WO1997046251A1 - PEPTIDES IMMUNOREACTIFS PAR RAPPORT AUX aPL, LEURS CONJUGUES ET PROCEDES DE TRAITEMENT DES PATHOLOGIES DEPENDANTES DE L'ANTICORPS aPL - Google Patents
PEPTIDES IMMUNOREACTIFS PAR RAPPORT AUX aPL, LEURS CONJUGUES ET PROCEDES DE TRAITEMENT DES PATHOLOGIES DEPENDANTES DE L'ANTICORPS aPL Download PDFInfo
- Publication number
- WO1997046251A1 WO1997046251A1 PCT/US1997/010075 US9710075W WO9746251A1 WO 1997046251 A1 WO1997046251 A1 WO 1997046251A1 US 9710075 W US9710075 W US 9710075W WO 9746251 A1 WO9746251 A1 WO 9746251A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- apl
- phage
- antibody
- peptide
- analog
- Prior art date
Links
- 0 *C(COCCOCCOCCSCc1cc(CSCCOCCOCCOCC(*)=O)c(CSCCOCCOCCOCC(*)=O)cc1CSCCOCCOCCOCC(*)=O)=O Chemical compound *C(COCCOCCOCCSCc1cc(CSCCOCCOCCOCC(*)=O)c(CSCCOCCOCCOCC(*)=O)cc1CSCCOCCOCCOCC(*)=O)=O 0.000 description 1
- UTXIKCCNBUIWPT-UHFFFAOYSA-N BrCc1cc(CBr)c(CBr)cc1CBr Chemical compound BrCc1cc(CBr)c(CBr)cc1CBr UTXIKCCNBUIWPT-UHFFFAOYSA-N 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0008—Antigens related to auto-immune diseases; Preparations to induce self-tolerance
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/03—Peptides having up to 20 amino acids in an undefined or only partially defined sequence; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- 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
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- 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
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- 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
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
- C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
- C07K14/4713—Autoimmune diseases, e.g. Insulin-dependent diabetes mellitus, multiple sclerosis, rheumathoid arthritis, systemic lupus erythematosus; Autoantigens
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
- G01N33/54353—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals with ligand attached to the carrier via a chemical coupling agent
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/564—Immunoassay; Biospecific binding assay; Materials therefor for pre-existing immune complex or autoimmune disease, i.e. systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, rheumatoid factors or complement components C1-C9
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6878—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids in eptitope analysis
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/92—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving lipids, e.g. cholesterol, lipoproteins, or their receptors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
- A61K2039/6093—Synthetic polymers, e.g. polyethyleneglycol [PEG], Polymers or copolymers of (D) glutamate and (D) lysine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- Antiphospholipid antibodies occur in autoimmune diseases such as systemic lupus erythematosus (SLE) and antiphospholipid antibody syndrome (APS) as well as in association with infections and drug therapy.
- SLE systemic lupus erythematosus
- APS antiphospholipid antibody syndrome
- APS is characterized by one or more clinical features such as arterial or venous thrombosis, thrombocytopenia and fetal loss.
- APS may be primary or it may be associated with other conditions, primarily SLE (PHOSPHOLIPID-BINDING ANTIBODIES (Harris et al., eds., CRC Press, Boca Raton, FL, 1991); McNeil et al. ADVANCES IN IMMUNOLOGY, Vol. 49, pp.
- the invention also encompasses a method of biopanning phage random peptide libraries to identify and isolate peptides which bind to aPL antibody comprising: (a) reacting affinity-purified aPL antibody with phage bearing random peptide inserts; (b) recovering phage bearing random peptide inserts which bind to the aPL antibody; (c) infecting a microorganism with phage recovered in (b); and (d) culturing the infected microorganism in an antibiotic-containing medium in order to isolate the phage.
- aPL-specific epitope represent the analogs of the aPL-specific epitope. These peptides are then synthesized and ranked for strength of binding using competition assays.
- Another aspect of the invention is aPL antibody-binding analogs that bind specifically to B cells to which an aPL epitope binds. Optimized analogs lack T cell epitope(s).
- Figure 2 shows that resin-bound analog 5A12 immunospecifically binds to affinity-purified IgG designated ACA-6501.
