EP1198244A2 - Strategie pour des vaccins therapeutiques a base de glucides - Google Patents

Strategie pour des vaccins therapeutiques a base de glucides

Info

Publication number
EP1198244A2
EP1198244A2 EP00951149A EP00951149A EP1198244A2 EP 1198244 A2 EP1198244 A2 EP 1198244A2 EP 00951149 A EP00951149 A EP 00951149A EP 00951149 A EP00951149 A EP 00951149A EP 1198244 A2 EP1198244 A2 EP 1198244A2
Authority
EP
European Patent Office
Prior art keywords
sialic acid
cells
polysialic
conjugate
modified
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Withdrawn
Application number
EP00951149A
Other languages
German (de)
English (en)
Inventor
Harold J. Jennings
Subash Sad
Zhongwu Guo
Tianmin Liu
Qinling Yang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
National Research Council of Canada
Original Assignee
National Research Council of Canada
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by National Research Council of Canada filed Critical National Research Council of Canada
Publication of EP1198244A2 publication Critical patent/EP1198244A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7012—Compounds having a free or esterified carboxyl group attached, directly or through a carbon chain, to a carbon atom of the saccharide radical, e.g. glucuronic acid, neuraminic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7008—Compounds having an amino group directly attached to a carbon atom of the saccharide radical, e.g. D-galactosamine, ranimustine
    • 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
    • A61K39/0011—Cancer antigens
    • A61K39/001169—Tumor associated carbohydrates
    • 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
    • A61K39/02—Bacterial antigens
    • A61K39/095—Neisseria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/515—Animal cells
    • A61K2039/5152—Tumor cells
    • 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
    • A61K2039/6031—Proteins
    • A61K2039/6037—Bacterial toxins, e.g. diphteria toxoid [DT], tetanus toxoid [TT]

