WO1998008541A1 - Inhibition de la reaction immunitaire primaire et/ou secondaire a l'administration repetee d'un vecteur adenoviral au moyen d'anticorps specifiques de cd40l - Google Patents
Inhibition de la reaction immunitaire primaire et/ou secondaire a l'administration repetee d'un vecteur adenoviral au moyen d'anticorps specifiques de cd40l Download PDFInfo
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- WO1998008541A1 WO1998008541A1 PCT/US1997/016487 US9716487W WO9808541A1 WO 1998008541 A1 WO1998008541 A1 WO 1998008541A1 US 9716487 W US9716487 W US 9716487W WO 9808541 A1 WO9808541 A1 WO 9808541A1
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- cd40l
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
-
- 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
- C07K14/4712—Cystic fibrosis
-
- 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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2799/00—Uses of viruses
- C12N2799/02—Uses of viruses as vector
- C12N2799/021—Uses of viruses as vector for the expression of a heterologous nucleic acid
- C12N2799/022—Uses of viruses as vector for the expression of a heterologous nucleic acid where the vector is derived from an adenovirus
Definitions
- the present invention relates to the use of antibodies specific for a helper T cell (T h ) ligand (CD40L). that binds to a receptor (CD40) that is found on B cells and other anigen presenting cells (APCs) and which is required for their activation.
- T h helper T cell
- CD40L helper T cell
- APCs anigen presenting cells
- the antibodies of the invention are useful in reducing the host immune response to recombinant Adenoviral (Ad) vectors carrying a therapeutic transgene. thereby allowing effective repeat administration of such Ad vectors to a host.
- El -deleted replication-defective adenoviral (Ad) vectors are attractive vehicles for gene transfer to host cells because of their ability to transduce a wide variety of dividing and non-dividing cells in vivo (Stratford-Perricaudet et al., Hum. Gene Ther. 1:241 -256 (1990); Rosenfeld et al., £eR 68:143-155 (1992); Zabner et al.. Cell 75:207-216 (1993). Crystal et al.. Nat. Genetics 8:42-51 H 94 Zabner et al.. Nat. Genetics 6:75-83 (1994)).
- Such vectors have been used for transfer of the gene encoding normal human cystic fibrosis transmembrane conductance regulator (CFTR) into airway epithelial cells of experimental animals (e.g. mice, cotton rats, monkeys) and to airway epithelium of individuals with cystic fibrosis (CF) (Rosenfeld et al., £eii : 143-155 (1992); Zabner et al., C ⁇ ll 75_:207-216 (1993); Crystal et al.. Nat. Genetics 8:42-51 (1994); Zabner et al..
- CFTR cystic fibrosis transmembrane conductance regulator
- Such vectors have transiently produced normal chloride ion channel function in CF patient airway epithelial cells.
- Ad vectors The treatment of chronic diseases like CF with Ad vectors will likely require repeated administrations of Ad vectors containing the CFTR gene throughout the lifetime of the patient.
- effectiveness of current Ad vectors is limited by the difficulty in obtaining successful readministration to an individual using a vector of the same Ad serotype, because of adverse immunologic responses.
- Various groups have demonstrated that a strong dose-dependent humoral immune response is induced by Ad vectors leading to the development of Ad-specific neutralizing antibodies, which leads to the inactivation by the host of readministered vector. (Yang et al., .1. Virol. 69:2004-2015 (1995); Kaplan et al.. Gene Ther. 3: 1 17-127 ( 1996); Smith et al.. Gene Ther.
- CTLA4-Ig blocks the B7-CD28 pathway of T cell co- stimulation, which is required for optional activation of T cells.
- Ad-specific antibody levels were reduced in CTLA4-Ig treated mice, the inhibition was not sufficient to allow secondary gene transfer via repeat administration of the vector under the conditions tested (Kay et al., Nat. Genetics 11: 191 -197 (1995)).
- interferon- ⁇ interferon- ⁇
- IL-12 interleukin- 12
- INF- ⁇ is known to upregulate MHC class I on antigen presenting cells (Yang et al.. Proc. Natl. Acad. Sci. USA 92:7257-7261 ( 1995)).
- both INF-Y and IL- 12 while capable of inhibiting humoral immunity, might enhance the elimination of Ad vector transduced cells by CTLS (enhanced T h! response).
- CTLS enhanced T h! response
- TCR T cell receptor
- MHC antigen-major histocompatibility complex
- APC antigen presenting cell
- CD40 is a 50kd molecule that has been identified on the surface of immature and mature B lymphocytes which, when crosslinked by antibodies, induces B cell proliferation.
