CA1314245C - Process for the preparation of conjugates in which a monovalent carboxylic ionophore is associated by means of a covalent bond with a macromolecule, which are useful as immunotoxin potentiators - Google Patents
Process for the preparation of conjugates in which a monovalent carboxylic ionophore is associated by means of a covalent bond with a macromolecule, which are useful as immunotoxin potentiatorsInfo
- Publication number
- CA1314245C CA1314245C CA000481505A CA481505A CA1314245C CA 1314245 C CA1314245 C CA 1314245C CA 000481505 A CA000481505 A CA 000481505A CA 481505 A CA481505 A CA 481505A CA 1314245 C CA1314245 C CA 1314245C
- Authority
- CA
- Canada
- Prior art keywords
- ionophore
- macromolecule
- conjugate
- antibody
- monensin
- 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.)
- Expired - Fee Related
Links
- 230000000236 ionophoric effect Effects 0.000 title claims abstract description 75
- 239000002555 ionophore Substances 0.000 title claims abstract description 46
- 230000002637 immunotoxin Effects 0.000 title claims abstract description 41
- 239000002596 immunotoxin Substances 0.000 title claims abstract description 41
- 229940051026 immunotoxin Drugs 0.000 title claims abstract description 41
- 231100000608 immunotoxin Toxicity 0.000 title claims abstract description 41
- 229920002521 macromolecule Polymers 0.000 title claims abstract description 35
- 238000000034 method Methods 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 230000008569 process Effects 0.000 title claims abstract description 11
- 239000012634 fragment Substances 0.000 claims abstract description 12
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 5
- 239000000813 peptide hormone Substances 0.000 claims abstract description 4
- 102000003839 Human Proteins Human genes 0.000 claims abstract description 3
- 108090000144 Human Proteins Proteins 0.000 claims abstract description 3
- 239000003446 ligand Substances 0.000 claims abstract description 3
- 229930191564 Monensin Natural products 0.000 claims description 57
- GAOZTHIDHYLHMS-KEOBGNEYSA-N monensin A Chemical group C([C@@](O1)(C)[C@H]2CC[C@@](O2)(CC)[C@H]2[C@H](C[C@@H](O2)[C@@H]2[C@H](C[C@@H](C)[C@](O)(CO)O2)C)C)C[C@@]21C[C@H](O)[C@@H](C)[C@@H]([C@@H](C)[C@@H](OC)[C@H](C)C(O)=O)O2 GAOZTHIDHYLHMS-KEOBGNEYSA-N 0.000 claims description 57
- GAOZTHIDHYLHMS-UHFFFAOYSA-N Monensin A Natural products O1C(CC)(C2C(CC(O2)C2C(CC(C)C(O)(CO)O2)C)C)CCC1C(O1)(C)CCC21CC(O)C(C)C(C(C)C(OC)C(C)C(O)=O)O2 GAOZTHIDHYLHMS-UHFFFAOYSA-N 0.000 claims description 51
- 229960005358 monensin Drugs 0.000 claims description 51
- 150000001875 compounds Chemical class 0.000 claims description 19
- 238000006243 chemical reaction Methods 0.000 claims description 17
- 230000008878 coupling Effects 0.000 claims description 15
- 238000010168 coupling process Methods 0.000 claims description 15
- 238000005859 coupling reaction Methods 0.000 claims description 15
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 14
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 11
- 230000003213 activating effect Effects 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- AHTFMWCHTGEJHA-UHFFFAOYSA-N s-(2,5-dioxooxolan-3-yl) ethanethioate Chemical compound CC(=O)SC1CC(=O)OC1=O AHTFMWCHTGEJHA-UHFFFAOYSA-N 0.000 claims description 7
- 108091006905 Human Serum Albumin Proteins 0.000 claims description 6
- 102000008100 Human Serum Albumin Human genes 0.000 claims description 6
- DANUORFCFTYTSZ-UHFFFAOYSA-N epinigericin Natural products O1C2(C(CC(C)(O2)C2OC(C)(CC2)C2C(CC(O2)C2C(CC(C)C(O)(CO)O2)C)C)C)C(C)C(OC)CC1CC1CCC(C)C(C(C)C(O)=O)O1 DANUORFCFTYTSZ-UHFFFAOYSA-N 0.000 claims description 6