Definitions

  • This invention relates to the field of medical treatments and therapeutic compositions for use therein. More specifically, it relates to methods and compositions for treatment and prophylaxis of cancer in human patients.
  • Creating cancer vaccines is problematic, due largely to the fact that patients fail to mount an effective immune response to cancerous cells, because cancer cells fail to produce immunogenic markers that sufficiently distinguish them from normal cells. Although the patterns of cell surface carbohydrate antigens of cancer cells differ from those of normal cells, the individual structures of their antigens are identical.
  • the antibodies so induced are usually of low titer and poor endurance (mostly IgM). Despite this drawback, they are used, on the basis that, after surgical or chemical treatment of cancer, the antibody levels will remain sufficiently high, during a short convalescence period, to dispose of any remaining cancer cells.
  • Polysialic acid is expressed in a number of important human cancers, including small cell lung cancer, neuroblastoma and Wilms' tumor. It is strongly expressed in neonatal tissue, but is not prevalently expressed in normal human tissue following the neonatal period (1 month). Normal cells express a variety of different sialylated surface antigens.
  • a modified B polysaccha de of N. meninqitidis is prepared chemically, from the polysacchahde isolated from N. meninqitidis.
  • the modified polysacchahde has sialic acid residue N-acetyl groups (C 2 ) replaced by a saturated or unsaturated C 3 . 5 acyl group.
  • This modified polysacchahde is conjugated to an immunologically suitable protein to produce a conjugate of enhanced immunogenicity.
  • a mammal may be immunized with the vaccine composition, to induce a specific immune response in the animal suitable to provide active protection from N. meninqitidis infection.
  • blood may be collected and the gamma globulin fraction may be separated from the immune serum, to provide a fraction for administration to a suitable subject to provide passive protection against or to treat on-going infection caused by these microorganisms.
  • N-propionylated and N- levulinoyl-D-mannosamine as precursors.
  • N-propionylated-D- mannose was introduced into a cancer cell line (hepatoma).
  • the sialic acid component of a sialic acid unit-containing cell surface marker characteristic of cancerous mammalian cells is modified so that cells normally expressing such a marker express instead a modified sialic acid unit-containing cell surface marker which is strongly immunogenic.
  • the present invention enables, in a portion of patient cells which regularly express ⁇ 2-8 polysialic acid (i.e. various types of cancer cells), the expression of a highly immunogenic surface antigen namely, modified ⁇ 2-8 sialic acid.
  • Antibodies specific for the modified antigen which can be induced using a conjugate of a suitable portion of the modified sialic acid unit- containing marker (such as ⁇ 2-8 polysialic acid) and a protein, can then be used to eliminate cells such as the aforementioned cancer cells which express ⁇ 2-8 polysialic acid.
  • Vaccines can be prepared utilizing conjugates of the modified sialic acid-containing marker (such as modified ⁇ 2-8 polysialic acid), or utilizing antibodies produced in response to exposure of a suitable subject to the modified sialic acid-containing marker, for managing cancer conditions which involve cancer cells characterized, at least in part, by expression of modified sialic acid unit containing marker.
  • Appropriate antibodies can be induced in the patient using a modified polysialic acid-protein conjugates such as an N-acylated- ⁇ 2-8 polysialic acid-protein conjugate, or alternatively the antibody can be raised outside the patient's body, by known techniques such as hybridoma incubation, and administered passively to the patient following antigen modification.
  • a process of enhancing the specific immunogenicity of viable, proliferating mammalian cancer cells to levels sufficient to allow the effective recognition and destruction of such cells by an immuno-response in vivo which comprises providing to said cells a chemically modified precursor of a suitable sialic acid unit- containing cell surface marker capable of rendering said cancer cells immunologically distinctive from related, normal cells; causing biochemical incorporation of said modified precursor into the sialic acid unit-containing cell surface marker during intracellular synthetic processes; and eventual surface expression of said sialic acid unit-containing surface marker incorporating said modified precursor in a form capable of eliciting said level of immune response.
  • a further aspect of the invention comprises immunogenic mammalian cancer cells, said cells having surface markers incorporating modified sialic acid units capable of initiating an immune response in the mammalian system containing them which is sufficiently strong to effectively combat the proliferation and even the viability of such cells.
  • a further aspect of the invention provides a conjugate of a modified ⁇ 2-8 polysialic acid incorporating N-acylated D-mannosamine units and a protein and the use of the conjugate in the preparation of a vaccine for managing cancer conditions in mammalian patients.
  • Another aspect of the invention provides use of chemically modified sialic acid precursors, such as N-propionylated mannosamine, in creating mammalian cancer cells expressing sialic acid unit-containing surface markers capable of eliciting an immune response, conjugates of a modified ⁇ 2-8 polysialic acid incorporating N-acylated D-mannosamine units and a protein and the use of these conjugates, to combat said mammalian cancer cells.
  • chemically modified sialic acid precursors such as N-propionylated mannosamine
  • Figure 1 is a graphical representation of results obtained from experiments described in Example 3.
  • Figure 2 is a graphical representation of results obtained from experiments described in Example 3.
  • Figures 3A and 3B are graphical representations of results obtained from experiments described in Example 4.
  • Figures 4A, B and C are graphical representations of results obtained from experiments described in Example 5.
  • sialic acid- unit containing cell surface marker for modification contiguous sialic acid residues.
  • contiguous sialic acid residues are large enough to stimulate an effective immune response.
  • polysialic acid refers to two or more contiguous sialic acid residues.
  • N-acylation of ⁇ 2-8 polysialic acid is N-acylation of ⁇ 2-8 polysialic acid. This can be accomplished by feeding the cells an N-acylated precursor of ⁇ 2-8 polysialic acid, for example N-propionylated-D-mannosamine, which in the natural intracellular biochemical synthesis of ⁇ 2-8 polysialic acid becomes chemically incorporated therein and thus results in the production of N-propionylated ⁇ 2-8 polysialic acid.
  • N-acylated ⁇ 2-8 polysialic acids are strongly immunogenic, in contrast to the naturally expressed ⁇ 2-8 polysialic acid.
  • Antibodies specific for the modified antigens can be induced by normal antibody raising techniques using a corresponding chemically modified polysialic acid-protein conjugate, such as an N-acylated cc2-8 polysialic acid- protein conjugate.
  • N-acylated ⁇ 2-8 polysialic acids for antibody production and vaccine preparation may be produced from commercially available poly-2,8-N- acetylneuraminic acid using methods disclosed herein. Alternatively, though less preferably, they may be purified by standard means from cells expressing them.
  • Examples of cells expressing N-acylated ⁇ 2-8 polysialic acid include cells such as RMA tumor cells which normally produce 2-8 poly-N-acetylneuraminic acid, when induced to use an N-propionated precursor such as N-propionated mannosamine.
  • RMA tumor cells which normally produce 2-8 poly-N-acetylneuraminic acid