- Such other APCs include, inter alia, macrophages, dendritic cells, langerhans cells, endothelial cells, basal epithelial cells and thymic cells. (See, e.g.. Foy et al., Ann-
- CD40L also called CD40 ligand or CD40L
- CD40L CD40 ligand
- CD40L (g ⁇ 39) has been shown to be expressed transiently at high levels on activated CD4' T cells (Noelle et al., Proc. Natl. Acad. Sci. USA 89:6550-6554
- CD40L gp39
- CD40L also appears to play an important role in the generation of cellular immune responses as a component of the cascade of events leading to the production of helper cytokines (Foy et al., Ann. Rev. Immunol. 14:591-617 ( 1996); Stuber et al., J. Exp. Med.
- the present invention is directed to reducing the immune response of a host to administered adenoviral (Ad) vectors carrying a therapeutic transgene, thereby allowing for repeat readministration of such vectors to the host without (or with minimized) adverse immune responses.
- Ad adenoviral
- Ad vectors are especially attractive for use in delivering a therapeutic transgene to host cells, e.g.. in gene therapy, based in part on their ability to efficiently transfer the transgene into host cells, particularly non-dividing cells, in vivo.
- significant immune response to such Ad vectors, inflammation and loss of transgene expression has limited the effective use of
- the immune response to Ad vectors appears to be mediated through activation of CD4 + T cells by viral antigens leading to CD8 + cytotoxic T lymphocyte (CTL) and humoral immune responses to the vector.
- CTL cytotoxic T lymphocyte
- the CD40 ligand (CD40L) on T cells and CD40 receptors on B cells and other APCs are involved in generating the adverse immune response to administered Ad vectors.
- the present invention thus provides for co-administration of monoclonal antibodies (MAbs) specific for CD40L together with recombinant Ad vectors in order to minimize or ablate the host immune response to the administered Ad vector, thereby allowing for repeat administration of such vectors and persistent transgene expression.
- MAbs monoclonal antibodies
- MAb to murine CD40L provided for transient blockade of co-stimulation between activated T cells (CD4 ) and B cells/antigen presenting cells (APCs) and inhibited neutralizing antibodies and the cellular response to a co-administered Ad vector.
- Co-administered anti-CD40L MAb also provided for increased persistence of expression of the transgene delivered to host cells by the Ad vector.
- the administration of anti-CD40L MAb interfered with secondary immune (antibody) responses in a preimmunized host to readministered Ad vectors, thereby allowing for repeat administrations of the vector, with high levels of transgene expression.
- antibody secondary immune
- the anti-CD40L MAb is a specific MAb designated MR1, which is a hamster-derived anti-murine CD40L MAb.
- the expressed transgene is the DNA for CFTR or ⁇ -galactosidase.
- Fig. 1 shows the effect of MR1 on the development of Ad-specific antibodies following administration of Ad2/CFTR2 vector.
- Panel A shows Ad-specific serum antibodies.
- Panel B shows Ad-specific IgA levels in the lung.
- Fig. 2 shows the effect of MR1 on efficient readministration of a second dose of an Ad vector.
- the graphs show ⁇ -galactosidase expression in the presence and absence of administered MR1.
- Fig. 3 depicts the effect of MR1 on CTL responses in mice intranasally administered Ad2/ ⁇ Gal4.
- Fig. 4 shows the effect of MR1 on persistence of transgene ( ⁇ -gal) expression in mice.
- Fig. 5 shows decreased lung inflammation to Ad2/CFTR2 in MR 1 -treated mice.
- Fig. 6 shows the effect of MR1 administration on the secondary immune response to Ad vectors.
- Fig. 7 shows the effect of MR1 administration on Ad-specific antibody neutralizing titers upon readministration of Ad vectors.
- Fig. 8 shows the effects of MR1 administration on transgene expression ( ⁇ -gal) upon a third administration of Ad vector.
- the present invention is directed to diminishing or inhibiting adverse immunologic responses in a host individual to an administered Adenoviral (Ad) vector comprising a therapeutic transgene.
- the invention involves co-administering to said host individual an effective amount of an inhibitor for CD40L on CD4 + T cells, particularly an antibody, and more particularly a monoclonal antibody (MAb) specific for CD40L.
- the dosage, timing, and routes of administering the Ad vector and CD40L specific MAb to the host is chosen to be most effective in minimizing or inhibiting the primary and secondary humoral and cellular immune responses in the host to the administered vector. JThus, Ad-specific neutralizing antibodies, CTLs and inflammatory responses are reduced.
- the administration of CD40L specific antibodies allows for repeat administration of the same adenoviral vectors to the host, with minimized adverse immunological consequences and persistent transgene expression in treated host cells.
