EP1009432A1 - Composition et procede pour prevenir des rejets de greffe ou d'autres reponses immunitaires non adaptives des lymphocytes t - Google Patents

Composition et procede pour prevenir des rejets de greffe ou d'autres reponses immunitaires non adaptives des lymphocytes t

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Publication number
EP1009432A1
EP1009432A1 EP98930097A EP98930097A EP1009432A1 EP 1009432 A1 EP1009432 A1 EP 1009432A1 EP 98930097 A EP98930097 A EP 98930097A EP 98930097 A EP98930097 A EP 98930097A EP 1009432 A1 EP1009432 A1 EP 1009432A1
Authority
EP
European Patent Office
Prior art keywords
interrupter
administered
agents
treatment
rejection
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Withdrawn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
EP98930097A
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German (de)
English (en)
Other versions
EP1009432A4 (fr
Inventor
David M. Harlan
Alan D. Kirk
Stuart J. Knechtle
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.)
US Department of Navy
Wisconsin Alumni Research Foundation
Original Assignee
US Department of Navy
Wisconsin Alumni Research Foundation
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Publication date
Application filed by US Department of Navy, Wisconsin Alumni Research Foundation filed Critical US Department of Navy
Publication of EP1009432A1 publication Critical patent/EP1009432A1/fr
Publication of EP1009432A4 publication Critical patent/EP1009432A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2875—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF/TNF superfamily, e.g. CD70, CD95L, CD153, CD154
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • 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
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • 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
    • 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
    • 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
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503—Immunoglobulin superfamily
    • C07K14/70521—CD28, CD152