  • N-propionated precursor such as N-propionated mannosamine.
  • Tetanus toxoid TT is a specific, suitable example of such a protein.
  • polysialic acids may express polysialic acids of varying lengths (ranging from 2 contiguous sialic acid residues to at least 60, 100 and likely as many as 200 contiguous sialic acid residues), it may be desirable to select the length of polysialic acid used to induce an immune response.
  • a first class of antibodies recognizes "short" polysialic acids, having at least 2 and no more than 10 to 12 sialic acid residues.
  • a second class of antibodies recognizes "long” polysialic acids, having at least 10 or 12 sialic acid residues.
  • Antibodies recognizing "short” polysialic acids can be distinguished from those recognizing "long” polysialic acids by routine experimentation, in light of the disclosure contained herein and of the prior art, and particularly, Pon, et al. J. Exp. Med.. Vol. 185(11 ), pages 1929-1938, 1997.
  • a conjugate of a modified polysialic acid and a protein where the length of the polysialic acid is selected to be either short or long preferably between 2 and 12 contiguous sialic acid residues are used in the conjugate. Even more preferably, between 4 and 10 contiguous sialic acid residues are used. Yet more preferably, between 6 and 8 contiguous sialic acid residues are used.
  • preferably between 10 and 200 contiguous sialic acid residues are used in the conjugate. More preferably, between 12 and 100 contiguous sialic acid residues are used. Yet more preferably, between 14 and 60 contiguous sialic acid residues are used.
  • polysialic acid unit-containing cell surface marker for modification is ⁇ 2-8 polysialic acid, since this marker is well recognized as a characteristic of certain cancer cells, and its biochemical synthesis is quite well understood.
  • N-acyl modifications can be made to the polysialic acid for use in the present invention, by appropriate chemical modification of the mannosamine precursor.
  • R-COOH an acid (or acid equivalent such acid halide, anhydride, etc.) of formula R-COOH where R represents a C, alkyl group, straight or branch chained, a C,_ 6 alkenyl group, straight or branch chained, a C,. 6 ketonic group or the like.
  • Specific preferred examples include butyric acid, acrylic acid, propionic acid and levulinic acid.
  • Colominic acid 500 mg was N-deacetylated in 2N NaOH (15ml) containing NaBH 4 (50 mg) for 7 hours at 105°C. The solution was neutralized with 5N HCI to ca. pH 8.0 and then dialyzed against distilled water overnight. The resulting product was sized by passing a Bio-Gel A.5 column to collect the fraction of MW ⁇ 10-1 1 kD. After lyophilization, deacetylated GBMP was obtained (370 mg. 1 H NMR of the product indicated that the deacetylation was complete.
  • NPrGBMP-TT conjugate NPrGBMP 150 mg was activated by oxidation of the non-reducing terminus using NalO 4 (100 mg) in 0.1 N NaOAc-HOAc solution at pH 6.5 overnight. The mixture was dialyzed against distilled water and then lyophilized.
  • NPrGBMP-TT conjugate (8.1-8.2 mg).
  • Sialic acid content of the conjugate was determined using the resorcinol method and the protein content was measured using BCA protein microanalysis. The final conjugate was found to contain about 20% (wt wt) of sialic acid, which is equivalent to 4 sialic acid chains per TT molecule.
  • the second pure portion was the expected product of NPrMan (6.4 g) as a mixture of both -(60%) and ⁇ -anomers (40%).
  • Tumor cells were incubated with the precursor N- propionylated mannosamine (2 mg/ml) for various time periods indicated in Figure 1 in RPMI plus 8% FBS. After each incubation, cells were harvested and incubated with either 13D9 ("mAb13D9", anti-N-propionyl polysialic acid) or 735 ("mAb735", anti-N-acetyl polysialic acid) monoclonal antibodies. Subsequently, cells were stained with FITC anti-mouse lgG2a antibody and fixed with 1 % formaldehyde before analysis by Flow cytometry.
  • 13D9 mAb13D9
  • 735 anti-N-acetyl polysialic acid
  • Figure 1 clearly indicates that the binding of 13D9 antibody on tumor cells increases with the duration of incubation of the precursor N-propionylated mannosamine in the previous culture.
  • the binding of 735 antibody (which recognizes N-acetyl polysacchahde) is down-regulated with the incorporation of N-propionylated mannosamine.
  • Figure 2 shows the measurement of the mean fluorescent intensity of tumor cells binding to 13D9 or 735 antibodies.
  • the expression of N- propionyl groups on the surface polysialic acid of tumor cells is associated with a reduction in their expression of N-acetyl groups. This data suggests that the precursor N-propionylated mannosamine is metabolized efficiently by the tumor cells.
  • N-propionylated sialic acid makes cells more susceptible to killing by the antibody 13D9 (anti-N-propionyl polysialic acid). After feeding tumor cells with the precursor for various time intervals (indicated in Figure 3), cells were harvested and incubated with either
  • Figure 3A depicts results obtained from incubating RMA cells with NPrMan (4 mg/ml) and harvesting aliquots at specified time intervals. The harvested aliquots were washed with PBS and with either: complement and no antibody, complement and mAb13D9, or complement and mAb735.
  • Figure 3B depicts results obtained from incubating RBL-2H3 cells with specified concentrations of NPrMan. At daily intervals, cells were harvested, washed with PBS and incubated with mAb13D9 and rabbit complement, and then subjected to the cytotoxicity assay.
  • N-propionyl mannosamine which gets expressed on the surface polysialic acid residues of the tumor cells.
  • This expression of N-propionyl polysialic acid makes the tumor cells vulnerable to immune attack depending on the presence of antibody against N-propionyl polysialic acid.
  • mice were inoculated with RMA cells (10 6 cells/mouse) and 5 days after inoculation the mice were treated daily (by i.p. injection near the tumor site) with mAb 13D9 (200 ⁇ g/mouse) and precursor NPrMan (5 mg/mouse) for a period of 8 days. Tumor growth was routinely monitored by measurement of tumor size. In combination with NPrMan, mAb 13D9 had a greater effect on tumor size than mAb 13D9 alone, although mAb 13D9 alone was also able to reduce tumor size when compared with a control group of mice (Figs. 4A, 4B and 4C).
  • Figure 4A depicts results from individual C57BL/6 mice which were injected subcutaneously with 1x10 6 RMA tumor cells in the shaven area of the rear flank. After 5 days, groups of 5 or 6 mice were injected daily, with mAb 13D9 (200 ⁇ g, intraperitoneally) and NPrMan (5 mg, intraperitoneally).
  • Figures 4B and 4C depict the results of similar experiments wherein mice were injected with (B) mAb 13D9 alone (200 ⁇ g, intraperitoneally) or (C) with PBS. Tumor growth was monitored routinely by measuring the tumor size. A control lgG2a mAb did not inhibit tumor growth.
  • mice were carried out as described in Example 5 using RMA cells except that in this case the spleens of the mice were analyzed for the presence of metastatic cells.
  • the metastasis of tumor cells can be controlled by modification of surface polysialic acid glycoconjugates to their N-propionylated analogs and then applying immunotherapy based on antibodies specific for the modified antigen.
  • These antibodies could be either passively administered as described herein, or induced in situ by direct immunization using an appropriate N- propionated (NPr) polysialic acid - protein conjugate vaccine.
  • compositions capable of being used as anti-cancer vaccines and, further, a process for enhancing the specific immunogenicity of mammalian cancer cells, and exploiting this enhanced immunogenicity in a vaccination approach to the management of cancer in human patients.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • Immunology (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Oncology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)

