EP0870030A1 - Polypeptide mit il-16-aktivität, verfahren zu ihrer herstellung und verwendung - Google Patents
Polypeptide mit il-16-aktivität, verfahren zu ihrer herstellung und verwendungInfo
- Publication number
- EP0870030A1 EP0870030A1 EP96944582A EP96944582A EP0870030A1 EP 0870030 A1 EP0870030 A1 EP 0870030A1 EP 96944582 A EP96944582 A EP 96944582A EP 96944582 A EP96944582 A EP 96944582A EP 0870030 A1 EP0870030 A1 EP 0870030A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- seq
- polypeptide
- nucleic acid
- sequence
- ser
- 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.)
- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/52—Cytokines; Lymphokines; Interferons
- C07K14/54—Interleukins [IL]
- C07K14/5446—IL-16
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- LL-16 Interleukin-16 is a lymphokine, which is also known as "lymphocyte chemoattracting factor” (LCF) or “immunodeficiency virus suppressing lymphokine” (ISL).
- LCF lymphocyte chemoattracting factor
- ISL immunodeficiency virus suppressing lymphokine
- IL-16 and its properties are described in WO 94/28134, WO 96/31607 and by Cruikshank, W W, et al, Proc Natl Acad. Be USA 91 (1994) 5109-51 13 and described by Baier, M, et al., Nature 378 (1995) 563.
- the recombinant production of IL-16 is also described there.
- IL-16 is a protein with a molecular mass of 13.385 D.
- the object of the present invention is to improve the activity of LL-16 and to provide LL-16 forms which show low immunogenicity and are advantageously suitable for therapeutic use.
- the object of the invention is achieved by a nucleic acid with which the expression of a polypeptide with interleukin-16 activity can be achieved in a prokaryotic or eukaryotic host cell, said nucleic acid in the region coding for said polypeptide
- a) corresponds to the DNA sequence nucleotides 54-1175 from SEQ LD NO 1 or its complementary strand
- Such a nucleic acid preferably encodes a polypeptide with improved LL-16 activity, particularly preferably improved natural LL-16 from primates, such as human LL-16 or LL-16 of a monkey species or another mammal, such as a mouse.
- Fig. 2 of WO 94/28134 does not describe the correct sequence of LL-16.
- the start codon "ATG” does not begin with nucleotide 783, but with nucleotide 54.
- This reading frame is obtained if an A is inserted after nucleotide 156, a C after nucleotide 398 and a G after nucleotide 780.
- the correct reading frame is shown in SEQ LD NO: 1.
- This sequence shows still further differences from FIG. 2 of WO 94/28134. However, these are only nucleotide exchanges (eg 313 G in A, 717 C in A).
- the nucleic acid according to the invention also codes for a polypeptide which can be processed in its production.
- Such a polypeptide which is thus extended compared to the LL-16 known from WO 94/28134, shows an improved activity.
- Monomeric LL-16 with improved activity has a molecular weight of 13.9-39 kD, preferably approximately 15-35 kD, and is thus up to three times as large as the C-terminal LL-16 described in WO 94/28134 Fragment
- the sequence of LL-16 can differ to a certain extent from the protein sequences encoded by such DNA sequences.
- sequence variations of LL-16 muteins can be amino acid exchanges, deletions or additions.
- amino acid sequence of LL-16 is preferably at least 75%, particularly preferably at least 90% identical to the amino acid sequence of SEQ LD NO 1
- Variants of parts of the amino and nucleic acid sequence SEQ LD NO 1 / SEQ ID NO.2 are for example in the international application WO 96/31607 and German patent application 195 47 933 5 described
- Particularly preferred IL-16 muteins with improved activity begin at the N-terminus with amino acids 235-244 from SEQ LD NO.1 / 2 or a part thereof. Particularly preferred N-termini are described in SEQ LD NO 3-12
- the LL muteins with improved activity at the C-terminus can be shortened by preferably 1-20 amino acids.
- IL-16 is to be understood as meaning a polypeptide with the activity of LL-16 or preferably with an improved activity.
