WO2001077360A2 - Methods for ansamitocin production - Google Patents
Methods for ansamitocin production Download PDFInfo
- Publication number
- WO2001077360A2 WO2001077360A2 PCT/GB2001/001661 GB0101661W WO0177360A2 WO 2001077360 A2 WO2001077360 A2 WO 2001077360A2 GB 0101661 W GB0101661 W GB 0101661W WO 0177360 A2 WO0177360 A2 WO 0177360A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- ansamitocins
- ansamitocin
- culture medium
- toluene
- solvent
- Prior art date
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Classifications
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/18—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing at least two hetero rings condensed among themselves or condensed with a common carbocyclic ring system, e.g. rifamycin
- C12P17/181—Heterocyclic compounds containing oxygen atoms as the only ring heteroatoms in the condensed system, e.g. Salinomycin, Septamycin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/18—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing at least two hetero rings condensed among themselves or condensed with a common carbocyclic ring system, e.g. rifamycin
- C12P17/188—Heterocyclic compound containing in the condensed system at least one hetero ring having nitrogen atoms and oxygen atoms as the only ring heteroatoms
Definitions
- This invention relates to processes for the preparation of ansamitocins, in particular ansamitocins which can be converted to maytansinol.
- Actinosynnema spp. such as Actinosynnema pretiosum produce a number of related ansamitocins.
- the major product is ansamitocin P-3 with an isobutyryl moiety at the C-3 position.
- Other ansamitocins differing only in the C-3 acyl side chain are produced as minor components, P- 1 (ethionyl moiety), P-2 (propionyl moiety), P-3' (butyryl moiety), P-4 (isovaleryl moiety) and P-4' (valeryl moiety). All these compounds may undergo reductive cleavage to produce a common product, maytansinol (form P-0).
- these methods require adding a filter aid and a water-miscible solvent to whole fermentation broth, removing solids and extracting the aqueous fraction with a water-immiscible solvent, concentrating and precipitating with petroleum ether, purifying the precipitate using silica chromatography, and crystallizing followed by further chromatography or re-crystallization.
- One aspect of the present invention is a method for preparing purified ansamitocins comprising the steps of: a. culturing an ansamitocin-producing microorganism in a liquid culture medium; b. treating the culture medium to facilitate solvent extaction of ansamitocins; c. extracting ansamitocins from the culture medium with an aromatic hydrocarbon solvent; e. concentrating the extracted ansamitocins; and f. purifying the ansamitocins by crystallization.
- Another aspect of the present invention is a method for preparing purified ansamitocins comprising the steps of: a. culturing an ansamitocin-producing microorganism in a liquid culture medium; b. extracting ansamitocins from the culture medium with an aromatic hydrocarbon solvent; c. concentrating the extracted ansamitocins; and d. purifying the ansamitocins by crystallization.
- Methods are provided for preparing purified ansamitocins without a filtration step.
- the methods comprise the steps of culturing an ansamitocin-producing microorganism in a liquid culture medium, treating the culture medium to release ansamitocins from the microorganism into the culture medium thereby facilitating solvent extraction, extracting ansamitocins from the treated culture medium with an aromatic hydrocarbon solvent, concentrating the extracted ansamitocins, and purifying the ansamitocins by crystallization.
- the treatment step can be omitted.
- the purified ansamitocins may be reduced to maytansinol and include ansamitocin P-3, P-1, P-2, P-3', P-4 and P-4'.
- the purified ansamitocins contain only very low levels of undesirable ansamitocins with modifications at other sites in the molecule.
- the ansamitocin-producing microorganism is Actinosynnema spp. Particularly preferred is Actinosynnema pretiosum ATCC 31565. Also particularly preferred is Actinosynnema pretiosum ATCC 31281.
- the microorganisms can be grown by fermentation culture techniques well-known to those skilled in the art such as those disclosed in U.S. Pat. No. 4,450,234.
- One embodiment of the method of the invention uses treatment of the microorganism to aid release of intracellular ansamitocins and render cell-associated ansamitocins more amenable to solvent extraction.
- exemplary treatment methods include sonication, increased pressure or increased temperature.
- the treatment is a heat treatment.
- the heat treatment can be conducted at about 60°C to about 80°C.
- the heat treatment step is conducted at about 75°C which kills the microorganism and facilitates solvent extraction of ansamitocins.
- no treatment step is used prior to extraction since approximately 60% of total ansamitocins can be found in the culture medium.