- Figure 8 illustrates the dramatic drop in sequence diversity of the isolated clones by the fourth round of biopanning.
- Figure 9 illustrates that three clones (3A12, 3B3 and 3A5) exhibited a very strong immunospecific signal in the phage-capture ELISA using ACA-6635 whereas all clones tested were unreactive with normal IgG.
- the analog may be a peptide, carbohydrate, lipid, lipopolysaccharide, nucleic acid or other biochemical entity. Further, the chemical structure of neither the immunogen nor the analog need be defined for the purposes of this invention.
- the term “analog” of an immunogen also encompasses the term “mimotope.”
- the term “mimotope” intends a molecule which competitively inhibits the antibody from binding the immunogen. Because it specifically binds the antibody, the mimotope is considered to mimic the antigenic determinants of the immunogen.
- T cell epitopes can also be determined by measuring secretion of T cell-derived lymphokines by methods well known in the art. Analogs that fail to induce statistically significant incorporation of thymidine above background are deemed to lack T cell epitopes. It will be appreciated that the quantitative amount of thymidine incorporation may vary with the immunogen. Typically a stimulation index below about 2-3, more usually about 1-2, is indicative of a lack of T cell epitopes.
- Conjugation of the aPL antibody-binding analog to the valency platform molecule may be effected in any number of ways, typically involving one or more crosslinking agents and functional groups on the analog and valency platform molecule.
- the "y” library is the same as the “y”' library except that it lacks the 6 and 8 amino acid inserts. These peptide inserts for both “y” and “y' “ libraries are flanked by cysteine residues at both the amino and carboxyl ends to form cyclic, more rigid structures. Proline residues are incorporated outside these cysteine residues for reasons similar to those for the "x” libraries above.
- the "x,” “y' “, and “y” libraries are located five residues from the amino terminus of the native p-III protein.
- the "z” library consists of random eight amino acid inserts located at the amino terminus of the p-III protein and do not contain any flanking proline or cysteine residues. A combination of the "x,” “y' “ and “z” libraries represents eleven different libraries each with approximately one hundred million different peptide inserts.
- a Tolerogen For a Tolerogen to be generally effective, it must bind a major portion of the aPL antibodies in the majority of patients. It is important to determine if several antibodies from different patients bind identical residues within the eighty-four amino acid 5th domain of ⁇ 2 -GPI which has been suggested by others to contain the target epitope. If several antibodies bind identical residues, a single mimotope derived from the structural data of the peptides can be constructed which will react with all the antibodies. On the other hand, if the antibodies bind to different residues, a unique tolerogen would be required for each antibody. Site-directed mutagenesis was performed to identify if key residues involved in aPL antibody binding reside in the 5th domain of ⁇ 2 -GPI.
- BSA bovine serum albumin
- Phage to be tested by micropanning were obtained from the agar plates generated by biopanning. Each clone to be tested was transferred using sterile toothpicks to a separate well of a round-bottom 96-well microtitration plate (Corning, Corning, NY) containing 250 ⁇ L 2YT/Tet per well and cultured overnight at 37°C. Clone designations are based on the screening antibody, the biopanning round of origin, and the location of the clone in the overnight culture plate, e.g., ACA- 6501/3B10 refers to the clone isolated by ACA-6501 in the third round located in the well designated BIO on the microtitration plate. Following overnight incubation, phage cultures were centrifuged using a microtitration plate holder at 1300 x g for 10 minutes at RT. Supernatants constituted the source of "neat" phage.
- variable amounts of each of six peptides were mixed with 22 ⁇ L ACA-6501 serum diluted with 3% fish gelatin in 1 :1 TBS/PBS (final dilution of 1 :400) in a final volume of 220 ⁇ L using Eppendorf microcentrifuge tubes.
- tube #1 were mixed 181.3 ⁇ L of 3% fish gelatin in TBS-PBS, 16.7 ⁇ L of peptide stock solution plus 22 ⁇ L of ACA-6501 serum diluted 40 times in 3% fish gelatin/TBS -PBS.