- LL-16 preferably shows the stated effect in the test method described in international application WO 96/31607 or stimulates cell division according to WO 94/28134
- viruses preferably HTV-1, HLV-2 or SIV.
- hybridize under stringent conditions means that two nucleic acid fragments hybridize with one another under standardized hybridization conditions, as described, for example, in Sambrook et al., "Expression of cloned genes in E. coli” in Molecular Cloning: A laboratory manual (1989) , Cold Spring Harbor Laboratory Press, New York, USA.
- Such conditions are, for example, hybridization in 6.0 x SSC at about 45 ° C, followed by a washing step at 2 x SSC at 50 ° C.
- the salt concentration in the washing step can be selected, for example, between 2.0 x SSC at 50 ° C for low stringency and 0.2 x SSC at 50 ° for high stringency.
- the temperature of the wash step can be varied between room temperature, approx. 22 ° C for low stringency and 65 ° C for high stringency.
- LL-16 is preferably produced recombinantly in prokaryotic or eukaryotic host cells. Such production methods are described, for example, in WO 94/28134 and WO 96/31607, which are also the subject of the disclosure of the present invention for this purpose. However, in order to define and reproducibly obtain the forms of LL-16 according to the invention by recombinant production, additional measures must be taken via the recombinant production processes familiar to the person skilled in the art.
- Recombinant LL-16 can be produced by the methods familiar to the person skilled in the art.
- a DNA is first produced which is able to produce a protein which has the activity of LL-16.
- the DNA is cloned into a vector that can be transferred to a host cell and replicable there.
- a vector contains operator elements which are necessary for the expression of the DNA sequence.
- This vector which contains the LL-16 sequence and the operator elements, is transferred into a vector which is able to express the DNA of LL-16.
- the host cell is cultivated under conditions which are suitable for the amplification of the vector, and LL-16 is obtained. Appropriate measures are taken to ensure that the protein can assume an active tertiary structure in which it shows LL-16 properties
- the nucleic acid sequence of the protein can also be modified. Such modifications are, for example.
- the protein is preferably expressed in microorganisms, in particular in prokaryotes, and there in E. coli
- the expression vectors must contain a promoter which allows expression of the protein in the host organism.
- promoters are known to the person skilled in the art and are, for example, lac promoter (Chang et al., Nature 198 (1977) 1056), trp promoter (Goeddel et al., Nuc. Acids Res. 8 (1980) 4057), ⁇ PL promoter (Shimatake et al, Nature 292 (1981) 128) and T5 promoter (U.S. Patent No. 4,689,406).
- Synthetic promoters such as the tac promoter (US Pat. No. 4,551,433) are also suitable.
- Coupled promoter systems such as the T7 RNA polymerase / promoter system are also suitable (Studier et al, J Mol. Biol. 189 (1986) 113). .
- Hybrid promoters comprising a bacteriophage promoter and the operator region of the microorganism are also suitable (EP-A 0 267 851).
- an effective ribosome binding site is required.
- this ribosome binding site is referred to as the Shine-Dalgarno (SD) sequence (Sambrook et al., "Expression of cloned genes in E. coli" in Molecular Cloning: A laboratory manual
- a DNA sequence which codes for the N-terminal part of an endogenous bacterial protein or another stable protein is usually attached to the 5'- End of the sequence coding for LL-16 fused. Examples include lacZ (Phillips and Silhavy, Nature 344 (1990) 882-884), trpE (Yansura, Meth. Enzymol. 185
- the fusion proteins are preferably cleaved with enzymes (Carter P. in Ladisch, MR et al. Eds., Protein Purification: From Molecular Mechanisms to Large-Scale Processes, ACS Symposium Series No. 427, American Chemical Society (1990) 181-193).
- cleavage sites are the IgA protease cleavage site (WO 91/11520, EP-A 0 495 398), the ubiquitin cleavage site (Miller et al., Bio / Technology 7 (1989) 698), the enterokinase cleavage site (Maroux et al., J. Biol. Chem. 241 (1971) 5031) and the Factor Xa cleavage site (Nagai et al., Nature 309 (1984) 810).
- the proteins expressed in this way in bacteria are obtained in a conventional manner by digesting the bacteria and isolating the proteins.