- Ansamitocins can be extracted from culture medium with the use of aromatic hydrocarbon solvents.
- the aromatic hydrocarbons have a particular selectivity for the ansamitocins over other broth constituents, which ensures only simple processes are required downstream to isolate pure product.
- the aromatic hydrocarbon solvent is toluene or xylene. Particularly preferred is toluene as this is more amenable to low temperature evaporation.
- the properties of toluene and xylene are such that the solvent and aqueous layers are readily separated under gravity without the need for mechanical separation and thus greater containment of the process and increased operator safety are achieved.
- the extraction can be conducted at about 20°C to about 60°C. Preferably, the extraction is conducted at about 45°C.
- the pH of the aqueous solution prior to extraction should be in the range 3 to 9.
- the pH is near neutrality, i.e., pH 6 to 8.
- one equivalent volume of solvent to whole broth ( 1 : 1 ) is preferred for the extraction.
- Alternative ratio ranges of 2: 1 to 1 :4 can also be used.
- the solutions are generally mixed slowly with stirring and the mixture stirred until about >80% of the ansamitocins have been extracted into the organic layer.
- the mixture is left to settle under gravity at a temperature between 15°C and 50°C. The preferred temperature for settling is about 45°C.
- the organic layer is removed, and concentration of the extract by volume reduction of the solvent may be carried out in vacuo or by other methods well-known to those skilled in the art.
- concentration of the extract by volume reduction of the solvent may be carried out in vacuo or by other methods well-known to those skilled in the art.
- the concentrated extract can be optionally dissolved in a polar solvent such as methanol, and clarified using a membrane filter such as PTFE, or a depth filter such as silica or alumina.
- Crystallization is used to purify the desired ansamitocins, particularly P-3, by reducing the levels of unwanted ansamitocins.
- a preferred solvent mixture for crystallization is ethyl acetate and heptane. Such crystallization is performed in a conventional manner. To aid dissolution of the solid for crystallization, a small volume of methanol or similar polar solvent may be added prior to addition of ethyl acetate and then treatment with larger volumes of heptane, optionally with stirring and cooling to afford the crystallized product. The product may be recrystallized following the same procedure.
- the impure ansamitocins extracted from the fermentation broth may be purified using silica gel, e.g., by passing a solution of the solvent extract through a bed of silica.
- Solvents used for the chromatography may be toluene and toluene-methanol mixes. Other solvents known to those skilled in the art can also be used.
- the fractions containing ansamitocin P-3 are pooled and concentrated under reduced pressure.
- Quantitation of ansamitocin P-3 in broth and extraction samples can be determined on a C18 Waters Q Spherisorb S5 ODS2 column, 4.6 x 250 mm, with a 10mm guard column. UV detection is at 252 nm and 205 nm.
- An isocratic mobile phase of lml/min 60% MeCN (0.05% TFA) in water (0.05% TFA) and a 20 ⁇ l injection volume are used.
- Quantitation of ansamitocin P-3 in waste streams and other low-level samples requiring high sensitivity can be determined on a C18 Waters Spherisorb S5 ODS2 column, 5 4.6 x 250mm, with a 10mm guard column and LC-MS-MS atmospheric pressure electrospray ionisation detection system, +ve ion mode, 30V cone voltage.
- the molecular ions of the major species were selected and the fragmentation patterns observed were a predominant 547 ion indicating N-methylated and a 533 indicating N-demethylated.
- An isocratic mobile phase of lml/min 60% MeCN l o (0.05% TFA) in water (0.05% TFA) and a 20 ⁇ l injection volume are used.
- the process of the invention can be used to make cell-binding agent/maytansinoid complexes which are useful as tumor-activated pro-drugs.
- Ansamitocins prepared by the process of the invention can undergo reductive cleavage to maytansinol which can be used as described in U.S. Patent No. 5,208,020 to produce N-methyl-L-alanine containing 15 maytansinoid derivatives.
- These derivatives are then conjugated to cell-binding agents, preferably antibodies, via various linkers such as a disulfide link.
- An exemplary cell-binding agent/maytansinoid complex can be prepared by a process comprising the following steps:
- step 25 linking the thiol-containing maytansinoid produced by step (3) to the dithiopyridyl cell-binding agent of step (4) by a disulfide link.