- variable amounts of each of four test peptides were mixed with 22 ⁇ L of ACA-6501 serum diluted with sample diluent in a final volume of 220 ⁇ L using Eppendorf microcentrifuge tubes. Specifically, in tube #1, 188 ⁇ L of sample diluent, 10 ⁇ L of peptide stock solution (2 mg - 4 mg/mL diluent), and 22 ⁇ L of AC-6501 serum diluted 1 :35 in sample diluent were added. To tube #2, 158 ⁇ L sample diluent, 40 ⁇ L peptide stock solution and 22 ⁇ L of 1 :35 diluted ACA-6501 serum were added.
- the residue was triturated with 2 X 50 mL of Et 2 O and the white opaque residue was treated with 5 mL of 92/3/2/3 TFA/anisole/EDT/Me 2 S for 1 hour.
- the product was precipitated by adding the mixture to 40 mL of Et 2 O in a 50 mL polypropylene centrifuge tube. The precipitate was cooled to 0°C and centrifuged for 5 minutes at 2000 rpm. The supernatant was decanted and the pellet was washed with Et 2 O and recentrifuged. The pellet was dried and dissolved in 4 mL of 50/50 CH 3 CN/H 2 O.
- the thiobenzoate ester, compound 28 was prepared from compound 27.
- Example 15 Synthesis of a (LJP685) 4 /MTU-ATU-AHAB-TEG conjugate,
Abstract
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP10500927A JP2000512981A (ja) | 1996-06-06 | 1997-06-06 | aPL免疫応答性ペプチド、その結合体およびaPL抗体媒介病理のための処置方法 |
AU36404/97A AU734638B2 (en) | 1996-06-06 | 1997-06-06 | aPL immunoreactive peptides, conjugates thereof and methods of treatment for aPL antibody-mediated pathologies |
EP97933138A EP0954531A1 (fr) | 1996-06-06 | 1997-06-06 | PEPTIDES IMMUNOREACTIFS PAR RAPPORT AUX aPL, LEURS CONJUGUES ET PROCEDES DE TRAITEMENT DES PATHOLOGIES DEPENDANTES DE L'ANTICORPS aPL |
CA002256449A CA2256449A1 (fr) | 1996-06-06 | 1997-06-06 | Peptides immunoreactifs par rapport aux apl, leurs conjugues et procedes de traitement des pathologies dependantes de l'anticorps apl |
NO985636A NO985636L (no) | 1996-06-06 | 1998-12-03 | aPL immunoreaktive peptider, konjugater derav og metoder for behandling av aPL antistoff-medierte patologier |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/660,092 | 1996-06-06 | ||
US08/660,092 US6207160B1 (en) | 1995-06-07 | 1996-06-06 | aPL immunoreactive peptides, conjugates thereof and methods of treatment for aPL antibody-mediated pathologies |
US76050896A | 1996-12-05 | 1996-12-05 | |
US08/760,508 | 1996-12-05 |
Publications (2)
Publication Number | Publication Date |
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WO1997046251A1 true WO1997046251A1 (fr) | 1997-12-11 |
WO1997046251A9 WO1997046251A9 (fr) | 1998-06-04 |
Family
ID=27097975
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1997/010075 WO1997046251A1 (fr) | 1996-06-06 | 1997-06-06 | PEPTIDES IMMUNOREACTIFS PAR RAPPORT AUX aPL, LEURS CONJUGUES ET PROCEDES DE TRAITEMENT DES PATHOLOGIES DEPENDANTES DE L'ANTICORPS aPL |
Country Status (7)
Country | Link |
---|---|
EP (1) | EP0954531A1 (fr) |
JP (1) | JP2000512981A (fr) |
KR (1) | KR20000016414A (fr) |
AU (1) | AU734638B2 (fr) |
CA (1) | CA2256449A1 (fr) |
NO (1) | NO985636L (fr) |
WO (1) | WO1997046251A1 (fr) |
Cited By (71)
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WO1999064595A1 (fr) * | 1998-06-09 | 1999-12-16 | La Jolla Pharmaceutical Company | POLYPEPTIDES β2GPI THERAPEUTIQUES ET DIAGNOSTIQUES DE DOMAINE 1 ET PROCEDES D'UTILISATION CORRESPONDANTS |
US6040136A (en) * | 1990-12-03 | 2000-03-21 | Genentech, Inc. | Enrichment method for variant proteins with altered binding properties |