- 238000001727 in vivo Methods 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- DANUORFCFTYTSZ-BIBFWWMMSA-N nigericin Chemical compound C([C@@H]1C[C@H]([C@H]([C@]2([C@@H](C[C@](C)(O2)C2O[C@@](C)(CC2)C2[C@H](CC(O2)[C@@H]2[C@H](C[C@@H](C)[C@](O)(CO)O2)C)C)C)O1)C)OC)[C@H]1CC[C@H](C)C([C@@H](C)C(O)=O)O1 DANUORFCFTYTSZ-BIBFWWMMSA-N 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 239000012736 aqueous medium Substances 0.000 claims description 3
- 125000001931 aliphatic group Chemical group 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 102000004169 proteins and genes Human genes 0.000 abstract description 13
- 108090000623 proteins and genes Proteins 0.000 abstract description 13
- 239000000562 conjugate Substances 0.000 description 51
- 210000004027 cell Anatomy 0.000 description 36
- 239000000243 solution Substances 0.000 description 30
- 108010071390 Serum Albumin Proteins 0.000 description 14
- 102000007562 Serum Albumin Human genes 0.000 description 14
- 239000000047 product Substances 0.000 description 13
- 238000000502 dialysis Methods 0.000 description 12
- 235000018102 proteins Nutrition 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 239000000427 antigen Substances 0.000 description 10
- 102000036639 antigens Human genes 0.000 description 10
- 108091007433 antigens Proteins 0.000 description 10
- 239000012429 reaction media Substances 0.000 description 10
- 230000000694 effects Effects 0.000 description 9
- 230000003389 potentiating effect Effects 0.000 description 9
- 239000000376 reactant Substances 0.000 description 9
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 8
- 150000003573 thiols Chemical class 0.000 description 8
- 125000003277 amino group Chemical group 0.000 description 7
- 239000000872 buffer Substances 0.000 description 7
- 239000008363 phosphate buffer Substances 0.000 description 7
- 241000699670 Mus sp. Species 0.000 description 6
- 230000004913 activation Effects 0.000 description 6
- 238000010348 incorporation Methods 0.000 description 6
- 238000011534 incubation Methods 0.000 description 6
- -1 lysyl radicals Chemical class 0.000 description 6
- 210000002381 plasma Anatomy 0.000 description 6
- 150000003254 radicals Chemical class 0.000 description 6
- 230000001988 toxicity Effects 0.000 description 6
- 231100000419 toxicity Toxicity 0.000 description 6
- 229910019142 PO4 Inorganic materials 0.000 description 5
- 238000005119 centrifugation Methods 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 125000002228 disulfide group Chemical group 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 5
- 239000010452 phosphate Substances 0.000 description 5
- 238000001243 protein synthesis Methods 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- 230000014616 translation Effects 0.000 description 5
- 125000000217 alkyl group Chemical group 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 230000000875 corresponding effect Effects 0.000 description 4
- 230000003013 cytotoxicity Effects 0.000 description 4
- 231100000135 cytotoxicity Toxicity 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 description 3
- 102000009027 Albumins Human genes 0.000 description 3
- 108010088751 Albumins Proteins 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 102000057297 Pepsin A Human genes 0.000 description 3
- 108090000284 Pepsin A Proteins 0.000 description 3
- 101710177166 Phosphoprotein Proteins 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 210000001185 bone marrow Anatomy 0.000 description 3
- 239000000470 constituent Substances 0.000 description 3
- 230000001472 cytotoxic effect Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 229940111202 pepsin Drugs 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000000700 radioactive tracer Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 108060003951 Immunoglobulin Proteins 0.000 description 2
- 238000012404 In vitro experiment Methods 0.000 description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 241000699660 Mus musculus Species 0.000 description 2