Abstract

Le composant d'acide sialique d'un marqueur de surface de cellule contenant une unité d'acide sialique caractéristique des cellules cancéreuses de mammifère, tel que l'acide α2-8 polysialique, est modifié, de sorte que les cellules qui normalement expriment ce marqueur, expriment à la place un marqueur de surface de cellule contenant une unité d'acide sialique modifié qui est fortement immunogène. Cette invention permet, par exemple, dans une partie des cellules de patient qui régulièrement expriment un acide α2-8 polysialique (c'est à dire divers types de cellules cancéreuses), l'expression d'un antigène de surface hautement immunogène, à savoir l'acide α2-8 polysialique modifié. Il est souhaitable que cette modification soit une N-acylation d'un précurseur de cet acide sialique, de sorte que ce précurseur N-acylé soit incorporé chimiquement dans l'acide polysialique au cours de sa synthèse biochimique intracellulaire. Des anticorps spécifiques de cet antigène modifié, que l'on peut produire en utilisant un conjugué d'une partie adaptée du marqueur contenant l'unité d'acide sialique modifiée (tel que l'acide α2-8 polysialique) et une protéine, peuvent ensuite être utilisés pour éliminer des cellules qui expriment l'acide α2-8 polysialique. On peut préparer des vaccins en utilisant des conjugués de ce marqueur contenant l'acide sialique modifié, ou en utilisant des anticorps produits par un sujet adapté exposé à un marqueur contenant l'acide sialique modifié, de façon à gérer des états cancéreux qui mettent en oeuvre des cellules caractérisées, au moins en partie, par l'expression d'un marqueur contenant une unité d'acide sialique modifié.
EP00951149A 1999-07-29 2000-07-28 Strategie pour des vaccins therapeutiques a base de glucides Withdrawn EP1198244A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CA2279134 1999-07-29
CA002279134A CA2279134A1 (fr) 1999-07-29 1999-07-29 Strategie nouvelle pour les vaccins therapeutiques a base de glucides
PCT/CA2000/000886 WO2001009298A2 (fr) 1999-07-29 2000-07-28 Nouvelles strategies pour des vaccins therapeutiques a base de glucides