Definitions

  • This invention relates to the field of tissue transplantation, and more particularly to the use of monoclonal antibodies specific for T cell determinants in blocking cell mediated immune responses resulting in allograft or xeongraft rejection.
  • This invention further relates to the prevention or reversal of graft organ rejection and other counter- adaptive T lymphocyte mediated immune responses.
  • the invention provides compositions and an order and method of treatment to reduce or prevent the rejection of graft organs in primates or man, and to prevent disease resulting from a poorly targeted T lymphocyte mediated immune response .
  • Organ transplantation between genetically non- identical individuals invariably results in immunological rejection of the organ through T cell dependent mechanisms unless that rejection process is bridled by administering drugs that suppress T cell function.
  • Both calcineurin phosphatase inhibitors and glucocorticosteroids are used clinically, and both prevent the T cell mediated release of activating cytokines, particularly IL-2. Therapy with these agents is imperfect however. Both act by impairing signaling through the T cell antigen receptor (TCR) , the sole mediator of T cell antigen specificity, and act on all T cells indiscriminately.
  • TCR T cell antigen receptor
  • the effect of these drugs is not lasting such that cessation of immunosuppression has generally resulted in graft loss even after prolonged rejection free survival.
  • transplant recipients must suffer the consequences of non-specific immunosuppression. These consequences include an increased risk of infection and malignancy as well as significant drug related expense and toxicity.
  • T cell activation requires both TCR mediated signals and simultaneously delivered costimulatory signals have accumulated over the past 20 years [1] .
  • These important costimulatory signals are provided at least in part by the T cell based CD28 molecule when bound to its counter receptors CD80(B7-1) or CD86 (B7-2) , hereafter referred to collectively as B7, on antigen presenting cells (APCs) and perhaps parenchymal cells [1,2,3].
  • APCs antigen presenting cells
  • CD40L CD154
  • CD40L also plays an important role in T cell activation at least in part by up-regulating B7 [4,5] .
  • CD40 and CD154 play a fundamental role in establishing T dependent B cell activity [6,7].
  • T cell molecule CTLA4 (CD152) , appears to down- regulate costimulation and TCR mediated activation, at least in part by competing with CD28 for B7 and by delivering a unique negative signal to the TCR signal transduction complex [8] .
  • an object of this invention is a combination of drugs to prevent rejection of transplanted cells, tissues, or organs from either an allogeneic or a xenogeneic source by administering agents that interfere with T cell costimulatory signaling via CD28 when given in conjunction with agents that interfere with the CD40:CD154 interaction.
  • Another object is a method of treatment to reverse ongoing organ rejection by administering agents that interfere with T cell costimulatory signaling via CD28 when given in conjunction with agents that interfere with the CD40:CD154 interaction.
  • a third object recognizes that reversal of an ongoing rejection process can be stopped by administering agents that interfere with T cell costimulatory signaling via CD28 when given in conjunction with agents that interfere with the CD40.CD154 interaction.
  • a fourth object is that for patients currently being treated with standard immunosuppressive therapies (e.g. glucocorticoids, calcineurin phosphatase inhibitors, mycophenolate mofetil) to prevent the rejection of a transplant or to prevent graft versus host disease, those toxic and expensive medications could be discontinued and replaced with short course therapy with agents that interfere with T cell costimulatory signaling via CD28 when given in conjunction with agents that interfere with the CD40:CD154 interaction.
  • standard immunosuppressive therapies e.g. glucocorticoids, calcineurin phosphatase inhibitors, mycophenolate mofetil
  • a fifth object is that for patients with a transplanted organ undergoing chronic rejection, agents that interfere with T cell costimulatory signaling via CD28 when given in conjunction with agents that interfere with the CD40:CD154 interaction can block this undesired immune reaction.
  • a sixth and most general object is to prevent and/or treat disease states resulting from a counter- adaptive immune response such as the various T- lymphocyte mediated autoimmune illnesses (e.g. insulin dependent diabetes mellitus, multiple sclerosis, etc.) and the various allergic disease states (e.g. hay fever) .
  • T- lymphocyte mediated autoimmune illnesses e.g. insulin dependent diabetes mellitus, multiple sclerosis, etc.
  • allergic disease states e.g. hay fever
  • a seventh object is to test the hypothesis that CTLA4-Ig and the anti-human CD154 specific monoclonal antibody are capable of inducing tolerance to allografted or even xenografted tissues in humans, and in a more general sense to ameliorate (prevent or treat) all counter-adaptive T-lymphocyte mediated disease states.
  • agents that interfere with the interaction of the CD28 and/or CD152 CTL4
  • their B7 family ligands CD80 and/or CD86
  • agents that interfere with the interaction of CD40 and CD154 CD40L
  • These agents will be administered parenterally (intramuscularly, subcutaneously, or most preferably intravenously) in a standard pharmaceutical carrier (i.e. iv infusion with saline, water, or other buffer) .
  • Agents will be administered after cells, tissue (s), or organ (s) have been transplanted. Initial dosing will be administered as soon as the graft is transplanted at a dose of between 5-20 mg/kg body weight (each agent) . Doses will then be administered on days 2,4,6,8,12,16, and 28 post transplant. Thereafter, should signs of immune rejection ensue, dosing will be repeated to reverse the rejection episode. During this retreatment, dosing will be administered as per the initial induction therapy post transplan .