- 108010039491 Ricin Proteins 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- 125000003158 alcohol group Chemical group 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 150000001718 carbodiimides Chemical class 0.000 description 2
- 238000012412 chemical coupling Methods 0.000 description 2
- 239000007822 coupling agent Substances 0.000 description 2
- 231100000433 cytotoxic Toxicity 0.000 description 2
- 229940127089 cytotoxic agent Drugs 0.000 description 2
- 239000002254 cytotoxic agent Substances 0.000 description 2
- 231100000599 cytotoxic agent Toxicity 0.000 description 2
- 239000003145 cytotoxic factor Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000012636 effector Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 102000018358 immunoglobulin Human genes 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- 125000005439 maleimidyl group Chemical group C1(C=CC(N1*)=O)=O 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000005445 natural material Substances 0.000 description 2
- ZHCAAFJSYLFLPX-UHFFFAOYSA-N nitrocyclohexatriene Chemical group [O-][N+](=O)C1=CC=C=C[CH]1 ZHCAAFJSYLFLPX-UHFFFAOYSA-N 0.000 description 2
- 238000011580 nude mouse model Methods 0.000 description 2
- NMHMNPHRMNGLLB-UHFFFAOYSA-N phloretic acid Chemical compound OC(=O)CCC1=CC=C(O)C=C1 NMHMNPHRMNGLLB-UHFFFAOYSA-N 0.000 description 2
- 238000011533 pre-incubation Methods 0.000 description 2
- 230000000717 retained effect Effects 0.000 description 2
- 238000002798 spectrophotometry method Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 2
- 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
- 125000001894 2,4,6-trinitrophenyl group Chemical group [H]C1=C(C(*)=C(C([H])=C1[N+]([O-])=O)[N+]([O-])=O)[N+]([O-])=O 0.000 description 1
- 125000001917 2,4-dinitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C(=C1*)[N+]([O-])=O)[N+]([O-])=O 0.000 description 1
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 description 1
- SVOAXTTVWPHOQW-UHFFFAOYSA-N 2-acetylsulfanylbutanedioic acid Chemical compound CC(=O)SC(C(O)=O)CC(O)=O SVOAXTTVWPHOQW-UHFFFAOYSA-N 0.000 description 1
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical group NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 101710181478 Envelope glycoprotein GP350 Proteins 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 235000019766 L-Lysine Nutrition 0.000 description 1
- 231100000111 LD50 Toxicity 0.000 description 1
- 229930182504 Lasalocid Natural products 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 108010039918 Polylysine Proteins 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 229920005654 Sephadex Polymers 0.000 description 1
- 239000012507 Sephadex™ Substances 0.000 description 1
- 229920002684 Sepharose Polymers 0.000 description 1
- 239000004280 Sodium formate Substances 0.000 description 1
- 241001655322 Streptomycetales Species 0.000 description 1
- TUCNEACPLKLKNU-UHFFFAOYSA-N acetyl Chemical compound C[C]=O TUCNEACPLKLKNU-UHFFFAOYSA-N 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 210000003567 ascitic fluid Anatomy 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 231100000050 cytotoxic potential Toxicity 0.000 description 1
- 238000000326 densiometry Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 230000007071 enzymatic hydrolysis Effects 0.000 description 1
- 238000006047 enzymatic hydrolysis reaction Methods 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 210000004754 hybrid cell Anatomy 0.000 description 1
- 210000004408 hybridoma Anatomy 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 150000002431 hydrogen Chemical group 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 125000002633 imido ester group Chemical group 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 231100000110 immunotoxic Toxicity 0.000 description 1