- ATCC 31565 ansamitocin P-3 titer 75.1 mg/L, 82.6g P-3) were heat-treated in situ at 75°C for 60 mins to kill the microorganism and facilitate solvent extraction of the ansamitocins. to 45°C was added and the mixture was maintained at 45°C. Phases were agitated such that a vortex of upper toluene phase was drawn into the lower broth phase but without emulsification or complete homogenization of the phases. Extraction was carried out for 45 hours, followed by separation under gravity which occurred within 30 min. (Extraction stage yield 90.3%.)
- 1,127L of the toluene extract, containing the ansamitocins, were concentrated to 22L using a falling film evaporator (FFE).
- FFE falling film evaporator
- the concentrate was transferred to a 50L rotary evaporator and evaporated to low volume (evaporation rate 14.6L/hr).
- the FFE was rinsed with 2 x 20L toluene and the rinsings passed to the evaporator to ensure complete transfer of product.
- the concentrate was evaporated to dryness.
- the dry extract was taken up in 7.2L of 4% methanol in toluene and loaded onto a silica column (Kieselgel 60, 4.8L bed volume packed in 4% methanol in toluene, 15.0cm diam. x 27.0cm, loading rate 120 mL/min).
- the column was eluted isocratically using 4% methanol in toluene at a flow rate of 227-384 mL/min and produced tight bands of color.
- Initial fractions were one bed volume; fractions 3 to 6 were collected as half bed volumes.
- Fractions were monitored by TLC (Kieselgel 60 F254 plates, run in 5% methanol in dichloromethane, visualized by UV at 254nm) and those containing ansamitocins were monitored by HPLC and LC-MS. Fraction selection for crystallization was based on HPLC and LC-MS analysis of the fractions to optimize ansamitocin P-3 recovery and minimize undesired ansamitocins. Fractions 5 to 10 containing ansamitocin P-3 were bulked and evaporated to produce a solid containing 54.6g of P-3. At this stage the product contained 77.1% ansamitocin P-3, and a total of 96.1% of the desired ansamitocins.
- the mixture was cooled on ice and further aliquots of heptane (200 and 400 mL) were added until 3.9g of P-3 (6.8%) remained in the mother liquor.
- the mother liquors were removed by aspiration, using a sintered filter line assembly.
- the crystals were washed with 2 x 150 mL 1:3 ethyl acetate:heptane.
- the crystals were dried in situ on a rotary evaporator, initially under low vacuum, followed by high vacuum (1.0-1.3 mbar) at 30°C for 88.5 hours. 76.4g of crystals were obtained.
- the concentrate containing 34.5 g ansamitocin P-3 was taken up in 3 L toluene and loaded onto a silica column (Kieselgel 60, 3.0 L bed volume, packed in toluene, 13.8 cm diam. x 16.6cm).
- the column was topped with a 4 cm bed of sand.
- the column was washed with 5L of toluene, followed by 20L of 2% MeOH in toluene, which was collected
- the crystals were recovered by aspiration of the dark brown mother liquors.
- the methanol solution was evaporated to dryness and re-dissolved in 85 mL of methanol at 50°C. 510 mL of ethyl acetate was added to the solution followed by 200 mL of heptane. The mixture was cooled to ambient and a further 990 mL of heptane was slowly added as crystallisation commenced. 4.14 g of ansamitocin P-3 remained in the mother liquor. A further 400 mL of heptane was added and the mixture cooled on ice. 2.7 g of ansamitocin P-3 remained in the mother liquor.
- the mother liquor was removed by aspiration and the crystals were dissolved in 110 mL of methanol and 520 mL ethyl acetate at 50°C. Heptane was added in two 75 mL aliquots, the mixture was cooled to ambient and another 900 mL added. A further 400 mL of heptane was added and the mixture cooled on ice and left overnight to crystallize. HPLC analysis indicated 2.3 g of ansamitocin P-3 remained in the mother liquor.
- the mother liquor was removed by aspiration and the crystals were washed with heptane:ethyl acetate, 3: 1 and were dried under vacuum (0.6 mBar) overnight. The 47.8 g of crystals contained 84.3% ansamitocin P-3, and a total of 97.0% desired acylated ansamitocins.