- the adenoviral (Ad) vector is an Ad 2 vector having a substantially deleted El region and E4 region (except for open reading frame 6).
- the vector further comprises a therapeutic transgene operably linked to expression control sequences (promoter, poly A-tail) inserted into the deleted El region of the vector.
- the vector is Ad2/CFTR2 which contains the DNA coding for cystic fibrosis transmembrane regulator and can, upon administration to airway epithelial cells of CF patients, result in functional chloride ion channel activity in such cells. (Zabner et al.. J. Clin. Invest. 97: 1504- 151 1 (1996)).
- Other vectors useful in the present invention include Ad2/ ⁇ -Gal2 and Ad2/ ⁇ -
- Ad vectors express ⁇ -gal in host cells which can be used as a marker for transgene expression.
- Other Ad vectors comprising additional therapeutic transgenes are within the scope of the invention.
- the effectiveness of the approach to reducing adverse immune responses to Ad vectors is demonstrated in a standard mouse model system, particularly Balb/c mice.
- the Ad vectors used in the invention are intranasally administered to the mice, resulting in Ad infection of host airway epithelial cells (e.g. in the lung).
- CD40L on CD4 T cells was blockaded by co- administration of anti-murine CD40L MAb, particularly the hamster-derived MRl antibody. While whole purified MRl antibody was used, it is expected that fragments of such antibodies, e.g. (Fab') 2 , Fab, Fv and others should also be useful in producing the desired response.
- the anti-human CD40L antibodies for inhibiting inmmune responses to Ad vectors in humans can be either polyclononal or monocional antibodies (MAbs). Such antibodies can be of animal origin such as rabbit or rodent MAbs.
- the anti-human DC40L antibodies can be of human origin. Such antibodies also can be of animal origin. _ £. rodent MAbs, that have been "humanized” using techniques known by those skilled in the art.
- Anti-CD40L MAbs may be made as known in the art. A detailed recitation of methods for producing such antibodies is provided in published PCT application WO95/06666, incorporated herein by reference. Techniques can be used to produce such MAbs in mice, hamsters and rabbits. Likewise, human MAbs to CD40L may be obtained as described in WO95/06666. MRl, a hamster anti-mouse CD40L was produced in ascites fluid and purified by ion exchange HPLC as described by Noelle et al., Proc. Natl. Acad. Sci. USA 89:6550- 6554 ( 1992), incorporated herein by reference.
- antibodies contemplated for use in the present invention include anti-human CD40L MAbs of urine origin as disclosed in WO95/06666 (Example 6). Such antibodies include, inter alia, the hybridomas designated 89-76 and 24-31 that have been deposited with the ATCC.
- anti CD40L antibodies for administration of anti CD40L antibodies to humans, it may be preferable to use antibodies of human origin or those that have been "humanized” to avoid or reduce potential adverse immunological responses to rodent MAbs (e.g. mouse or hamster). It is believed, however, that any such potential adverse effects should be minimal, since the reason for administering antibodies to CD40L is to reduce or inhibit immune responses to a foreign antigen.
- Techniques known to those of skill in the art, e.g.. recombinant technology may be used to construct "humanized" anti-CD40L antibodies that maintain the high binding affinity of the rodent MAbs.
- CDRs rodent complementarity determining regions
- FR framework
- Each V domain contains three CDRs flanked by four FRs.
- the CDRs fold to form the antigen binding site of the antibody, while the FRs support the structural conformations of the V domains.
- Balb/c mice purchased from Taconic Laboratories (Germantown. NY) were used as the model system for assessing the effectiveness of anti-CD40L MAbs in reducing immune responses to administered Ad vectors.
- mice were injected intraperitoneally (IP) with a total of four injections each of 200-250 ⁇ g purified antibody (MRl ) starting on day -2 relative to the time of administering the Ad vectors.
- IP intraperitoneally
- MRl purified antibody
- Ad2/CFTR2 is an Ad2 based vector in which substantially all of the adenoviral
- El region has been deleted and replaced with a CFTR transgene expression cassette comprising a PGK promoter, the CFTR encoding sequence and a BGH poly A site and most of the E4 region has been deleted, except for open reading frame 6 (ORF-6).
- Ad2CFTR2 Ad2CFTR2 to nasal epithelia of CF patients has resulted in restoration of a functional chloride ion channel in treated cells. Zabner et al. J. Clin.
- Ad2/ ⁇ Gal2 is derived from Ad2/CFTR2, but with the CFTR expression cassette replaced by a DNA fragment comprising the CMV promoter, the lacZ( ⁇ -galactosidase encoding) gene and a 5' nuclear localization signal from the SV40T antigen.