- 230000002625 immunotoxic effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- BBMULGJBVDDDNI-OWKLGTHSSA-N lasalocid Chemical compound C([C@@H]1[C@@]2(CC)O[C@@H]([C@H](C2)C)[C@@H](CC)C(=O)[C@@H](C)[C@@H](O)[C@H](C)CCC=2C(=C(O)C(C)=CC=2)C(O)=O)C[C@](O)(CC)[C@H](C)O1 BBMULGJBVDDDNI-OWKLGTHSSA-N 0.000 description 1
- 229960000320 lasalocid Drugs 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 230000000527 lymphocytic effect Effects 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 229920000656 polylysine Polymers 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 230000002633 protecting effect Effects 0.000 description 1
- 239000012460 protein solution Substances 0.000 description 1
- WHMDPDGBKYUEMW-UHFFFAOYSA-N pyridine-2-thiol Chemical compound SC1=CC=CC=N1 WHMDPDGBKYUEMW-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 description 1
- 235000019254 sodium formate Nutrition 0.000 description 1
- FNUFHLAIHWESDA-UHFFFAOYSA-M sodium;2,3,4-trinitrobenzenesulfonate Chemical compound [Na+].[O-][N+](=O)C1=CC=C(S([O-])(=O)=O)C([N+]([O-])=O)=C1[N+]([O-])=O FNUFHLAIHWESDA-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 229940014800 succinic anhydride Drugs 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
- A61K47/6811—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin
- A61K47/6817—Toxins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/01—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing oxygen
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Toxicology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8408073A FR2564839B1 (fr) | 1984-05-23 | 1984-05-23 | Conjugues associant par liaison covalente un ionophore carboxylique monovalent et une macromolecule et leur utilisation comme agents potentialisateurs des immunotoxines |
| FR8408073 | 1984-05-23 | ||
| FR8411208 | 1984-07-13 | ||
| FR8411208A FR2567521B1 (fr) | 1984-07-13 | 1984-07-13 | Nouveaux ionophores actives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1314245C true CA1314245C (en) | 1993-03-09 |
Family
ID=26223983
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000481505A Expired - Fee Related CA1314245C (en) | 1984-05-23 | 1985-05-14 | Process for the preparation of conjugates in which a monovalent carboxylic ionophore is associated by means of a covalent bond with a macromolecule, which are useful as immunotoxin potentiators |
Country Status (12)
| Country | Link |
|---|---|
| US (3) | US4919928A (OSRAM) |
| EP (1) | EP0162781B1 (OSRAM) |
| AU (1) | AU600651B2 (OSRAM) |
| CA (1) | CA1314245C (OSRAM) |
| DE (1) | DE3571928D1 (OSRAM) |
| DK (1) | DK164457C (OSRAM) |
| ES (1) | ES8604228A1 (OSRAM) |
| GR (1) | GR851229B (OSRAM) |
| IE (1) | IE58480B1 (OSRAM) |
| IL (1) | IL75228A (OSRAM) |
| NZ (1) | NZ212118A (OSRAM) |
| PT (1) | PT80501B (OSRAM) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1314245C (en) * | 1984-05-23 | 1993-03-09 | Franz Jansen | Process for the preparation of conjugates in which a monovalent carboxylic ionophore is associated by means of a covalent bond with a macromolecule, which are useful as immunotoxin potentiators |
| ATE104309T1 (de) * | 1987-10-30 | 1994-04-15 | American Cyanamid Co | Dischwefel-analoge von ll-e33288 antitumorverbindungen. |
| US5219564A (en) * | 1990-07-06 | 1993-06-15 | Enzon, Inc. | Poly(alkylene oxide) amino acid copolymers and drug carriers and charged copolymers based thereon |
| US5612034A (en) * | 1990-10-03 | 1997-03-18 | Redcell, Inc. | Super-globuling for in vivo extended lifetimes |
| KR100710461B1 (ko) * | 2005-10-12 | 2007-04-24 | (주)씨에스이 | 소음기를 구비한 진공포장장치 |
| CN110167577B (zh) * | 2016-11-16 | 2024-05-10 | 普渡研究基金会 | 配体离子载体共轭物 |
Family Cites Families (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3832358A (en) * | 1973-01-15 | 1974-08-27 | Lilly Co Eli | Deshydroxymethyl derivatives of monensin |
