EP1075184A1 - Zusammensetzungen und verfahren zur aktiven impfung - Google Patents

Zusammensetzungen und verfahren zur aktiven impfung

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Publication number
EP1075184A1
EP1075184A1 EP99921790A EP99921790A EP1075184A1 EP 1075184 A1 EP1075184 A1 EP 1075184A1 EP 99921790 A EP99921790 A EP 99921790A EP 99921790 A EP99921790 A EP 99921790A EP 1075184 A1 EP1075184 A1 EP 1075184A1
Authority
EP
European Patent Office
Prior art keywords
receptor
transmembrane protein
cells
interleukin
protein
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Withdrawn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
EP99921790A
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English (en)
French (fr)
Other versions
EP1075184A4 (de
Inventor
David B. Agus
David Scheinberg
Wendy Roberts
Andrew D. Zelenetz
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.)
Memorial Sloan Kettering Cancer Center
Original Assignee
Sloan Kettering Institute for Cancer Research
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Filing date
Publication date
Application filed by Sloan Kettering Institute for Cancer Research filed Critical Sloan Kettering Institute for Cancer Research
Publication of EP1075184A1 publication Critical patent/EP1075184A1/de
Publication of EP1075184A4 publication Critical patent/EP1075184A4/de
Withdrawn legal-status Critical Current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
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • 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
    • A61K39/001102—Receptors, cell surface antigens or cell surface determinants
    • A61K39/001103—Receptors for growth factors
    • A61K39/001104—Epidermal growth factor receptors [EGFR]
    • 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
    • A61K39/001102—Receptors, cell surface antigens or cell surface determinants
    • A61K39/001103—Receptors for growth factors
    • A61K39/001106—Her-2/neu/ErbB2, Her-3/ErbB3 or Her 4/ErbB4
    • 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
    • A61K39/001102—Receptors, cell surface antigens or cell surface determinants
    • A61K39/001103—Receptors for growth factors
    • A61K39/001109—Vascular endothelial growth factor receptors [VEGFR]
    • 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
    • A61K39/001102—Receptors, cell surface antigens or cell surface determinants
    • A61K39/001111—Immunoglobulin superfamily
    • A61K39/001112—CD19 or B4
    • 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
    • A61K39/001102—Receptors, cell surface antigens or cell surface determinants
    • A61K39/001116—Receptors for cytokines
    • A61K39/001119—Receptors for interleukins [IL]
    • 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
    • A61K39/001102—Receptors, cell surface antigens or cell surface determinants
    • A61K39/001124—CD20
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55577—Saponins; Quil A; QS21; ISCOMS
    • 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
    • A61K2039/6081—Albumin; Keyhole limpet haemocyanin [KLH]
    • 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
    • A61K2039/70—Multivalent vaccine

