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EP1395290A2 - Immunoconjugues d'anticorps de cd44 cytotoxiques - Google Patents

Immunoconjugues d'anticorps de cd44 cytotoxiques

Info

Publication number
EP1395290A2
EP1395290A2 EP02753054A EP02753054A EP1395290A2 EP 1395290 A2 EP1395290 A2 EP 1395290A2 EP 02753054 A EP02753054 A EP 02753054A EP 02753054 A EP02753054 A EP 02753054A EP 1395290 A2 EP1395290 A2 EP 1395290A2
Authority
EP
European Patent Office
Prior art keywords
compound
antibody molecule
antibody
conjugate
maytansinoid
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Withdrawn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
EP02753054A
Other languages
German (de)
English (en)
Inventor
Günther Adolf
Karl-Heinz Heider
Erik Patzelt
Marlies Sproll
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.)
Boehringer Ingelheim International GmbH
Original Assignee
Boehringer Ingelheim International GmbH
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 Boehringer Ingelheim International GmbH filed Critical Boehringer Ingelheim International GmbH
Priority to EP02753054A priority Critical patent/EP1395290A2/fr
Publication of EP1395290A2 publication Critical patent/EP1395290A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6849—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/68033—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a maytansine
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • the invention relates to novel conjugates of antibodies with cytotoxic compounds, pharmaceutical compositions comprising such compounds, and their use in tumor therapy.
  • Maytansine and derivatives act as anti-mitotic agents (inhibitors of tubulin polymerization), similar as vincristine, but with markedly higher potency than vincristine or other established chemotherapeutic agents (DM1 is toxic to cells in vitro at ⁇ 10 "10 M concentration).
  • DM1 is toxic to cells in vitro at ⁇ 10 "10 M concentration.
  • the antibody conjugate has a toxicity which is several orders of magnitude lower on antigen-negative cells compared to antigen-positive cells.
  • the linkage by disulfide bonding has the advantage that these bonds are readily cleaved inside the target cells by intracellular glutathione, releasing highly toxic free drug.
  • CD44 is a protein which is expressed in several different isoforms on the surface of a wide variety of cell types.
  • the smallest isoform, standard CD44 (CD44s), which is expressed by a variety of different cells, is thought to mediate cell attachment to extracellular matrix components and may transmit a co-stimulus in lymphocyte and monocyte activation.
  • CD44v6 splice variants of CD44 which contain the domain v6 (CD44v6) in the extracellular region.
  • the physiological role of CD44v6 is not yet fully understood.
  • CD44v6 as well as other variant exons (CD44v3, CD44v5, CD44v7/v8, CD44vl0) has been shown to be a tumor-associated antigen with a favorable expression pattern in human tumors and normal tissues (Heider et al., 1995; Heider et al., 1996; Dall et al., 1996; Beham-Schmid et al., 1998; Tempfer et al., 1998; Wagner et al., 1998) and has been subject to antibody-based diagnostic and therapeutic approaches, in particular radioimmunotherapy (RIT) of tumors (Verel et al, 2002; Stromer et al., 2000; WO 95/33771; WO 97/21104).
  • RIT radioimmunotherapy
  • L is a linker moiety
  • said antibody molecule has binding specificity for an epitope within said sequence. More preferably, the antibody molecule specifically binds to a peptide having the amino acid sequence SEQ ID NO: 2, even more preferably having the amino acid sequence SEQ ID NO: 3.
  • Such antibody molecules may be easily produced with methods known in the art (WO 95/33771 , WO 97/21104), e.g. by immunising laboratory animals with chemically synthesised peptides having the aforementioned sequences, e.g.