| FR2437213A1 (fr) * | 1978-09-28 | 1980-04-25 | Cm Ind | Produits cytotoxiques formes par liaison covalente de la chaine a de la ricine avec un anticorps et leur procede de preparation |
| FR2463144A1 (fr) * | 1979-08-13 | 1981-02-20 | Syntex Inc | Nouveaux diesters de laidlomycine, leur procede de production, compositions a usage veterinaire les contenant et leur utilisation pour accroitre le rendement d'assimilation des aliments chez un ruminant |
| US4431665A (en) * | 1979-08-13 | 1984-02-14 | Syntex (U.S.A.) Inc. | Acylated laidlomycin derivatives |
| JPS57106626A (en) * | 1980-12-22 | 1982-07-02 | Teijin Ltd | Cytotoxic protein complex and its preparation |
| FR2498192A2 (fr) * | 1981-01-22 | 1982-07-23 | Pasteur Institut | Nouveau compose polypeptidique thiole provenant d'un fragment de la toxine tetanique, son procede d'obtention et ses applications |
| FR2516794B1 (fr) * | 1981-11-20 | 1985-10-25 | Sanofi Sa | Nouveaux medicaments anticancereux pour le traitement des leucemies t constitues de la chaine a de la ricine et d'un anticorps monoclonal specifique |
| FR2521010B1 (fr) * | 1982-02-09 | 1985-07-19 | Sanofi Sa | Medicaments comportant en tant qu'association au moins une immunotoxine et au moins un ionophore carboxylique monovalent |
| FR2522968B1 (fr) * | 1982-03-10 | 1986-03-28 | Sanofi Sa | Medicament cytotoxique forme de l'association d'a u moins une immunotoxine et de la chloroquine |
| JPS59116229A (ja) * | 1982-12-24 | 1984-07-05 | Teijin Ltd | 細胞毒性複合体を活性成分とする癌治療用剤およびその製造法 |
| JPS59116232A (ja) * | 1982-12-24 | 1984-07-05 | Teijin Ltd | 細胞毒性複合体及びその製造法 |
| CA1214774A (en) * | 1983-02-10 | 1986-12-02 | Yusei Shiraga | Benzodiazepine derivative |
| US4542027A (en) * | 1984-02-23 | 1985-09-17 | Syntex (U.S.A.) Inc. | Laidlomycin phenylcarbamate |
| CA1314245C (en) * | 1984-05-23 | 1993-03-09 | Franz Jansen | Process for the preparation of conjugates in which a monovalent carboxylic ionophore is associated by means of a covalent bond with a macromolecule, which are useful as immunotoxin potentiators |
-
1985
- 1985-05-14 CA CA000481505A patent/CA1314245C/en not_active Expired - Fee Related
- 1985-05-17 IL IL75228A patent/IL75228A/xx not_active IP Right Cessation
- 1985-05-20 NZ NZ212118A patent/NZ212118A/en unknown
- 1985-05-20 GR GR851229A patent/GR851229B/el unknown
- 1985-05-21 EP EP85400998A patent/EP0162781B1/fr not_active Expired
- 1985-05-21 PT PT80501A patent/PT80501B/pt not_active IP Right Cessation
- 1985-05-21 DE DE8585400998T patent/DE3571928D1/de not_active Expired
- 1985-05-21 DK DK224785A patent/DK164457C/da not_active IP Right Cessation
- 1985-05-22 ES ES543367A patent/ES8604228A1/es not_active Expired
- 1985-05-22 IE IE127985A patent/IE58480B1/en not_active IP Right Cessation
- 1985-05-23 AU AU42793/85A patent/AU600651B2/en not_active Ceased
-
1987
- 1987-04-06 US US07/034,712 patent/US4919928A/en not_active Expired - Fee Related
-
1989
- 1989-12-27 US US07/457,858 patent/US4977280A/en not_active Expired - Fee Related
- 1989-12-28 US US07/458,444 patent/US5144009A/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| GR851229B (OSRAM) | 1985-11-25 |
| IL75228A0 (en) | 1985-09-29 |
| US5144009A (en) | 1992-09-01 |
| EP0162781B1 (fr) | 1989-08-02 |
| DK224785D0 (da) | 1985-05-21 |
| AU4279385A (en) | 1985-11-28 |
| NZ212118A (en) | 1990-11-27 |
| ES543367A0 (es) | 1986-01-16 |
| US4977280A (en) | 1990-12-11 |
| DK164457C (da) | 1992-11-16 |
| DK224785A (da) | 1985-11-24 |
| DK164457B (da) | 1992-06-29 |
| AU600651B2 (en) | 1990-08-23 |
| EP0162781A1 (fr) | 1985-11-27 |
| ES8604228A1 (es) | 1986-01-16 |
| DE3571928D1 (en) | 1989-09-07 |
| PT80501B (fr) | 1986-12-16 |
| IL75228A (en) | 1990-06-10 |
| US4919928A (en) | 1990-04-24 |
| IE58480B1 (en) | 1993-09-22 |
| PT80501A (fr) | 1985-06-01 |
| IE851279L (en) | 1985-11-23 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKLA | Lapsed |