- a fusion product is preferably used, which consists of the signal sequence which is suitable for the secretion of proteins in the host organisms used and the nucleic acid which codes for the protein.
- the protein is either secreted into the medium (for gram-positive bacteria) or into the periplasmic space (for gram-negative bacteria).
- a cleavage site is expediently provided, which allows the protein to be split off either during processing or in an additional step.
- signal sequences originate, for example, from ompA (Ghrayeb et al., EMBO J. 3 (1984) 2437), phoA (Oka et al., Proc. Natl. Acad. Sci. USA 82 (1985) 7212).
- Terminators are DNA sequences that signal the end of a transcription process. They are usually characterized by two structural peculiarities: an inversely repetitive G / C-rich region, the intramolecular can form a double helix and a number of U (or T) residues. Examples are the main terminator in the DNA of phage fd (Beck and Zink, Gene 16 (1981) 35-58) and rrnB (Brosius et al, J Mol Biol 148 (1981) 107-127)
- the expression vectors usually contain a selectable marker in order to select transformed cells.
- selectable markers are, for example, the resistance genes for ampicillin, chloramphenicol, erythromycin, kanamycin, neomycin and tetracycline (Davies et al, Ann Rev Microbiol 32 (1978) 469)
- ⁇ Bable markers are the genes for essential substances of the biosynthesis of substances necessary for the cell, such as histidine, tryptophan and leucine
- vectors are described for the following bacteria: Bacillus subtilis (Palva et al, Proc Natl Acad Sei USA 79 (1982) 5582), E. coli (Aman et al, Gene 40 (1985) 183, Studier et al, J Mol Biol 189 (1986) 1 13), Streptococcus cremoris (Powell et al, Appl Environ Microbiol 54 (1988) 655), Streptococcus lividans and Streptomyces lividans (U.S. Patent No. 4,747,056)
- yeast integrating YIp (yeast integrating plasmids) - vectors, replicating YRp (yeast replicon plasmids) - vectors and episomal YEp (yeast episomal plasmids) - vectors take place. Details on this are described, for example, in SM Kingsman et al, Tibtech 5 (1987) 53-57
- Another object of the invention is a prokaryotic or eukaryotic host cell which is transformed or transfected with a nucleic acid which codes for an LL-16 polypeptide according to the invention in such a way that the host cell expresses said polypeptide.
- a host cell usually contains one biologically functional nucleic acid vector, preferably a DNA vector, a plasmid DNA which contains this nucleic acid
- the invention furthermore relates to human interleukin-16 or interleukin-16 from primates, preferably human LL-16 with improved activity, as is obtainable as a product of prokaryotic or eukaryotic expression essentially free of other human proteins.
- LL-16 is a protein which occurs as a monomer or as a multimer consisting of monomeric LL-16 (hereinafter also referred to as subunits).
- the molecular weight of a monomeric LL-16 subunit is preferably 13.9-39 kD, particularly preferably 15-35 kD.
- nucleic acid and protein sequence of LL-16 described in WO 94/28134 do not correspond to the natural human sequences. This is just an LL-16 fragment with a non-natural N-terminus.
- a protein which is either identical to the natural protein or differs only slightly from the natural protein and / or shows at least comparable, preferably improved activity and immunogenicity.
- natural unprocessed or not yet secreted LL-16 contrary to the previous assumption, is a larger protein with a molecular weight of 13.9-39 kD. Its sequence is contained in the sequence records.
- polypeptides of the invention can additionally contain a defined content of metal ions, the number of metal ions per subunit preferably being 0.5 to 2.
- metal ions are suitable as metal ions in the sense of the invention, which are added in a defined amount in the preparation of the multimeric forms of LL-16.
- alkaline earth metals and elements of the subgroups are suitable.
- Alkaline earth metals, cobalt, zinc, selenium, manganese, nickel, copper, iron, magnesium, calcium, molybdenum and silver are particularly suitable.
- the ions can be one, two, three or tetravalent. Divalent ions such as Cu (II) ions are particularly preferred.