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Abstract
Description
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Priority Applications (13)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IL15224101A IL152241A0 (en) | 2000-04-12 | 2001-04-11 | Methods for ansamitocin production |
DE60121150T DE60121150T2 (en) | 2000-04-12 | 2001-04-11 | PROCESS FOR THE PREPARATION OF ANSAMITOCIN |
EP01966770A EP1272653B1 (en) | 2000-04-12 | 2001-04-11 | Methods for ansamitocin production |
CA002406188A CA2406188A1 (en) | 2000-04-12 | 2001-04-11 | Methods for ansamitocin production |
AU2001293335A AU2001293335B2 (en) | 2000-04-12 | 2001-04-11 | Methods for ansamitocin production |
JP2001575214A JP4832697B2 (en) | 2000-04-12 | 2001-04-11 | Manufacturing method of ansamitocin |
MXPA02010109A MXPA02010109A (en) | 2000-04-12 | 2001-04-11 | Methods for ansamitocin production. |
HU0300473A HUP0300473A3 (en) | 2000-04-12 | 2001-04-11 | Methods for ansamitocin production |
NZ521868A NZ521868A (en) | 2000-04-12 | 2001-04-11 | Methods for ansamitocin production |
BR0109975-2A BR0109975A (en) | 2000-04-12 | 2001-04-11 | Method for producing ansamitocins |
PL01365577A PL365577A1 (en) | 2000-04-12 | 2001-04-11 | Methods for ansamitocin production |
AU9333501A AU9333501A (en) | 2000-04-12 | 2001-04-11 | Methods for ansamitocin production |
NO20024893A NO20024893L (en) | 2000-04-12 | 2002-10-10 | Methods for ansamitocin production |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US19636100P | 2000-04-12 | 2000-04-12 | |
US60/196,361 | 2000-04-12 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2001077360A2 true WO2001077360A2 (en) | 2001-10-18 |
WO2001077360A3 WO2001077360A3 (en) | 2002-09-12 |
Family
ID=22725075
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB2001/001661 WO2001077360A2 (en) | 2000-04-12 | 2001-04-11 | Methods for ansamitocin production |
Country Status (21)
Country | Link |
---|---|
US (2) | US6573074B2 (en) |
EP (1) | EP1272653B1 (en) |
JP (1) | JP4832697B2 (en) |
KR (1) | KR20030036159A (en) |
CN (1) | CN1432068A (en) |
AR (1) | AR028002A1 (en) |
AT (1) | ATE331804T1 (en) |
AU (2) | AU9333501A (en) |
BR (1) | BR0109975A (en) |
CA (1) | CA2406188A1 (en) |
CZ (1) | CZ20023356A3 (en) |
DE (1) | DE60121150T2 (en) |
ES (1) | ES2266243T3 (en) |
HU (1) | HUP0300473A3 (en) |
IL (1) | IL152241A0 (en) |
MX (1) | MXPA02010109A (en) |
NO (1) | NO20024893L (en) |
NZ (1) | NZ521868A (en) |
PL (1) | PL365577A1 (en) |
WO (1) | WO2001077360A2 (en) |
ZA (1) | ZA200208159B (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1468077A2 (en) * | 2002-01-29 | 2004-10-20 | Immunogen, Inc. | Mutant actinosynnema pretiosum strain with increased maytansinoid production |
EP1806365A1 (en) | 2006-01-05 | 2007-07-11 | Boehringer Ingelheim International GmbH | Antibody molecules specific for fibroblast activation protein and immunoconjugates containing them |
CN100420754C (en) * | 2006-10-26 | 2008-09-24 | 浙江海正药业股份有限公司 | Method for preparing anthracene Ensamu bacterial |
Families Citing this family (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6333410B1 (en) | 2000-08-18 | 2001-12-25 | Immunogen, Inc. | Process for the preparation and purification of thiol-containing maytansinoids |
AR030612A1 (en) * | 2000-09-12 | 2003-08-27 | Smithkline Beecham Corp | PROCEDURE AND INTERMEDIATES |
JP2006510349A (en) * | 2002-08-08 | 2006-03-30 | スミスクライン・ビーチャム・コーポレイション | Method for isolation and purification of ansamitocin |
WO2005020883A2 (en) * | 2003-05-08 | 2005-03-10 | Immunogen, Inc. | Methods for the production of ansamitocins |
US7432088B2 (en) * | 2003-05-08 | 2008-10-07 | Immunogen Inc. | Methods for the production of ansamitocins |