  • This therapy employing agents that interfere with the interaction of both CD28/CD152 :B7 and CD40:CD154 will also be administered to individuals with signs indicating that they are developing a disease (including chronic rejection) , or that are already suffering with an illness, mediated completely or in part by activated T cells (including patients with a transplant currently receiving standard immunosuppressive therapy) .
  • Such "counter-adaptive" T cell responses also include diseases like the various autoimmune illnesses (for example insulin dependent diabetes mellitus, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, and systemic lupus erythematosus) as well as in states resulting from the sequela of an immune response like allergic illnesses (hay fever) .
  • the therapy will be administered in doses ranging from 2-20 mg/kg body weight (each agent) as frequently as every other day for up to 28 days.
  • treatment package will be termed “immune reeducation” and will consist of the drugs to be administered, the carrier solvent for those agents, and the infusion system to be used to administer the agent.
  • CTLA4-Ig and anti-CD154 were tested alone and in combination on rhesus peripheral blood leukocytes in vitro, and in rhesus monkeys transplanted with primarily vascularized renal allografts.
  • Fig. 2 (A) Survival and renal function as determined by serum creatinine following unmodified allogeneic renal transplantation (dashes) or transplantation following induction with CTI_A4-Ig alone (squares) or humanized anti-human CD154 alone (diamonds) . Open arrows indicate retreatment during biopsy proven rejection. Solid arrows continued survival. (B) Survival and renal function as determined by serum creatinine following unmodified allogenic renal transplantation (dashes) or transplantation following induction with both CTLA4-Ig and humanized anti-human CD154. Open circles indicate treatment on days 0,2,4,6,8,10, and 12 post-transplant . Closed circles indicate treatment on days 0,2,4,6,8,12,16, and 28 post-transplant . Open arrows indicate retreatment during biopsy proven rejection for the animal depicted in open circles. Solid arrows indicate continued survival free of rejection since transplantation.
  • Fig. 3. (A) Renal allograft histology showing acute cellular rejection following unmodified renal allotransplantation in rhesus monkeys. (B) Renal allograft histology showing acute cellular rejection prior to reversal with humanized anti-human CD154. (C) Normal renal allograft histology from an animal with normal renal function 163 days following transplantation and induction with CTLA4-Ig and humanized anti-human CD154. (D) A perivascular lymphoid aggregate with the allograft shown in C. These nests of lymphocytes exist in the allograft despite normal function and the absence of immunosuppression. All micrographs are 250x.
  • Fig. 4 Mixed lymphocyte responses against donor lymphocytes and third party lymphocytes for two rhesus monkeys 150 days after allotransplantation with rejection free survival and normal renal function and without any chronic therapy. Both donor and third party responsiveness is maintained.
  • skin grafts placed on a rhesus monkey 6 months following successful allotransplantation revealed donor specific tolerance. Three skin grafts were placed: one from the host (an autograft to control for surgical technique) , one from the allogeneic kidney donor, and one from a third party donor. Only the third party donor skin was rejected at day 14 (and counting) since the grafting. This data indicates that functional donor specific tolerance has been achieved despite failure of the allo-MLR to reflect it.
  • the invention is applicable to both xeno- and allo- transplants, and for more general application to disease states resulting from counter-adaptive T- lymphocyte responses.
  • the invention comprises a composition involving the parenteral administration for an agent interfering with the T cell costimulatory receptors' (CD28/CD152) ability to bind with B7 in close time sequence to administration of an agent preventing signaling through CD152.
  • CTLA4-Ig provides insurance against B7 expression that escapes the effects of humanized anti-human CD154. In that instance, considerable time seems to be required to mount an effective acute rejection with the few cells that escape initial blockade.
  • the rhesus monkey model used in this study has been shown repeatedly to be a rigorous test of immune manipulation - one that isakily sensitive to even minor changes in allograft function or adverse effects on recipient wound healing and immune function [13,15,19].
  • it has obvious biological similarity to human renal transplantation. Specifically, genes that encode MHC proteins are well conversed between rhesus monkeys and humans [20-22] , and their rejection of vascularized organs closely parallel that seen clinically [13,15,19]. Nevertheless, issues of optimal dosing and treatment time course remain to be resolved.
  • Human CTLA4-Ig and a control fusion protein-IgGl were prepared as previously described [2] and shipped in solution by Genetics Institute, Cambridge, MA.
  • the anti-CD40 ligand antibody humanized anti-human CD154 was prepared as previously described [6,7] and shipped in solution by Biogen Corporation, Cambridge, MA.
  • the hamster anti-mouse CD28 monoclonal antibody PV-1 (IgGl, clone G62) was purified from hybridoma culture supernatants and used as in isotype control monoclonal antibody.
  • Donor-recipient combinations and animals chosen for third party cells were selected based on genetic non-identity at both MHC class I and class II.
  • Class I disparity was established by one-dimensional isoelectric focusing as previously described [13] .
  • Class II disparity was established based on the results of unidirectional mixed lymphocyte reactions (MLRs) .
  • MLRs mixed lymphocyte reactions
  • the animal's DRB loci were verified to be disparate by denaturing gradient gel electrophoresis and direct sequencing of the second exon of DRB as previously described [14] . Vigorous in vitro T cell responsiveness of the recipient towards the donor was confirmed in vitro for all donor-recipient pairs.
  • the experiments described in this study were conducted according to the principles set forth in the "Guide for the Care and Use of Laboratory Animals" Institute of Laboratory Animals Resources, National Research Council, DHHS, Pub. No. (NIH) 86-23 (19850) .