- the ions are preferably added as solutions of MgCl2, CaCl2, MnCl2, BaCl2, LiCl 2 , Sr (N ⁇ 3) 2 , Na 2 MoO 4 , AgCl 2 or Cu (II) acetate.
- the polypeptide according to the invention can be prepared by cultivating a prokaryotic or eukaryotic host cell which has been transformed or transfected with a nucleic acid sequence according to claims 1 or 2 under suitable nutrient conditions and, if appropriate, isolating the desired polypeptide. If the preparation of the polypeptide in If a gene therapy treatment is to take place in vivo, the polypeptide is of course not isolated from the cell.
- polypeptides according to the invention are particularly suitable for the treatment of pathological conditions which are caused by viral replication, in particular retroviral replication, and for immunomodulation.
- pathological conditions which are caused by viral replication, in particular retroviral replication, and for immunomodulation.
- diagnostic test methods are also described in the latter
- the polypeptides according to the invention can preferably be used for immunosuppression. This immunosuppression is preferably carried out by inhibiting the helper function of the THQ and / or TH] and TH2 cells.
- the polypeptides according to the invention are accordingly of therapeutic value in all diseases in which an immune-regulatory component is postulated in the pathogenesis, in particular hyperimmunity.
- myocarditis, endocarditis and pericarditis can be considered as EL-16-treatable diseases in cardiology / angiology, for example in pulmonology wise bronchitis, asthma, in hematology autoimmune Europe and transplant rejection, in gastroenterology chronic gastritis, in endocrinology diabetes mellitus type I, in nephrology glomerulonephritis, diseases in the rheumatic type, diseases in ophthalmology, in neurology, such as multiple sclerosis , in dermatology eczema.
- the polypeptides according to the invention can be used in autoimmune diseases, allergies and to avoid transplant rejections
- Another object of the invention is the use of the nucleic acids according to the invention in the context of gene therapy.
- Vector systems suitable for this are, for example, retroviral or non-viral vector systems
- Another object of the invention is a polyclonal or monoclonal anti-LL-16 antibody or an immunoactive fragment thereof and methods for producing such antibodies and their use for the determination of LL-16 and for the determination of viral infections in eukaryotic cells and in particular in Suction cell material.
- LL-16 can also be used to determine virus-activated mammalian cells, in particular T cells.
- the production of such antibodies is carried out by immunization with a polypeptide according to the invention, which preferably corresponds essentially to the sequence amino acids 1-244 from SEQ LD NO 1/2 and which binds to such a peptide.
- An antibody is preferably used which does not bind to the polypeptide of the sequence amino acids 245-374 from SEQ LD NO 1/2.
- the production of such an antibody is carried out according to the methods familiar to the person skilled in the art
- RNA isolation kit RNA isolation kit, Stratagene
- the lysate was kept on ice for 15 min.
- the aqueous phase was then mixed with 6 ml of isopropanol to precipitate the RNA and Stored for 2 hours at -20 ° C.
- the precipitate was finally washed once with pure ethanol and dissolved in 150 ⁇ l H2O.
- the yield was determined photometrically and was 120 ⁇ g
- the mixture for the cDNA synthesis contained 10 ⁇ g RNA, 0.2 ⁇ g oligo-dT, 13 mM DTT and 5 ⁇ l “bulk first strand reaction mix” (first-strand cDNA synthesis kit, Pharmacia) in an amount of 15 ⁇ l.
- the mixture was incubated at 37 ° C for 1 hour and then stored at -20 ° C for later use
- Amplification, cloning of LL-16 cDNA and production of an expression clone are carried out as described in WO 94/28134 or WO 96/31607, taking into account the changed sequences.
- an N-terminal extension by several histidine residues is required
- Pre-cultures are prepared from stock cultures (plate smear or ampoules stored at -20 ° C), which are shaken and incubated at 37 ° C.
- the volume in the next higher dimension is 1-10% by volume.
- Ampicillin 50-100 mg / l
- Enzymatically digested protein and / or yeast extract as the N and C source and glycerol and / or glucose as the additional C source are used as nutrients.
- the medium is buffered to pH 7 and metal salts are added in physiologically acceptable concentrations to stabilize the fermentation process.