Definitions

  • This application relates to an active vaccine approach to the treatment of cancer and other diseases.
  • the approach is applicable to a number of cancers and diseases, although a preferred embodiment provides an active vaccine for treatment of B cell Non- Hodgkin ' s Lymphoma (NHL) .
  • NDL Non- Hodgkin ' s Lymphoma
  • NHL is characterized by a clonal proliferation of malignant B cells.
  • the treatment of NHL across a broad spectrum of patients remains a challenge, although numerous therapeutic approaches have been proposed and tried.
  • anti-idiotype therapy Treatments have been proposed based on anti-idiotype therapy.
  • anti-idiotype therapy a cell surface molecule which is expressed by malignant cells but not by normal cells is used to create patient-specific antibodies which are then administered to the patient. See, Miller, et al, New Engl. J. Med. 306: 517-522 (1982).
  • Autologous patient- derived idiotype proteins have also been conjugated with keyhole limpet hemocyanin to produce a vaccine which has demonstrated efficacy and can elicit B and T cell immune responses.
  • Hybridoma-derived idiotype was co-cultured with patient-derived dendritic cells which acted as antigen presenters upon re-infusion into the patient and showed clinical efficacy. Hsu et al., Nature
  • Rituximab (Ritvaxan, IDEC/Genentech) is a chimeric human/murine antibody approved for the treatment of patients with relapsed or refractory low-grade or follicular CD20 + B cell NHL. Maloney et al, Blood 90: 2188-2195 (1997).
  • NHL is treated, not by administration of an anti-CD20 monoclonal antibody, but by the administration of CD20 itself, or an immunogenic fragment of the extracellular portion thereof, coupled to or administered with an antigenic carrier moiety such as keyhole limpet hemocyanin (KLH).
  • KLH keyhole limpet hemocyanin
  • the same approach can be used for therapeutics for other diseases and conditions in which target cells possess a transmembrane protein, and is particularly applicable to those diseases and conditions for which administration of antibodies to transmembrane proteins or peptides (i.e., passive therapy) have been shown to provide therapeutic benefits, and especially in the situations where the target is also capable of transducing or receiving a signal important for cell growth or function.
  • This would include, for example, Her2/neu, VEGF receptor, epidermal growth factor receptor, the CD 19 molecule, interleukin-2 -receptor, interleukin-4- receptor, and the P-glycoprotein, also known as the multidrug-resistance protein.
  • Figs. 1A and B show ELISA results for formation of antibodies to human and mouse CD20 in vaccinated mice
  • Figs. 2A and B shows results for binding of control Bl antibodies or antibodies in plasma from a mouse treated with human CD20-KLH conjugate with Raji B
  • Fig. 3 shows CP19 + B cell levels in mice treated with human or mouse CD20- KLH conjugate
  • Fig. 4 shows the domain structure of human Her2
  • Fig. 5 shows the domain structure of human EGFR
  • Figs. 6A-D shows the cross-reactivity of antibodies generated in response to human or mouse CD20 fragments
  • Figs. 7A-D show the importance of carrier protein and adjuvant in generating an immune response
  • Figs. 8A-D shows the immune response generated using different adjuvants
  • Figs. 9A-I shows CP19 + B cell levels in mice treated with human or mouse CD20-KLH conjugate.
  • the present invention provides an active vaccine therapy which can be used in the treatment of a variety of cancers and related conditions in which it is desirable to bring about the death of a target group of cells.
  • immunotherapies targeting cells have sought to obtain a cellular immune response (T-cells that recognize the target cells) , since a humoral immune response (antibodies that recognize the target cells) alone is not deemed sufficient to achieve the desired result of cell death.
  • the present invention departs from this conventional wisdom, and effectively utilizes a humoral immune response against the target cells to provide therapeutic benefit.
  • the targets for therapy include cell surface proteins that when bound by a ligand signal to the cell.
  • the vaccine induced antibody response will mimic ligand binding and cause similar signaling events which can imitate the process of programmed cell death (apoptosis) or halt the cell from growing or change the cancer cell's sensitivity to chemotherapy.
  • a peptide antigen is prepared which contains at least an immunogenic portion of the extracellular domain of CD20 coupled to or administered with an antigenic carrier protein.
  • the CD20 component of the peptide antigen may be syngeneic or it may be xenogeneic.
  • human patients may be treated with a peptide vaccine containing a human or a mouse CD20-fragment.
  • a suitable fragment is the 44 amino acid peptide spanning amino acids 136 to 179 of the sequence of mouse or human CD20. (Seq. ID Nos. 1 and 2) Other immunogenic fragments derived from the extracellular domain of CD20, or the entire
  • CD20 molecule may also be used.
  • Seq. ID. Nos. 3 and 4 shows the nucleic acid and amino acid sequences, respectively, of exon VI (the extracellular domain) of human CD20 as reported by Tedder et al., J. Immunol. 142: 2560-2568 (1989).
  • an "immunogenic fragment” is a molecule which includes at least a portion of the extracellular domain of a transmembrane protein to direct and immunological response to that transmembrane protein when the immunogenic fragment is coupled to or administered with an antigenic carrier protein effective to break tolerance and administered with an adjuvant. It is not required that the immunogenic fragment alone be effective to stimulate an immune response, although such stimulation would not take a given fragment outside the scope of the present invention.
  • a preferred antigenic carrier protein is keyhole limpet hemocyanin which can be coupled to peptides using techniques described in Pierce Catalog Protocol.