WO2001013110A2 (fr) * | 1999-08-17 | 2001-02-22 | Osteometer Biotech A/S | Reactions auto-immunes specifiques contre des epitopes isomerises/optiquement inverses: application destinee au diagnostic des maladies auto-immunes |
US6197526B1 (en) | 1999-01-04 | 2001-03-06 | Dyax Corp. | Polypeptides for binding human factor VIII and fragments of human factor VIII |
US6207160B1 (en) | 1995-06-07 | 2001-03-27 | La Jolla Pharmaceutical Company | aPL immunoreactive peptides, conjugates thereof and methods of treatment for aPL antibody-mediated pathologies |
WO2001032858A1 (fr) * | 1999-11-05 | 2001-05-10 | Novozymes A/S | Procede de criblage a haut debit (hts) |
US6238860B1 (en) | 1998-11-05 | 2001-05-29 | Dyax Corp. | Binding moieties for human parvovirus B19 |
US6399578B1 (en) | 1998-12-09 | 2002-06-04 | La Jolla Pharmaceutical Company | Conjugates comprising galactose α1,3 galactosyl epitopes and methods of using same |
WO2002064612A2 (fr) | 2001-02-09 | 2002-08-22 | Human Genome Sciences, Inc. | Recepteur de chemokine de la g-proteine humaine (ccr5) hdgnr10 |
US6458953B1 (en) | 1998-12-09 | 2002-10-01 | La Jolla Pharmaceutical Company | Valency platform molecules comprising carbamate linkages |
WO2006028742A2 (fr) | 2004-09-01 | 2006-03-16 | Dynavax Technologies Corporation | Procedes et compositions permettant d'inhiber des reponses immunitaires innees et auto-immunite correspondante |
US7081242B1 (en) | 1999-11-28 | 2006-07-25 | La Jolla Pharmaceutical Company | Methods of treating lupus based on antibody affinity and screening methods and compositions for use thereof |
US7112438B2 (en) | 1999-01-04 | 2006-09-26 | Dyax Corp. | Binding molecules for human factor VIII and factor VIII-like proteins |
US7118872B2 (en) | 2000-08-18 | 2006-10-10 | Dyax Corp. | Binding polypeptides for B lymphocyte stimulator protein (BLyS) |
US7255868B2 (en) | 2001-06-21 | 2007-08-14 | Dynavax Technologies Corporation | Chimeric immunomodulatory compounds and methods of using the same—I |
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WO2009154025A1 (fr) | 2008-06-20 | 2009-12-23 | 国立大学法人岡山大学 | ANTICORPS CONTRE UN COMPLEXE LDL/β2GPI OXYDÉ ET SON UTILISATION |
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WO2018200742A1 (fr) | 2017-04-25 | 2018-11-01 | The Usa, As Represented By The Secretary, Dept. Of Health And Human Services | Anticorps et procédés de diagnostic et de traitement d'infection par le virus d'epstein barr |
EP4230649A2 (fr) | 2017-04-25 | 2023-08-23 | The U.S.A. As Represented By The Secretary, Department Of Health And Human Services | Anticorps et procédés de diagnostic et de traitement d'infection par le virus d'epstein barr |
WO2019018629A1 (fr) | 2017-07-19 | 2019-01-24 | The Usa, As Represented By The Secretary, Dept. Of Health And Human Services | Anticorps et procédés de diagnostic et de traitement d'infection par le virus de l'hépatite b |
WO2020227554A1 (fr) | 2019-05-09 | 2020-11-12 | Genentech, Inc. | Procédés de préparation d'anticorps |
CN112480209A (zh) * | 2020-11-16 | 2021-03-12 | 昆明学院 | 一种抗皮肤光损伤保护活性多肽rl-pl9及其应用 |
Also Published As
Publication number | Publication date |
---|---|
NO985636L (no) | 1999-02-08 |
JP2000512981A (ja) | 2000-10-03 |
EP0954531A1 (fr) | 1999-11-10 |
AU3640497A (en) | 1998-01-05 |
KR20000016414A (ko) | 2000-03-25 |
NO985636D0 (no) | 1998-12-03 |
AU734638B2 (en) | 2001-06-21 |
EP0954531A4 (fr) | 1999-08-31 |
CA2256449A1 (fr) | 1997-12-11 |
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