- the fermentation is carried out as a feed batch with a mixed yeast extract / C-source dosage.
- the fermentation temperature is 25-37 ° C.
- the aeration rate, speed control and dosage rate keep the dissolved oxygen partial pressure (p ⁇ 2) ⁇ 20%
- the column was then rinsed with 300 ml of 50 mM sodium phosphate, 0.5 M NaCl, pH 7.0 and the LL-16 fusion protein then with a gradient of 0 M to 300 mM imidazole, pH 7.0 in 50 mM sodium phosphate, 0.1 M NaCl, pH 7.0 (2 * 0.5 1 gradient volume) eluted.
- Fractions containing LL-16 were identified by SDS-PAGE and combined.
- 300 mg of the fusion protein thus obtained were dialyzed at 4 ° C. against 20 1 20 mM imidazole, pH 5.5 and then for 30 minutes to remove turbidity. centrifuged at 20,000 g. The supernatant from the centrifugation was then adjusted to pH 8.5 with NaOH, 0.3 mg of thrombin (Boehringer Mannheim GmbH) was added and the mixture was incubated at 37 ° C. for 4 hours. The gap was then adjusted to pH 6.5 with HCl and the conductivity was adjusted to 1.7 mS by dilution with H 2 O.
- the sample was applied to a Q-Sepharose FF column (45 ml; Pharmacia), which had previously been equilibrated with 20 mM imidazole, pH 6.5.
- LL-16 was eluted with a gradient of 0 to 0.3 M NaCl in 20 mM imidazole, pH 6.5.
- Fractions containing LL-16 were identified by SDS-PAGE, pooled and the LL-16 identity confirmed by mass analysis and N-terminal sequence analysis.
- the LL-16 obtained in this way had a purity of more than 95% in SDS-PAGE under reducing conditions.
- the analytical Superdex 75 FPLC column (Pharmacia) was treated with 25 mM Na phosphate, 0.5 M NaCl, 10% glycerol, pH 7.0 and a flow rate of 1 ml / min. eluted.
- the amount of protein applied in a volume of 100 to 150 ⁇ l was 1.5 to 15 ⁇ g protein.
- the detection took place at 220 nm.
- a Vydac, Protein & Peptide C18, 4x180 mm column was used for purity analysis using RP-HPLC.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Zoology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Animal Behavior & Ethology (AREA)
- Molecular Biology (AREA)
- Immunology (AREA)
- Veterinary Medicine (AREA)
- Toxicology (AREA)
- General Chemical & Material Sciences (AREA)
- Gastroenterology & Hepatology (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Virology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Peptides Or Proteins (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
Abstract
Description
Claims
Applications Claiming Priority (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19548295 | 1995-12-22 | ||
DE19548295 | 1995-12-22 | ||
DE19603492 | 1996-01-31 | ||
DE19603492 | 1996-01-31 | ||
DE19613866 | 1996-04-06 | ||
DE19613866 | 1996-04-06 | ||
DE19613886 | 1996-04-06 | ||
DE19613886 | 1996-04-06 | ||
PCT/EP1996/005662 WO1997023616A1 (de) | 1995-12-22 | 1996-12-17 | Polypeptide mit il-16-aktivität, verfahren zu ihrer herstellung und verwendung |
Publications (1)
Publication Number | Publication Date |
---|---|
EP0870030A1 true EP0870030A1 (de) | 1998-10-14 |
Family
ID=27438251
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP96944582A Withdrawn EP0870030A1 (de) | 1995-12-22 | 1996-12-17 | Polypeptide mit il-16-aktivität, verfahren zu ihrer herstellung und verwendung |
Country Status (7)
Country | Link |
---|---|
US (1) | US6207144B1 (de) |
EP (1) | EP0870030A1 (de) |
JP (1) | JP2000504561A (de) |