  • antigenic carrier proteins which can be used to break tolerance might be used in the invention include immunoglobulins, tuberculin, tetanus toxin and others well known in the art.
  • the peptide antigen containing the CD20 component and the antigenic carrier protein is formulated with a pharmaceutically acceptable adjuvant in a liquid carrier and administered to a patient suffering from NHL or another B cell disease.
  • the composition will generally be administered by injection, for example, intramuscular, subcutaneous or intradermal injection, but might also be administered by way of a DNA vaccine (See US Patent No. 5,580,859, incorporated herein by reference) or a viral vaccine, or after mixing with antigen presenting cells (APC's) such as dendritic cells, ex vivo.
  • APC's antigen presenting cells
  • the antigen may be administered without adjuvant by injection into a host prepared by prior or simultaneous injection of an immune adjuvant.
  • Specific amounts to be administered to a patient can be determined by monitoring the titer of anti-CD20 antibodies developed by the patient, or by an average group of patients using well-known technology.
  • CD20-KLH conjugates declines substantially (-30% decrease relative to controls). (Figs. 3 and 9).
  • the assay used to quantitate B cell depletion detects CD 19 which is also expressed on immature B cells that are CD20-. Thus, the 30% depletion actually underestimates the efficacy of the vaccine against CD20 + B cells. .
  • CD20 fragments are specific for the peptides used, yet are capable of inducing immunity to the corresponding peptide from other species (Figs. 6A-D). Studies showed that in most instances the peptide, carrier protein and adjuvant are all needed for optimal response, although some responses were detected using less than all of the components. (Figs. 7A-D). Several different adjuvants were also tested, and QS21 was found to be the most effective of those tested. (Fig. 8A-D).
  • the vaccines of the present invention are effective via at least two pathways.
  • the generation of a humoral immune response to CD20 is effective to some extent to reduce the numbers of B cells bearing CD20 antigen in a manner consistent with normal immunological response to a target antigen.
  • CD20 has a signaling function
  • the binding of antibody to the CD20 moiety activates this signaling function to trigger apoptotic cell death.
  • Such stimulation of apoptosis has been demonstrated to occur in vitro following passive treatments with a chimeric anti-CD20 antibody.
  • T cell mediated effector mechanisms are involved in the immune response.
  • Table 1 the mouse and human peptide sequences capable of binding to the corresponding mouse and human histocompatability antigens. This information was derived from a search of the NIH Bioinformatics and
  • the invention is not limited to this embodiment. Rather, the inventions encompasses the use of vaccine compositions comprising an immunogenic portions of the extracellular domain of transmembrane protein or peptide, particularly a transmembrane protein or peptide having signaling function, coupled to or administered with an antigenic protein and/or adjuvant to break tolerance.
  • a non-limiting example of another transmembrane protein which can be used in whole or in part in the method of the invention is Her-2/neu.
  • the Her-2/neu oncogene is a receptor-like tyrosine kinase that is expressed on the cell surface of a significant portion of solid tumors. It has been shown that patients with early stage breast cancer have a high titer of antibodies to Her-2/neu. Disis et al., J. Clin. Oncol. 15: 3363-3367 (19967). The amino acid sequence and domain structure of human Her-2/neu are shown in Seq. OD. No. 5 and Fig. 4, and isolation and expression of the extracellular domain has been disclosed.
  • WO 90/14357 which is incorporated herein by reference.
  • a vaccine composition comprising at least an immunogenic portion of the extracellular domain of Her-2-neu (amino acids 22 to 652) coupled to or administered with an antigenic protein or peptide such a KLH can be used as a vaccine to provide the same therapeutic benefits using an active as opposed to a passive approach.
  • transmembrane protein which can be used in whole or in part in the method of the invention is epidermal growth factor receptor
  • EGFR vascular endothelial growth factor
  • a vaccine composition comprising at least an immunogenic portion of the extracellular domain of EGFR (amino acids 25 to 645) coupled to or administered with an antigenic protein or peptide such a KLH can be used as a vaccine to provide the same therapeutic benefits using an active as opposed to a passive approach.
  • Preferred immunogenic peptides would be selected from regions not deleted in the various types of truncated EGFR mutants associated with some cancers.
  • a further non-limiting example of a transmembrane protein which can be used in whole or in part in the method of the invention is VEGF receptor.
  • VEGF receptor A further non-limiting example of a transmembrane protein which can be used in whole or in part in the method of the invention.
  • a vaccine composition comprising at least an immunogenic portion of the extracellular domain of VEGF receptor coupled to or administered with an antigenic protein or peptide such a KLH can be used as a vaccine to provide the same therapeutic benefits using an active as opposed to a passive approach.
  • a transmembrane protein which can be used in whole or in part in the method of the invention is the IL-2 receptor.
  • the IL-2 receptor is expressed on most T-cells malignancies, and there is a data showing that antibodies to the IL-2 receptor can be used in the treatment of T-cell malignancies and autoimmune disorders.
  • a composition is made comprising at least an immunogenic portion of the extracellular domain of the IL-2 receptor (e.g., P55 or P75) , coupled to or administered with an antigenic carrier protein or peptide such as KLH. and used as a vaccine.