  • Unidirectional MLRs were performed on all animals prior to transplantation and on rejection free survivors after 100 days. Each animal was tested against all potential donors to establish the highest responder pairs for transplantation.
  • Responder cells (3 x 10 5 ) were incubated with irradiated stimulator cells (1 x 10 s ) at 37°C for 5 days. Cells were pulse- labeled with 3 H-thymidine and proliferation was monitored by 3 H-thymidine incorporation.
  • Polyclonal stimulation with Concanavilin A 25 mcg/ml served as a positive control. A stimulation index was calculated by normalization to self reactivity, which in all cases was near background incorporation.
  • CTLA4-Ig or humanized anti-human CD154 was added to the MLR on day 1 at concentrations ranging from 100 mcg/ml to 0.01 mcg/ml. Combined treatments were performed by varying the CTLA4-Ig concentration and holding the humanized anti-human CD154 concentration steady at 50 mcg/ml.
  • Peripheral blood lymphocyte phenotype analysis was performed prior to transplantation and periodically during and after drug therapy. Assays evaluated 0.2 ml of heparinized whole blood diluted with phosphate buffered saline and 1% fetal calf serum. FITC labeled Til, Bl (Coulter) , and FN18 (the generous gift of Dr.
  • CD2 T cell/NK cell
  • CD20 B cell
  • CD3 T cell positive cells respectively.
  • Red blood cells were removed from the preparation by ACK lysis buffer (0.15 M NH 4 C1, 1.0 mM KHC0 3 , 0.1 mM Na 2 EDTA, pH 7.3) treatment following staining.
  • Cells were subjected to flow cytometry immediately, or following fixation in 1% paraformaldehyde . Flow cytometry was performed using a Becton Dickinson FACSCAN.
  • Renal allotransplantation was performed as previously described [13] . Briefly, outbred juvenile (1-3 years of age) rhesus monkeys, seronegative for simian immunodeficiency virus, simian retrovirus, and herpes B virus, were obtained from the Primate Center (University of Wisconsin) or LABS (Yemassee, SC) . Procedures were performed under general anesthesia using ketamine (1 mg/kg, i.m.), xylazine (1 mg/kg, i.m.) and halothane (1%, inhaled). Transplantation was performed between genetically distinct donor-recipient pairs as determined by the MHC analysis described above.
  • the animals were heparinized during organ harvest and implantation (100 units/kg) .
  • the allograft was implanted using standard microvascular techniques to create an end to side anastamosis between the donor renal artery and recipient distal aorta as well as the donor renal vein and recipient vena cava. A primary ureteroneocystostomy was then created. Bilateral native nephrectomy was completed prior to closure. Animals were treated with intravenous fluid for approximately 36 hours until oral intake was adequate. Trimethaprim-sulfa was administered for 3 days for surgical antibiotic prophylaxis. Each animal received 81 mg of aspirin on the day of surgery.
  • Biopsies were performed on animals suspected of having rejection using a 20-gauge needle core device (Biopty-Cut, Bard) . Standard staining with hematoxylin and eosin was performed on frozen or formalin fixed tissue to confirm the diagnosis of rejection. Animals were euthanized at the time of anuria or if a weight loss of 15% of pre-transplant body weight occurred in accordance with AAALAC standards. All animals underwent complete gross and histopathological evaluation at the time of death.
  • CTLA4-Ig and humanized anti-human CD154 inhibited rhesus MLRs in a dose dependent fashion (Fig. 1) .
  • CTLA4-Ig was, however, more effective than humanized anti-human CD154 as a single agent in preventing T cell proliferation.
  • Substantial reduction in thymidine incorporation was seen at a CTLA4-Ig concentration of 0.1 mcg/ml, and further inhibition was achieved at higher concentrations.
  • Modest reduction in proliferation was achieved with humanized anti-human CD154 concentrations of 0.01 mcg/ml but inhibition was not substantially improved by increasing concentrations. Both agents acted synergistically, the combination inhibiting proliferation approximately 100 times more effectively than either agent alone did.
  • graft loss was due to cellular rejection indistinguishable from that seen in the control animals.
  • One animal was treated with CTLA4-Ig 20 mg/kg on the day of transplantation followed by a 12 day course of 10 mg/kg every other day and had graft survival prolonged to 30 days ⁇ Fig. 2A) ⁇ .
  • graft loss was due to acute cellular rejection.
  • Extrapolating from previously published work in the rat heterotopic cardiac allograft model of Turka, et al [9] a donor specific transfusion of lymph node derived lymphocytes (10 8 ) was given at the time of transplantation to this 2 animals.
  • Fig. 2A Two animals were treated with humanized anti-human CD154 alone (Fig. 2A) . Both animals received 20 mg/kg every other day beginning on the day of surgery and continuing for 14 post-operative days (8 doses total) . Both animals experienced extended rejection free survival, although transient creatinine elevations were recorded during the second and fourth post-operative weeks. Both animals rejected between 95 and 100 days post -transplant . Biopsy was performed on each animal to confirm the diagnosis (Fig. 3B) . Both animals were then retreated with 7 doses of humanized anti -human CD154 (20 mg/kg; one animal every other day and one animal daily) and both returned to normal graft function with no demonstrable adverse effects. They remain alive and well greater than 150 days__ after transplantation at the time of this writing.
  • both of these animals had transient increases in their creatinine combined with an increase in graft size during the fourth pos -operative week. It was hypothesized that this graft swelling reflected a second wave of infiltrating lymphocytes and therefore led to a modified dosage schedule such that both reagents were given on the day of surgery and on postoperative days 2,4,6,8, 12, 16, and 28. Two animals were treated with this modified regimen (Fig. 2B) . Both have experienced rejection free survival, free of illness or alterations in renal function for greater than 150 days. Both remain alive and well at the time of this writing. After 100 days of rejection free survival, MLRs were repeated against donor cells and third party cells.

