチップアレイのための混合モード固体基材の調製および使用 |
GB0224446D0 (en) * | 2002-10-21 | 2002-11-27 | Univ Cambridge Tech | Affinity adsorbents for immunoglobulins |
AU2003259007A1 (en) | 2002-10-31 | 2004-05-25 | Amersham Biosciences Ab | Use of urea variants as affinity ligands |
GB0228724D0 (en) * | 2002-12-09 | 2003-01-15 | Prometic Biosciences Ltd | Multidimensinal libraries |
US7700743B2 (en) | 2003-07-22 | 2010-04-20 | Millipore Corporation | Immobilised affinity medium and its use in separation |
-
2006
- 2006-06-26 US US11/994,145 patent/US20080220968A1/en not_active Abandoned
- 2006-06-29 EP EP06747980.8A patent/EP1899342B1/en active Active
- 2006-06-29 WO PCT/SE2006/000808 patent/WO2007004954A1/en active Application Filing
- 2006-06-29 AU AU2006266536A patent/AU2006266536A1/en not_active Abandoned
- 2006-06-29 KR KR1020087000257A patent/KR20080027330A/ko not_active Application Discontinuation
- 2006-06-29 CA CA002627592A patent/CA2627592A1/en not_active Abandoned
- 2006-06-29 CN CNA2006800244283A patent/CN101248075A/zh active Pending
- 2006-06-29 JP JP2008519227A patent/JP2009500604A/ja not_active Withdrawn
-
2009
- 2009-06-17 US US12/486,155 patent/US7625838B2/en active Active
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103084148A (zh) * | 2011-07-27 | 2013-05-08 | 帕尔公司 | 混合模式的配体 |
CN103084148B (zh) * | 2011-07-27 | 2016-02-24 | 帕尔公司 | 混合模式的配体 |
CN109847716A (zh) * | 2018-12-10 | 2019-06-07 | 哈尔滨工程大学 | 一种利用天然矿物为基的海水提铀吸附剂及其制备方法 |
CN109847716B (zh) * | 2018-12-10 | 2021-12-24 | 哈尔滨工程大学 | 一种利用天然矿物为基的海水提铀吸附剂及其制备方法 |
Also Published As
Publication number | Publication date |
---|---|
KR20080027330A (ko) | 2008-03-26 |
AU2006266536A1 (en) | 2007-01-11 |
EP1899342A4 (en) | 2010-04-07 |
JP2009500604A (ja) | 2009-01-08 |
EP1899342A1 (en) | 2008-03-19 |
US7625838B2 (en) | 2009-12-01 |
WO2007004954A1 (en) | 2007-01-11 |
US20080220968A1 (en) | 2008-09-11 |
EP1899342B1 (en) | 2013-11-27 |
CA2627592A1 (en) | 2007-01-11 |
US20090259029A1 (en) | 2009-10-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN101248075A (zh) | 作为选择性吸附IG的色谱吸附剂的[1,2,4]三唑并[I,5-a]嘧啶衍生物 | |
ES2405079T3 (es) | Métodos para purificar anticuerpos de la región Fc | |
JP6544808B2 (ja) | 突然変異免疫グロブリン結合ポリペプチド | |
JP5345539B2 (ja) | 抗体単離のためのスタフィロコッカスアウレウス由来のドメインcを含むクロマトグラフィーリガンド | |
AU2005217348B2 (en) | Antibody purification | |
ES2325362T3 (es) | Una proteina mutada de union a inmunoglobulina. | |
AU2002254683B2 (en) | Binding molecules for Fc-region polypeptides | |
JPH05508701A (ja) | 被分析物に結合するリガンドの同定方法 | |
EP1759196B1 (en) | Separation matrix and method of purification | |
CN107108701A (zh) | 修饰的κ轻链‑结合多肽 | |
CN103443120A (zh) | 免疫球蛋白结合性新型多肽 | |
EP2862879B1 (en) | Support for antibody purification, manufacturing method for same, and application for same | |
JP5192398B2 (ja) | タンパク質精製用の吸着体 | |
US20040101830A1 (en) | Method for identifying individual active entities from complex mixtures | |
CN113461823B (zh) | 靶向人IgE的单域抗体、人源化单域抗体及其应用 | |
Savane et al. | Molecular insight in the purification of immunoglobulin by pseudobiospecific ligand l-histidine and histidyl moieties in histidine ligand affinity chromatography (HLAC) by molecular docking | |
CN116769027B (zh) | 一种抗il-17纳米抗体、多肽及其应用 | |
JP2013256484A (ja) | 抗体認識結合タンパク質 | |
CN114591407A (zh) | 耐碱蛋白a变体及其应用 | |
Fong | Affinity bioseparations with smart polymer conjugates containing DNA, streptavidin, and antibody fragments |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
WD01 | Invention patent application deemed withdrawn after publication |
Open date: 20080820 |