  • the vaccine compositions of invention can be used alone or in combination (concurrently or sequentially) with drugs or chemotherapy agents that provide therapeutic benefit for the condition being treated.
  • suitable chemotherapy agents which can be used in combination with the CD20 based vaccine include alkylating agents, anthrocyclines, cis-platinum, fludarabine, corticosteroids and vinca alkaloids. These same chemotherapy agents which might be used in combination with other vaccine compositions for other forms of cancer.
  • EXAMPLE 1 44 amino acid fragments of the extracellular domains of humans and murine
  • CD20 (amino acids 136-179, Seq. ID Nos. 1 and 2) were synthesized using a solid-phase FMOC peptide synthesizer and coupled to KLH using the methodology described in the Pierce Catalog Protocol. The peptide coupled to KLH was then prepared for injection by formulation with QS-21 adjuvant. Balb/c mice were injected according to one of the following protocols on days 1, 8, 15, 22 and 50 of the experiment:
  • mice injected with human CD20 coupled to KLH (Fig. 1 A) or mouse CD20 coupled to KLH (Fig. IB) administration of xenogeneic antibody produced a significant polyclonal antibody response to both human and mouse CD20, while the response following administration of syngeneic antibody was principally limited to antibodies to the syngeneic form of CD20. Either xenogeneic or syngeneic peptide can therefore be used to generate an immune response.
  • Raji cells (a form of human B-cell lymphoma that expresses CD20 on its surface) were blocked with human IgG, washed and then incubated for 30 minutes on ice with a 1 :10 dilution of plasma from a mouse vaccinated with P-190-KLH control or huCD20-KLH.
  • Raji cells were incubated with Bl antibody, or IgG2 as an isotypic negative control. After washing, the cells were incubated with goat-anti-mouse antibody, washed and fixed with 1% paraformaldehyde.
  • Flow cytometry analysis was performed in a Becton-Dickinson FACScan. The results are shown in Figs 2A and 3B, wherein the shaded data set are the experimental data set and the outlined data set is the negative controls. As is apparent, there is a strong binding of mouse antibodies and Raji cells, comparable to that observed with Bl antibody .
  • the absolute number of CD 19 positive cells was significantly reduced in mice treated with either of the CD20 peptide conjugates.
  • the level of CD 19 positive cells is a reflection of the number of CD20 positive B cells, and the number of immature CD19 + , CD20- B cells in the samples.
  • the absolute number of CD19 + B cells actually underestimates the therapeutic efficacy of the treatment for elimination of CD20 + B cells, however, since CD 19 is expressed on B cell progenitor cells before expression of
  • mice were injected five times over two months with one of four treatment protocols as follows: human CD20 (44 aa fragment)-KLH plus QS1 human CD20 (44 aa fragment)-KLH human CD20 (44 aa fragment) plus QS21 KLH plus QS21 Blood was collected on week 9 for analysis by ELISA.
  • Sera from the vaccinated mice were diluted 1:200 and incubated on BSA blocked plates coated with msCD20, huCD20, P190 or KLH.
  • Secondary goat anti-mouse antibody conjugated to alkaline phosphatase was added, and the color change of p-nitrophenyl phosphate substrate was measured at 405 nm.
  • the results are summarized in Figs. 7A-D. In most instances the peptide, carrier protein and adjuvant are all needed for optimal response, although some responses were detected using less than all of the components.
  • EXAMPLE 4 Mice were vaccinated according to the schedule of Example 3 using one of four treatment protocols: human CD20 (44 aa fragment)-KLH plus QS21 adjuvant, mouse CD20 (44 amino acid fragment)-KLH plus QS21, PI 90 (irrelevant protein)-KLH +QS21 and KLH and QS21 alone.
  • Mouse serum samples were evaluated by ELISA for the presence of antibodies reactive with msCD20, huCD20, P190 and KLH. The results are shown in Figs. 6A-D.
  • Antibodies generated in mice after vaccination with human or mouse-derived CD20 fragments are specific for the peptides used, yet are capable of inducing immunity to the corresponding peptide from other species.
  • EXAMPLE 5 Mice were vaccinated five times over two months with huCD20 fragment- KLH conjugate with no adjuvant or in combination with one of three adjuvants: QS21, BCG or Alum. Serum samples from the vaccinated mice were tested by ELISA. The results are summarized in Figs. 8A-D. QS21 was found to be the most effective of those tested.
  • EXAMPLE 6 To confirm the observations of Example 2, nucleated spleen cells were recovered by centrifugation in a density gradient from mice vaccinated with a CD20-KLH conjugate (human or mouse) in the presence of QS21 adjuvant. 1 X 10 6 cells from each mouse were incubated with 2 ⁇ g of rat anti -mouse CD 19 FITC-labeled antibody or with isotope-matched FITC labeled rat antibody. Cells were washed, fixed and analyzed with a Becton Dickinson FACScaliber cytometer. Figs 9A-C, D-F and G-I show the results for three exemplary mice of each vaccination group. The decrease in the peak reflecting levels of CD 19 positive spleen cells in each of the mice is apparent.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
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  • Epidemiology (AREA)
  • Mycology (AREA)
  • Immunology (AREA)
  • Oncology (AREA)
  • Cell Biology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Vascular Medicine (AREA)
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  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
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EP99921790A 1998-05-08 1999-05-07 Zusammensetzungen und verfahren zur aktiven impfung Withdrawn EP1075184A4 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US8487098P 1998-05-08 1998-05-08
US84870P 1998-05-08
PCT/US1999/010065 WO1999057981A1 (en) 1998-05-08 1999-05-07 Compositions and methods for active vaccination