- Ad2/ ⁇ Gal4 is similar to Ad2/ ⁇ Gal2 but it contains a complete wild type E4 region rather than just ORF6.
- mice On the day of sacrifice, mice were euthanized with an IP injection of Somlethal.
- the lungs were cleared of blood by vascular per usion with phosphate buffered saline
- PBS paraformaldehyde containing 0.2% glutaraldehyde
- the lung sections were subjectively assessed for morphologic alterations on a scale of 0-
- Ad-specific serum antibodies were evaluated by ELISA techniques as follows. Serial 2-fold dilutions of sample were added to the wells of a 96 well plate coated with photochemically inactivated Ad2 (Lee Biomolecular Research, San Diego,
- Bound virus-specific antibodies were detected by the addition of horseradish peroxidase (HRP)-conjugated goat anti-mouse Ig (IgG, IgM, IgA-specific; Jackson Immunoresearch Laboratories, West Grove, PA). The titer was defined as the reciprocal of the highest dilution of sample which produced an O.D. 490 greater than 0.1.
- HRP horseradish peroxidase
- a standard curve was constructed using a monoclonal antibody against mouse IgA (Harlan Sera-Lab, Wales, England) to coat ELISA plates and capture known amounts of purified mouse IgA (Cappel).
- the O.D. 490 values obtained following the - U addition of HRP-conjugated goat antimouse IgA were plotted against the amounts of IgA standard (ng/ml) added to the wells.
- the concentrations of Ad-specific IgA present in BAL samples were then derived from the standard curve by linear regression analysis.
- CTL Cytoxic T Lymphocyte
- CTL cytotoxic T lymphocyte
- the culture medium consisted of RPMI-1640 medium (Gibco, Grand Island, NY) supplemented with 100 U/ml penicillin, 100 ⁇ g/ml streptomycin, 2 mM glutamine, 5xl 0 "5 M 2-mercaptoethanol, 20 mM HEPES buffer and 10% heat-inactivated fetal calf serum (Hyclone, Logan, UT). Cytolytic activity was assayed after 5-7 days of culture.
- Target fibroblasts were infected with Ad vector at an MOI of 100 for 48h and were treated with 100 U/ml recombinant mouse ⁇ -interferon (Genzyme. Cambridge. MA) for approximately 24 hr before use to enhance MHC Class I expression and antigen presentation to effector CTLS.
- the fibroblasts were labeled with 5 l Chromium ( 5 l Cr;
- lungs from individual mice were homogenized and assayed using the AMPGD kit obtained from Tropix, Bedford, MA.
- the protein concentration in an individual sample was determined using the BioRad DC reagent (BioRad, Hercules, CA) and the results are expressed as relative light units (RLU)/ ⁇ g protein.
- Ad specific neutralizing antibody titers serial 2-fold dilutions of an antibody sample were incubated with live Ad2/CFTR-2 for I hour at 37°C/5% CO in the wells of flat bottom 96 well plates. At the end of the incubation period, permissive 293 cells were added to the wells and the plates were incubated at 37°C/5% CO, for 72-96 hours. The assay was read when control 293 cells incubated alone reached >90% confluency.
- the neutralizing antibody titer was defined as the reciprocal of the highest dilution of sample that showed any detectable protection of 293 cells from cytopathic effects when compared to cells incubated with untreated virus or virus incubated with seronegative serum.
- CD40L MAb MRl (Example 1). 200 ⁇ g/injection mouse of MRl on days -2, +2, +6 and +10) was given (Example 2).
- Ad2/CFTR2 vector (10 9 LU.) was instilled intranasally on day 0.
- Ad specific antibodies were measured as in Example 5. Analysis of serum from these animals by ELISA showed a marked decrease in anti-Ad antibody (IgG + IgM + IgA) titers in MRl treated mice for up to 41 days.
- Fig. 1 A is a graph plotting Ad specific serum antibody titers measured by ELISA.
- mice were instilled intranasally with 10" IU of Ad2/ ⁇ Gal-4 on day 0 and injected with MRl (250 ⁇ g/mouse/injection) on days -2, +2, +5 and +8.
- the spleen cells were collected on day 21 , re-stimulated in vitro with infected syngeneic fibroblasts and tested for cytolytic activity.
- the results shown in Fig. 3 are mean percent lysis from triplicate wells at various target:effector ratios. Spleen cells from MRl treated mice showed decreased yet measurable levels of CTL activity compared to spleen cells from untreated control mice, albeit using an assay that is not strictly quantitative (Example 6).
- transgene expression measured by the quantitative galactosidase assay of Example 7 declined to background levels by day 21 in the untreated controls.