  • the expression vector furthermore contains selection marker genes like the dihydrofolate reductase (DHFR), glutamine synthetase, adenosine deaminase, adenylate deaminase genes, or the neomycin, bleomycin, or puromycin resistance genes.
  • DHFR dihydrofolate reductase
  • glutamine synthetase glutamine synthetase
  • adenosine deaminase adenylate deaminase genes
  • the neomycin, bleomycin, or puromycin resistance genes or the neomycin resistance genes.
  • antibody molecule/maytansinoid conjugates are those that are joined via a disulfide bond, as discussed above, that are capable of delivering maytansinoid molecules.
  • Such cell binding conjugates are prepared by known methods such as modifying monoclonal antibodies with succinimidyl pyridyl-dithiopropionate (SPDP) or pentanoate (SPP) (Carlsson et al, 1978). The resulting thiopyridyl group is then displaced by treatment with thiol-containing maytansinoids to produce disulfide linked conjugates.
  • step (b) reacting the antibody molecule of step (a) with a compound which is toxic to cells, said compound having one or more disulfide or thiol groups;
  • the conjugate may for example be clinically used ex vivo to remove tumor cells from bone marrow prior to autologous transplantation in cancer treatment.
  • the present invention relates to a method of treatment of cancer comprising applying a pharmaceutical composition as described before to a patient.
  • this aspect of the invention relates to a method of treatment of cancer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound as described above, or a pharmaceutical composition as described above.
  • the cancer is head and neck squamous cell carcinoma (SCC), esophagus SCC, lung SCC, skin SCC, breast adenocarcinoma (AC), lung AC, cervix SCC, pancreas AC, colon AC, or stomach AC.
  • the compound of formula (I) according to the invention will be supplied as solutions that are tested for sterility and for endotoxin levels.
  • suitable protocols of conjugate administration are as follows. Conjugates maybe given weekly for 1 to 6 weeks either as an i.v. bolus , or as a continuous infusion for 5 days. Bolus doses can be given in 50 to 100 ml of normal saline to which 5 to 10 ml of human serum albumin has been added. Continuous infusions can be given in 250 to 500 ml of normal saline, to which 25 to 50 ml of human serum albumin has been added, per 24 hour period. Dosages will generally be 10 mg to 400 mg/m of body surface area per application.
  • the dose applied to the patient per administration has to be high enough to be effective, but must be below the dose limiting toxicity (DLT).
  • DLT dose limiting toxicity
  • MTD maximum tolerated dose
  • the expert knows how to determine the MTD (Lambert et al., 1998).
  • the MTD can be expected to be in the range of 100 to 200 mg/m 2 .
  • intervals between applications may be longer, e.g. two to four weeks, preferably three weeks.
  • the MTD can be expected to be in the range of 200 to 300 mg/m .
  • application may be in 5 daily doses, followed by a break of several weeks after which treatment may be repeated.
  • the MTD per administration can be expected to be lower than 100 mg/m 2 .
  • conjugates can be administered as a single i.v. infusion with a rate of 3 mg/min every 21 days. Up to 7 cycles of treatment were applied. It is to be understood that the applied doses may well be out of the ranges given above if the clinical situation requires. For example, if the MTD is found to be higher than indicated, single administration may be at a higher dose than 400 mg/m 2 , or weekly may be at more than 200 mg/m 2 .
  • the invention relates to the use of a compound of formula (I) for the preparation of a pharmaceutical composition for the treatment of cancer.
  • the antibody molecule present in the pharmaceutical composition is the monoclonal antibody VFF-18, or a recombinant antibody having the CDR's of the antibody VFF- 18, preferably in a human framework.
  • the toxic compound has the formula (IE).