AU (1) | AU1301797A (de) |
CA (1) | CA2239704A1 (de) |
DE (1) | DE19681160D2 (de) |
WO (1) | WO1997023616A1 (de) |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE19614099A1 (de) * | 1996-04-10 | 1997-10-16 | Bundesrep Deutschland | Genomische Nukleinsäuren, die für Polypeptide mit IL-16-Aktivität codieren, Verfahren zu ihrer Herstellung und Verwendung |
US6444202B1 (en) | 1996-11-25 | 2002-09-03 | Bundesrepublic Deutschland, Vertreten Durch Den Bundesminister Fur Gesundheit | Processed polypeptides with IL-16 activity, processes for their production and their use |
BR9907216A (pt) * | 1998-01-24 | 2000-10-24 | Bundesrep Deutschland | Mutantes de il-16, processos para sua produção e utilização dos mesmos |
WO2004075855A2 (en) | 2003-02-26 | 2004-09-10 | Biomed Solutions, Llc | Process for in vivo treatment of specific biological targets in bodily fluid |
WO2008009079A2 (en) | 2006-07-20 | 2008-01-24 | Gilead Sciences, Inc. | Substituted pteridines useful for the treatment and prevention of viral infections |
WO2008009078A2 (en) | 2006-07-20 | 2008-01-24 | Gilead Sciences, Inc. | 4,6-dl- and 2,4,6-trisubstituted quinazoline derivatives useful for treating viral infections |
SI3097102T1 (en) | 2015-03-04 | 2018-02-28 | Gilead Sciences, Inc. | A TOOL RECEPTOR MODULING 4,6-DIAMINO-PYRIDO (3,2-D) PYRIMIDINE COMPOUNDS |
US10370342B2 (en) | 2016-09-02 | 2019-08-06 | Gilead Sciences, Inc. | Toll like receptor modulator compounds |
ES2826748T3 (es) | 2016-09-02 | 2021-05-19 | Gilead Sciences Inc | Derivados de 4,6-diamino-pirido[3,2-d]pirimidina como moduladores de receptores de tipo Toll |
TWI751516B (zh) | 2019-04-17 | 2022-01-01 | 美商基利科學股份有限公司 | 類鐸受體調節劑之固體形式 |
TWI751517B (zh) | 2019-04-17 | 2022-01-01 | 美商基利科學股份有限公司 | 類鐸受體調節劑之固體形式 |
TW202115056A (zh) | 2019-06-28 | 2021-04-16 | 美商基利科學股份有限公司 | 類鐸受體調節劑化合物的製備方法 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4624926A (en) * | 1981-01-02 | 1986-11-25 | The Research Foundation Of State University Of New York | Novel cloning vehicles for polypeptide expression in microbial hosts |
EP1155700A3 (de) * | 1993-05-21 | 2002-01-02 | Research Corporation Technologies, Inc | Chemoattraktion-auslösender Faktor aus Lymfozyten und dessen Verwendungen |
DE19513152A1 (de) | 1995-04-07 | 1996-10-10 | Bundesrep Deutschland | Verwendung eines "Immundefizienzvirus-supprimierenden Lymphokins (ISL)" zur Hemmung der Virusvermehrung, insbesondere von Retroviren |
-
1996
- 1996-12-17 AU AU13017/97A patent/AU1301797A/en not_active Abandoned
- 1996-12-17 WO PCT/EP1996/005662 patent/WO1997023616A1/de not_active Application Discontinuation
- 1996-12-17 EP EP96944582A patent/EP0870030A1/de not_active Withdrawn
- 1996-12-17 CA CA002239704A patent/CA2239704A1/en not_active Abandoned
- 1996-12-17 DE DE19681160T patent/DE19681160D2/de not_active Ceased
- 1996-12-17 JP JP9523287A patent/JP2000504561A/ja active Pending
- 1996-12-17 US US09/091,405 patent/US6207144B1/en not_active Expired - Fee Related
Non-Patent Citations (1)
Title |
---|
See references of WO9723616A1 * |
Also Published As
Publication number | Publication date |
---|---|
US6207144B1 (en) | 2001-03-27 |
CA2239704A1 (en) | 1997-07-03 |
WO1997023616A1 (de) | 1997-07-03 |
JP2000504561A (ja) | 2000-04-18 |
DE19681160D2 (de) | 1999-07-01 |
AU1301797A (en) | 1997-07-17 |
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