- transgene expression also declined but remained consistently higher than in untreated mice.
- Example 9 Lung tissue from the mice of Example 9 was examined as provided in Example 4 for evidence of histopathological changes in the peribronchial, perivascular and alveolar regions. Lung inflammation characterized by inflammatory cell infiltrates was present on day 5 and was not yet resolved at day 21. On day 5, there were no differences noted between the lungs of mice treated with the vector either with or without MRl antibody treatment (data not shown). However, as shown in Fig. 5, on day 21. there were fewer inflammatory changes in all regions of the lungs from mice treated with the MRl antibody. The inflammatory cell infiltrate was markedly reduced in the peribronchial/ peribronchiolar and perivascular regions.
- MRl was tested for its ability to interfere with the secondary antibody response in mice that had been preimmunized with an Ad vector.
- Mice were intranasally instilled with 10 8 IU of Ad2/CFTR2 on day 0.
- 10 8 IU of Ad2/CFTR2 was intranasally administered to the same mice. It had previously been determined that an intranasal instillation of 10 8 IU of Ad vector elicits both humoral and cellular immune responses to the vector in several strains of mice including BALB/c (data not shown).
- MRl injections were given around the time of the second virus administration on days 44, 48, 52 and 56.
- Fig. 6 shows that the secondary antibody response to Ad measured by ELISA (serial 2-fold dilutions of sera obtained at the indicated times) was quite robust in both MRl -treated and -untreated mice and was only slightly decreased in the MR1- treated mice.
- Ad neutralizing titers were clearly decreased in the mice that had received MRl along with the second administration of the Ad vector (Fig. 7).
- the decline in anti-Ad titers after reaching a peak around day 84, was more rapid in MRl treated mice compared to untreated mice (Fig. 6).
- Ad2/ ⁇ Gal-2 vector On Third Administration of Adenoviral Vectors A third intranasal administration of Ad2/ ⁇ Gal-2 vector was given on day 99 and ⁇ -galactosidase levels in the lung were measured on day 102.
- Control mice that had received the first (day 0) and second dose (day 50) of Ad2/CFTR2 showed only 6% of the ⁇ -galactosidase activity in lung homogenates compared to naive mice that received a single intranasal administration of Ad2/ ⁇ Gal-2 (Fig. 8).
- Mice that received MRl around the time of the second administration of Ad2/CFTR2 showed 10-fold higher levels of transgene expression after the third administration compared to untreated control mice (Fig. 8).
- the effectiveness of the third vector administration in the MRl treated animals was comparable to that obtained in naive mice.
Abstract
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WO2000050051A2 (fr) * | 1999-02-24 | 2000-08-31 | Oncolytics Biotech, Inc. | Reovirus pour le traitement de troubles cellulaires proliferants |
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US6576234B2 (en) | 1997-08-13 | 2003-06-10 | Oncolytics Biotech Inc. | Reovirus for the treatment of neoplasia |
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US7074406B2 (en) | 1995-11-07 | 2006-07-11 | Biogen Idec Inc. | Treating allergic diseases with humanized anti-CD40L antibody |
US7122187B2 (en) | 1995-11-07 | 2006-10-17 | Biogen Idec Inc. | Treating autoimmune diseases with humanized anti-CD40L antibody |
EP2147681A1 (fr) | 1997-10-29 | 2010-01-27 | Genzyme Corporation | Compositions et méthodes pour le traitement de maladies lysosomales |
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US6811775B2 (en) | 1999-02-24 | 2004-11-02 | Oncolytics Biotech Inc. | Reovirus for the treatment of cellular proliferative disorders |
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US8066985B2 (en) | 1999-02-24 | 2011-11-29 | Oncolytics Biotech Inc. | Reovirus for the treatment of cellular proliferative disorders |
US8071087B2 (en) | 1999-02-24 | 2011-12-06 | Oncolytics Biotech Inc. | Reovirus for the treatment of cellular proliferative disorders |
US8709443B2 (en) | 1999-02-24 | 2014-04-29 | Oncolytics Biotech Inc. | Reovirus for the treatment of cellular proliferative disorders |
WO2001094586A2 (fr) * | 2000-06-06 | 2001-12-13 | Idec Pharmaceuticals Corporation | Anticorps non agonistiques diriges contre gp 39 humaine, compositions les contenant et leur utilisation therapeutique |
JP2003535592A (ja) * | 2000-06-06 | 2003-12-02 | アイデック ファーマスーティカルズ コーポレイション | ヒトgp39に対する非アゴニスト抗体、含有する組成物、およびその治療的使用 |
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