  • the cancer is head and neck squamous cell carcinoma (SCC), esophagus SCC, lung SCC, skin SCC, breast adenocarcinoma (AC), lung AC, cervix SCC, pancreas AC, colon AC, or stomach AC.
  • CD44 splice variants confer metastatic behavior in rats: homologous sequences are expressed in human tumor cell lines. Cancer Res. 51: 5292-5297 (1991).
  • Geno- mic structure of DNA encoding the lymphocyte homing receptor CD44 reveals at least 12 alternatively spliced exons. Proc. Natl. Acad. Sci. U.S.A. 89: 12160-12164 (1992).
  • the Cell Titer 96 ® AQ ueo u s non-radioactive cell proliferation assay (Promega) was used. 5000 cells per well were seeded into 96-well plates in 90 ⁇ l medium without phenole red. Cells were allowed to settle down for 1 to 3 h and then serial dilutions of the immunoconjugate in 10 ⁇ l PBS were added. Cells without immunoconjugate served as negative control. Cells were incubated for 4 days at 37°C in a humified 5% CO 2 atmosphere and then 20 ⁇ l MTS/ PMS were added according to the manufacturer's recommendation.
  • BIWA 4 and BIWA 8 which have binding specificity for an epitope within SEQ ED NO: 1 were linked to the maytansinoid DM1 as described below.
  • the conjugate of BIWA 4 with DM1 was designated BIWI 1.
  • RPMI- 10 After tr psinisation and inactivation of trypsin with RPMI- 10 (90% RPMI 1640, 10% heat inactivated fetal calf serum), cells were washed once with RPMI-0 (RPMI 1640 without serum), and lxlO 7 cells were resuspended in 0.8 ml PJ > MI-0. After addition of the linearised DNA (20 ⁇ g per plasmid; cotransfection of vectors coding for light and heavy chain) the cells were electroporated using a Hoefer Electroporator under the following conditions: 1080 ⁇ F, 320 V, 1000 msec, 1 pulse.
  • 53 clones were seeded in 12 well plates in alfa-MEM lOd. After 3-6 days (depending on the confluency of the cells) supematants were tested again in the ⁇ / ⁇ ELISA (serial dilutions) and quantitated using a human IgGl standard. Cells were frozen and stored in liquid nitrogen. IgG contents of the 53 clones ranged from 12 - 417 ng/ml.
  • Antibody was purified from cell culture supernatant as follows. Antibody containing tissue culture supernatant was applied onto a 5 ml protein A sepharose column with a flow rate of 80-90 ml/h at 4 °C. After washing with 50 ml binding buffer (0.1 M sodium phosphate pH 7.5), the Ig fraction was eluted with elution buffer (0.1 M glycine-HCl pH 2.7). Absorption at 280 nm was monitored. Modification of BIWA 4 with SPP to form BIWA 4-SS-Py. BIWA 4 was supplied in liquid form at a concentration of 5 mg/mL in a PBS formulation containing Tween 20.
  • the antibody solution was dialysed against 50 mM potassium phosphate buffer, pH 6.5 containing 50 mM NaCl and 2 mM EDTA (Buffer A).
  • the BIWA 4 antibody was modified using SPP ((2-Pyridyl)-5-dithiopentanoic acid N-hydroxy succinimid ester) to introduce dithiopyridyl groups.
  • SPP ((2-Pyridyl)-5-dithiopentanoic acid N-hydroxy succinimid ester) to introduce dithiopyridyl groups.
  • the MAb in Buffer A (185 mg, 8 mg/mL) was modified with a 7-fold molar excess of SPP in EtOH (5% v/v of MAb solution). The reaction proceeded for 90 minutes at ambient temperature.
  • the conjugate eluted as a single peak at the position of monomeric MAb with a small amount of protein eluting earlier. Fractions were assayed for the number of DM1 molecules linked per MAb molecule. (Linked DM1 molecules were determined by measuring the absorbance at both 252 nm and 280 nm). Based on the results, fractions representing 63-77% of the column volume were pooled. The DM1 /MAb ratio in the pooled solution was found to be 3.1 and the yield of conjugated B WA 4 was 75% based on starting MAb.
  • the conjugate, BIWI 1 was evaluated by SDS-PAGE performed under non-reducing conditions and found to be composed primarily of a monomer species (>95%) with a minor amount ( ⁇ 5%) of dimeric conjugate.
  • A431 ATCC # CRL 1555; epidermoid carcinoma of the vulva
  • FaDu ATCC # HTB 43; squamous cell carcinoma of the pharynx.