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EP1198244A2 true EP1198244A2 (fr) 2002-04-24

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EP (1) EP1198244A2 (fr)
JP (1) JP2003506034A (fr)
AU (1) AU6420000A (fr)
CA (1) CA2279134A1 (fr)
IL (1) IL147776A0 (fr)
MX (1) MXPA02000958A (fr)
WO (1) WO2001009298A2 (fr)
ZA (1) ZA200200731B (fr)

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040009195A1 (en) * 2000-07-28 2004-01-15 Jennings Harold J Modified sialic acid vaccines
CA2399325A1 (fr) * 2001-08-21 2003-02-21 National Research Council Of Canada Vaccin contre le cancer de cellules entieres a base d'hydrates de carbone
KR20070060069A (ko) 2004-06-23 2007-06-12 칠드런즈 하스피틀 앤드 리써치 센터 앳 오클랜드 다당류 유도체 및 면역반응의 유도에서의 용도
US8148335B2 (en) 2004-06-23 2012-04-03 Children's Hospital & Research Center Oakland De-N-acetyl sialic acid antigens, antibodies thereto, and methods of use in cancer therapy
MX2008008185A (es) * 2005-12-23 2008-11-14 Childrens Hosp & Res Ct Oak Antigenos de acido des-n-acetil-sialico, anticuerpos para los mismos, y metodos de uso en la terapia de cancer.
WO2007116409A2 (fr) 2006-04-11 2007-10-18 Yeda Research And Development Co. Ltd. At The Weizmann Institute Of Science Vaccins améliorés comprenant des supports peptidiques multimères dérivés de la hsp60
AU2008272785B2 (en) 2007-07-03 2014-06-12 Children's Hospital & Research Center At Oakland Polysialic acid derivatives, methods of production, and uses in enhancing cancer antigen production and targeting
CA2690440A1 (fr) 2007-07-03 2009-01-08 Children's Hospital & Research Center At Oakland Derives d'acide oligosialique, procedes de fabrication et utilisations immunologiques
EP2173166A4 (fr) * 2007-07-03 2010-08-11 Childrens Hosp & Res Ct Oak Inhibiteurs de l'acide polysialique de-n-acétylase et procédés pour leur utilisation
US8640245B2 (en) 2010-12-24 2014-01-28 Kaspersky Lab, Zao Optimization of anti-malware processing by automated correction of detection rules

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US5811102A (en) * 1995-06-07 1998-09-22 National Research Council Of Canada Modified meningococcal polysaccharide conjugate vaccines

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Publication number Priority date Publication date Assignee Title
US5102663A (en) * 1988-10-18 1992-04-07 Sloan-Kettering Instutute For Cancer Research Vaccine for stimulating or enhancing production of antibodies against 9-O-acetyl GD3

Non-Patent Citations (2)

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Title
KAYSER H. ET AL, THE JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 267, no. 24, 25 August 1992 (1992-08-25), pages 16934 - 16938, XP000608481 *
KEPPLER O.T. ET AL, THE JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 270, no. 3, 20 January 1995 (1995-01-20), pages 1308 - 1314 *

Also Published As

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ZA200200731B (en) 2003-03-26
JP2003506034A (ja) 2003-02-18
MXPA02000958A (es) 2003-07-21
AU6420000A (en) 2001-02-19
CA2279134A1 (fr) 2001-01-29
IL147776A0 (en) 2002-08-14
WO2001009298A2 (fr) 2001-02-08
WO2001009298A3 (fr) 2001-08-23

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