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EP1075184A1 true EP1075184A1 (de) 2001-02-14
EP1075184A4 EP1075184A4 (de) 2002-01-30

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JP (1) JP2002514573A (de)
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WO (1) WO1999057981A1 (de)

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Publication number Priority date Publication date Assignee Title
US7198920B1 (en) 1999-01-29 2007-04-03 Corika Corporation HER-2/neu fusion proteins
EP1272214A1 (de) 2000-04-13 2003-01-08 Bio Life Science Forschungs- und Entwicklungsges.m.b.H. Vakzine gegen krebserkrankungen die sich stützt auf mimotope von auf tumorzellen exprimierte antigenen
US7229623B1 (en) 2000-08-03 2007-06-12 Corixa Corporation Her-2/neu fusion proteins
US6911204B2 (en) 2000-08-11 2005-06-28 Favrille, Inc. Method and composition for altering a B cell mediated pathology
BR0113235A (pt) * 2000-08-14 2004-06-08 Corixa Corp Composições e métodos para a terapia e a diagnose de malignidades associadas com her-2/neu
CU22979A1 (es) * 2000-12-08 2004-09-09 Centro Inmunologia Molecular Combinación inmunoterapéutica para el tratamiento de tumores que sobre-expresan receptores con actividad quinasa en residuos de tirosina
ES2394293T3 (es) * 2001-02-28 2013-01-30 Bio Life Science Forschungs- Und Entwicklungsges.M.B.H. Vacuna contra cánceres que están asociados con el oncogén HER-2/neu
CU23178A1 (es) * 2002-04-15 2006-09-22 Ct Ingenieria Genetica Biotech INMUNOTERAPIA ACTIVA ANTIANGIOGéNICA
FR2844514B1 (fr) * 2002-09-16 2007-10-19 Neovacs Produit immunogene stable comprenant des heterocomplexes antigeniques, compositions les contenant et procede de preparation
EP1576966A4 (de) * 2002-12-27 2006-07-26 Shenzhen Tsinghua Yuanxing Bio Verfahren zur herstellung eines impfstoffs, sowie anti-tumor-impfstoffe
WO2005007673A2 (en) * 2003-07-03 2005-01-27 Rush University Medical Center Immunogenic peptides
US20060018911A1 (en) * 2004-01-12 2006-01-26 Dana Ault-Riche Design of therapeutics and therapeutics

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US5801005A (en) * 1993-03-17 1998-09-01 University Of Washington Immune reactivity to HER-2/neu protein for diagnosis of malignancies in which the HER-2/neu oncogene is associated
US5550214A (en) * 1994-02-10 1996-08-27 Brigham And Women's Hospital Isolated antigenic oncogene peptide fragments and uses

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DATABASE PUBMED [Online] NCBI 11341784, 05 May 2004 PARRY ET AL: 'Identification of MUC1 proteolytic cleavage sites in vivo' *
See also references of WO9957981A1 *
SHAN DAMING ET AL: "Apoptosis of malignant human B cells by ligation of CD20 with monoclonal antibodies." BLOOD, vol. 91, no. 5, 1 March 1998 (1998-03-01), pages 1644-1652, XP002182861 ISSN: 0006-4971 *
ZHANG SHENGLE ET AL: "Augmenting the immunogenicity of synthetic MUC1 peptide vaccines in mice." CANCER RESEARCH, vol. 56, no. 14, 1996, pages 3315-3319, XP002097413 ISSN: 0008-5472 *

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JP2002514573A (ja) 2002-05-21
CA2330212A1 (en) 1999-11-18
WO1999057981A1 (en) 1999-11-18

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