US7276497B2 (en) * | 2003-05-20 | 2007-10-02 | Immunogen Inc. | Cytotoxic agents comprising new maytansinoids |
US20070135629A1 (en) * | 2005-12-08 | 2007-06-14 | Millennium Pharmaceuticals, Inc. | Isolation of ansamitocins |
EA028220B1 (en) | 2011-05-27 | 2017-10-31 | Глаксо Груп Лимитед | Immunoconjugate comprising bcma (cd269/tnfrsf17) binding protein, medical use thereof and pharmaceutical composition |
CN102505023A (en) * | 2011-11-18 | 2012-06-20 | 华东理工大学 | Allos soluble expression method for aroF gene coded DAHP synthase of Actinosynenma pretiosum, as well as recombinant vector and gene expression engineering bacteria used in method |
CN108276427A (en) * | 2018-01-14 | 2018-07-13 | 常州大学 | The extraction of ansamitocin P-3 a kind of and isolation and purification method |
CN110117626A (en) * | 2018-02-06 | 2019-08-13 | 上海键合医药科技有限公司 | A kind of zymotechnique preparing Ansamitocins P3 |
SI3956332T1 (en) | 2019-04-18 | 2023-05-31 | Indena S.P.A. | Diasteroselective process for the preparation of thiol- or disulfide-containing maytansinoid esters and intermediates thereof |
CN113444106A (en) * | 2020-03-25 | 2021-09-28 | 重庆乾泰生物医药有限公司 | Preparation method of high-purity ansamitocin |
EP4347656A1 (en) | 2021-05-28 | 2024-04-10 | GlaxoSmithKline Intellectual Property Development Limited | Combination therapies for treating cancer |
CN117597450A (en) * | 2021-06-18 | 2024-02-23 | 杭州中美华东制药有限公司 | Purification method of ansamitocin P-3 |
EP4412713A1 (en) | 2021-10-05 | 2024-08-14 | GlaxoSmithKline Intellectual Property Development Ltd | Combination therapies for treating cancer |
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GB1554395A (en) * | 1977-03-31 | 1979-10-17 | Takeda Chemical Industries Ltd | Method for producing maytansinol and its derivatives |
US4228239A (en) * | 1977-11-18 | 1980-10-14 | Takeda Chemical Industries, Ltd | Method for producing antibiotic C-15003 P-3 |
EP0019934A1 (en) * | 1979-06-05 | 1980-12-10 | Takeda Chemical Industries, Ltd. | Antibiotic C-15003 PND and process for their preparation |
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EP0031430A2 (en) * | 1979-12-28 | 1981-07-08 | Takeda Chemical Industries, Ltd. | A method for the production of antibiotic C-15003 P-3 |
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GB1314019A (en) * | 1969-07-19 | 1973-04-18 | Rolland Sa A | Antibiotic substance and process for the extraction of such an antibiotic substance from a strain of pseudomonas |
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US4423211A (en) * | 1981-12-21 | 1983-12-27 | Merck & Co., Inc. | Process for the whole broth extraction of avermectin |
JPH0347090A (en) * | 1988-12-27 | 1991-02-28 | Takeda Chem Ind Ltd | Hybrid monoclonal antibody having bi-specificity |
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FR2656874B1 (en) * | 1990-01-11 | 1992-04-03 | Commissariat Energie Atomique | PROCESS FOR THE PRODUCTION AND EXTRACTION OF ANTI-OXIDANTS FROM A CULTURE OF MICROORGANISMS AND PHOTOBIOREACTOR FOR THE IMPLEMENTATION OF THIS PROCESS. |
DE4037441A1 (en) * | 1990-11-24 | 1992-05-27 | Basf Ag | METHOD FOR INCREASING THE RIBOFLAVIN GAIN IN SPRAY-DRIED FERMENTAL DISCHARGES IN RIBOFLAVIN FERMENTATIONS |
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2001
- 2001-04-09 US US09/828,758 patent/US6573074B2/en not_active Expired - Lifetime
- 2001-04-10 AR ARP010101696A patent/AR028002A1/en unknown
- 2001-04-11 WO PCT/GB2001/001661 patent/WO2001077360A2/en active IP Right Grant
- 2001-04-11 HU HU0300473A patent/HUP0300473A3/en unknown