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Abstract

On décrit un procédé qui permet de prévenir et inverser une crise de rejet de greffe allogénique pour interrompre tant l'interaction de CD80/CD86 et CD28/CTLA-4 que l'interaction de CD40 et CD154. On décrit en outre le résultat du procédé dans le traitement de maladies ou allergies auto-immunes.
EP98930097A 1997-06-11 1998-06-10 Composition et procede pour prevenir des rejets de greffe ou d'autres reponses immunitaires non adaptives des lymphocytes t Withdrawn EP1009432A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US4938997P 1997-06-11 1997-06-11
US49389P 1997-06-11
PCT/US1998/011910 WO1998056417A1 (fr) 1997-06-11 1998-06-10 Composition et procede pour prevenir des rejets de greffe ou d'autres reponses immunitaires non adaptives des lymphocytes t

Publications (2)

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EP1009432A1 true EP1009432A1 (fr) 2000-06-21
EP1009432A4 EP1009432A4 (fr) 2004-07-07

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EP98930097A Withdrawn EP1009432A4 (fr) 1997-06-11 1998-06-10 Composition et procede pour prevenir des rejets de greffe ou d'autres reponses immunitaires non adaptives des lymphocytes t

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EP (1) EP1009432A4 (fr)
JP (1) JP2002504120A (fr)
AU (1) AU748533B2 (fr)
CA (1) CA2291338A1 (fr)
IL (1) IL133070A0 (fr)
WO (1) WO1998056417A1 (fr)

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CA2358435A1 (fr) * 1999-01-08 2000-07-13 Stuart J. Knechtle Procede permettant de prolonger la duree de survie d'une greffe a l'aide d'immunotoxines et par blocage de costimulation des cd154 et cd28
JP2003520828A (ja) * 2000-01-27 2003-07-08 ジェネティクス インスティテュート，エルエルシー Ｃｔｌａ４（ｃｄ１５２）に対する抗体、これを含む結合体、およびその使用
US6797263B2 (en) 2000-05-12 2004-09-28 Beth Israel Deaconess Medical Center, Inc. Compositions and methods for achieving immune suppression
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CA2411962A1 (fr) * 2000-06-09 2001-12-20 Bristol-Myers Squibb Company Procedes de regulation de reponse immunitaire a mediation cellulaire au moyen du blocage des signaux lymphocytaires et du blocage de l'adhesion induite par l'antigene lfa-1
US20040022787A1 (en) 2000-07-03 2004-02-05 Robert Cohen Methods for treating an autoimmune disease using a soluble CTLA4 molecule and a DMARD or NSAID
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JP4463475B2 (ja) * 2001-01-31 2010-05-19 バイオジェン アイデック インコーポレイテッド 腫瘍疾患の治療における免疫調節性抗体の使用
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US20050101012A1 (en) 2001-03-12 2005-05-12 Gerold Schuler CD4+CD25+ regulatory T cells from human blood
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See also references of WO9856417A1 *

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AU748533B2 (en) 2002-06-06
AU7956798A (en) 1998-12-30
WO1998056417A1 (fr) 1998-12-17
EP1009432A4 (fr) 2004-07-07
JP2002504120A (ja) 2002-02-05
IL133070A0 (en) 2001-03-19
CA2291338A1 (fr) 1998-12-17

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