  • Tumor cell lines A431 and FaDu were received from ATCC and cultured in RPMI 1640 medium containing 10% fetal calf serum and supplements.
  • mice were randomised into the following treatment groups (treatment initial mean tumour volume/tumour volume range/number of mice):
  • Group 1 Control (PBS)/ 185 ⁇ 217 mm 3 / 19 - 424 mm 3 / 5 mice.
  • Group 2 BIWA 4 (21 mg/kg/d) / 133 ⁇ 115 mm 3 / 42 - 302 mm 3 / 5 mice.
  • Group 3 BIWI 1 (2.1 mg/kg/d) / 107 ⁇ 63 mm 3 / 42 - 205 mm 3 / 5 mice.
  • Group 4 BIWI 1 (7 mg/kg/d) / 132 ⁇ 73 mm 3 / 42 - 205 mm 3 / 5 mice.
  • Group 5 BIWI 1 (21 mg/kg/d) / 107 ⁇ 63 mm 3 / 42 - 205 mm 3 / 5 mice.
  • Group 1 Control (PBS)/ 142 ⁇ 82 mm 3 / 34 - 268 mm 3 / 8 mice.
  • Group 2 BIWA 4 (21 mg/kg/d) / 134 ⁇ 86 mm 3 / 42 - 268 mm 3 / 6 mice.
  • Group 3 BIWI 1 (2.1 mg/kg/d) / 149 ⁇ 96 mm 3 / 50 - 268 mm 3 / 6 mice.
  • Group 4 BIWI 1 (7 mg/kg/d) / 132 ⁇ 97 mm 3 / 42 - 268 mm 3 / 6 mice.
  • Group 5 BIWI 1 (21 mg/kg/d) / 129 ⁇ 74 mm 3 / 50 - 231 mm 3 / 6 mice.
  • lxlO 6 tumors cells were transplanted subcutaneously into the right flank of 6 week old female NMRI-nu nu mice. Treatment started when the tumors reached an average size of 107 to 185 mm 3 . Treatment consisted of i.v. injections of BIWI 1 given on five consecutive days, starting at day 1. 3 different doses of BEWI 1 were tested in parallel: 2.1 mg/kg/d BIWI 1 corresponding to 30 ⁇ g/kg/d DM1, 7 mg/kg/d BIWI 1 corresponding to 100 ⁇ g/kg/d DM1, and 21 mg/kg/d BIWI 1 co ⁇ esponding to 300 ⁇ g/kg/d DM1.
  • Control animals were either untreated (PBS) or treated with unconjugated antibody (control antibody, 21 mg/kg/d). Tumor growth was monitored by measuring tumor size. A tumor response was rated as complete response when the tumor completely disappeared at any time after start of treatment. The response was rated as partial response when the tumor volume decreased after treatment but thereafter started regrowing. The tolerability of the treatment was monitored by measuring mouse weight during the whole observation period.
  • BIWI 1 The in vitro cytotoxicity of BIWI 1 was evaluated using the antigen-positive cell lines A431 and FaDu, and the antigen-negative cell line A459. Cells were exposed to different concentrations of BIWI 1 for 4 days, then stained with MTS/ PMS and assayed on an ELISA plate reader. The surviving fractions of cells were then calculated using the GraphPad Prism ® software package. The results are shown in Figure 1. BIWI 1 was effective in killing the antigen-positive A431 cells with an IC 50 of about 7.6 x 10 *8 M and the second antigen-positive cell line, FaDu, with an IC 50 of about 2.4 x 10 " M.
  • mice Groups of 6 mice were treated with 2.1 mg/kg/d BIWI 1, 7 mg/kg/d BIWI 1, 21 mg/kg/d BIWI 1, and 21 mg/kg/d control antibody, respectively.
  • the average tumor size at start of treatment was 142 +/- 82 mm 3 (PBS), 134 +/- 86 mm 3 (control antibody), 129 +/- 74 mm 3 (21 mg/kg/d BIWI 1), 132 +/- 97 mm 3 (7 mg/kg/d BIWI 1), and 149 +/- 96 mm 3 (2.1 mg/kg/d BIWI 1), respectively.
  • the average tumor volume of each group during the observation period is shown in Figure 3.
  • the tolerability of BIWI 1 treatment was determined by monitoring mouse weight during the whole duration of the experiment in the 2 models.
  • the maximum observed average weight loss per group was 5% in FaDu xenografted mice treated with 21 mg/kg/d BIWI 1 (Figure 4).
  • the weight loss started around day 3 of treatment and lasted until day 10, thereafter animals regained weight and behaved similar as control animals. En all other dose groups weight loss was similar to vehicle control (PBS).
  • An average weight loss of 5% or less in all treatment groups indicates good tolerability of BIWI 1 treatment at the given doses in nude mice.
  • BIWI 1 does not cross-react with mouse CD44v6, only antigen- independent effects such as toxicity caused by free DM1 can be monitored in this experiment. 3.