- 2001-04-11 EP EP01966770A patent/EP1272653B1/en not_active Expired - Lifetime
- 2001-04-11 CZ CZ20023356A patent/CZ20023356A3/en unknown
- 2001-04-11 ES ES01966770T patent/ES2266243T3/en not_active Expired - Lifetime
- 2001-04-11 KR KR1020027013580A patent/KR20030036159A/en not_active Application Discontinuation
- 2001-04-11 CN CN01810371A patent/CN1432068A/en active Pending
- 2001-04-11 BR BR0109975-2A patent/BR0109975A/en not_active Application Discontinuation
- 2001-04-11 AU AU9333501A patent/AU9333501A/en active Pending
- 2001-04-11 MX MXPA02010109A patent/MXPA02010109A/en unknown
- 2001-04-11 IL IL15224101A patent/IL152241A0/en unknown
- 2001-04-11 DE DE60121150T patent/DE60121150T2/en not_active Expired - Lifetime
- 2001-04-11 JP JP2001575214A patent/JP4832697B2/en not_active Expired - Fee Related
- 2001-04-11 NZ NZ521868A patent/NZ521868A/en not_active IP Right Cessation
- 2001-04-11 AT AT01966770T patent/ATE331804T1/en not_active IP Right Cessation
- 2001-04-11 AU AU2001293335A patent/AU2001293335B2/en not_active Ceased
- 2001-04-11 PL PL01365577A patent/PL365577A1/en not_active Application Discontinuation
- 2001-04-11 CA CA002406188A patent/CA2406188A1/en not_active Abandoned
-
2002
- 2002-10-10 NO NO20024893A patent/NO20024893L/en not_active Application Discontinuation
- 2002-10-10 ZA ZA200208159A patent/ZA200208159B/en unknown
-
2003
- 2003-03-04 US US10/379,136 patent/US20030157669A1/en not_active Abandoned
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WO1991009134A1 (en) * | 1989-12-15 | 1991-06-27 | Takeda Chemical Industries, Ltd. | Biospecific antibody to cancer cell and enzyme with prodrug-activating characteristics |
Cited By (6)
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EP1468077A2 (en) * | 2002-01-29 | 2004-10-20 | Immunogen, Inc. | Mutant actinosynnema pretiosum strain with increased maytansinoid production |
EP1468077A4 (en) * | 2002-01-29 | 2006-06-07 | Immunogen Inc | Mutant actinosynnema pretiosum strain with increased maytansinoid production |
US7192750B2 (en) | 2002-01-29 | 2007-03-20 | Immunogen Inc. | Mutant Actinosynnema pretiosum strain with increased maytansinoid production |
AU2003238752B2 (en) * | 2002-01-29 | 2008-05-29 | Immunogen, Inc. | Mutant actinosynnema pretiosum strain with increased maytansinoid production |
EP1806365A1 (en) | 2006-01-05 | 2007-07-11 | Boehringer Ingelheim International GmbH | Antibody molecules specific for fibroblast activation protein and immunoconjugates containing them |
CN100420754C (en) * | 2006-10-26 | 2008-09-24 | 浙江海正药业股份有限公司 | Method for preparing anthracene Ensamu bacterial |
Also Published As
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NZ521868A (en) | 2004-11-26 |
NO20024893D0 (en) | 2002-10-10 |
CA2406188A1 (en) | 2001-10-18 |
IL152241A0 (en) | 2003-05-29 |
US20020015984A1 (en) | 2002-02-07 |
NO20024893L (en) | 2002-10-10 |
AU9333501A (en) | 2001-10-23 |
HUP0300473A2 (en) | 2003-06-28 |
EP1272653A2 (en) | 2003-01-08 |
JP2003530114A (en) | 2003-10-14 |
WO2001077360A3 (en) | 2002-09-12 |
KR20030036159A (en) | 2003-05-09 |
ATE331804T1 (en) | 2006-07-15 |
US6573074B2 (en) | 2003-06-03 |
US20030157669A1 (en) | 2003-08-21 |
CZ20023356A3 (en) | 2003-04-16 |
AR028002A1 (en) | 2003-04-23 |
DE60121150D1 (en) | 2006-08-10 |
PL365577A1 (en) | 2005-01-10 |
HUP0300473A3 (en) | 2004-07-28 |
DE60121150T2 (en) | 2007-05-16 |
EP1272653B1 (en) | 2006-06-28 |
MXPA02010109A (en) | 2003-02-12 |
ZA200208159B (en) | 2003-10-17 |
BR0109975A (en) | 2004-03-23 |
AU2001293335B2 (en) | 2005-02-24 |
CN1432068A (en) | 2003-07-23 |
ES2266243T3 (en) | 2007-03-01 |
JP4832697B2 (en) | 2011-12-07 |
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