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  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Cell Biology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • Peptides Or Proteins (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
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Abstract

La présente invention concerne de nouveaux conjugués d'anticorps de composés cytotoxiques, des compositions pharmaceutiques contenant lesdits conjugués, et leur utilisation dans le cadre de la thérapie du cancer. En particulier, l'invention a pour objet des conjugués d'anticorps qui sont spécifiques de CD44 avec des maytansinoïdes, de préférence avec N2-désacétyl-N2-(3-mercapto-1-oxopropyl)-maytansine (DM1).
EP02753054A 2001-05-18 2002-05-16 Immunoconjugues d'anticorps de cd44 cytotoxiques Withdrawn EP1395290A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP02753054A EP1395290A2 (fr) 2001-05-18 2002-05-16 Immunoconjugues d'anticorps de cd44 cytotoxiques

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP01112227 2001-05-18
EP01112227A EP1258255A1 (fr) 2001-05-18 2001-05-18 Conjugués d'un anticorps contre CD44 et d'un maytansinoide
EP02753054A EP1395290A2 (fr) 2001-05-18 2002-05-16 Immunoconjugues d'anticorps de cd44 cytotoxiques
PCT/EP2002/005413 WO2002094325A2 (fr) 2001-05-18 2002-05-16 Immunoconjugués d'anticorps de cd44 cytotoxiques

Publications (1)

Publication Number Publication Date
EP1395290A2 true EP1395290A2 (fr) 2004-03-10

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Application Number Title Priority Date Filing Date
EP01112227A Withdrawn EP1258255A1 (fr) 2001-05-18 2001-05-18 Conjugués d'un anticorps contre CD44 et d'un maytansinoide
EP02753054A Withdrawn EP1395290A2 (fr) 2001-05-18 2002-05-16 Immunoconjugues d'anticorps de cd44 cytotoxiques

Family Applications Before (1)

Application Number Title Priority Date Filing Date
EP01112227A Withdrawn EP1258255A1 (fr) 2001-05-18 2001-05-18 Conjugués d'un anticorps contre CD44 et d'un maytansinoide

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JP (1) JP2004529963A (fr)
KR (1) KR20030097883A (fr)
CN (1) CN1509187A (fr)
AR (1) AR035977A1 (fr)
BG (1) BG108366A (fr)
BR (1) BR0209862A (fr)
CA (1) CA2443438A1 (fr)
CO (1) CO5550468A2 (fr)
CZ (1) CZ20033477A3 (fr)
EA (1) EA200301159A1 (fr)
EE (1) EE200300568A (fr)
HR (1) HRP20030932A2 (fr)
HU (1) HUP0400046A3 (fr)
IL (1) IL157965A0 (fr)
MX (1) MXPA03010432A (fr)
NO (1) NO20035108D0 (fr)
NZ (1) NZ530167A (fr)
PE (1) PE20021097A1 (fr)
PL (1) PL365480A1 (fr)
SK (1) SK15582003A3 (fr)
WO (1) WO2002094325A2 (fr)
YU (1) YU91503A (fr)
ZA (1) ZA200307364B (fr)

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IL157965A0 (en) 2004-03-28
ZA200307364B (en) 2004-04-20
PL365480A1 (en) 2005-01-10
CO5550468A2 (es) 2005-08-31
WO2002094325A2 (fr) 2002-11-28
JP2004529963A (ja) 2004-09-30
KR20030097883A (ko) 2003-12-31
BG108366A (bg) 2004-09-30
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BR0209862A (pt) 2004-06-08
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EA200301159A1 (ru) 2004-06-24
NO20035108L (no) 2003-11-17
EP1258255A1 (fr) 2002-11-20
HUP0400046A2 (hu) 2004-04-28
AR035977A1 (es) 2004-07-28
CA2443438A1 (fr) 2002-11-28
HRP20030932A2 (en) 2004-04-30
HUP0400046A3 (en) 2006-02-28
WO2002094325A3 (fr) 2003-04-17
YU91503A (sh) 2006-05-25
SK15582003A3 (sk) 2004-04-06
NO20035108D0 (no) 2003-11-17

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