WO1994005329A1 - Stimulation of an antitumor t-cell response using anti-idiotypic antibodies - Google Patents

Stimulation of an antitumor t-cell response using anti-idiotypic antibodies Download PDF

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Publication number
WO1994005329A1
WO1994005329A1 PCT/US1993/008163 US9308163W WO9405329A1 WO 1994005329 A1 WO1994005329 A1 WO 1994005329A1 US 9308163 W US9308163 W US 9308163W WO 9405329 A1 WO9405329 A1 WO 9405329A1
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tumor
antibody
response
antitumor
cytotoxic
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PCT/US1993/008163
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English (en)
French (fr)
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Jenner Technologies
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Application filed by Jenner Technologies filed Critical Jenner Technologies
Priority to JP6507378A priority Critical patent/JPH08502954A/ja
Priority to EP93920425A priority patent/EP0666761A4/en
Priority to AU50973/93A priority patent/AU5097393A/en
Publication of WO1994005329A1 publication Critical patent/WO1994005329A1/en

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
    • 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
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39566—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against immunoglobulins, e.g. anti-idiotypic antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/42—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins
    • C07K16/4208—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an idiotypic determinant on Ig
    • C07K16/4241—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an idiotypic determinant on Ig against anti-human or anti-animal Ig
    • C07K16/4258—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an idiotypic determinant on Ig against anti-human or anti-animal Ig against anti-receptor Ig
    • C07K16/4266—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an idiotypic determinant on Ig against anti-human or anti-animal Ig against anti-receptor Ig against anti-tumor receptor Ig
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
    • G01N33/56966—Animal cells
    • G01N33/56972—White blood cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies

Definitions

  • the invention is related to the field of interfering with the progression of malignancies or other tumors. More specifically, the invention concerns use of anti- idiotypic antibodies to produce an antitumor cytotoxic and/or helper T-cell response.
  • mice with an anti-id preparation that appears to mimic the tumor antigen structure is said to induce anti-tumor immunity in tumor-bearing animals or humans
  • Nepom, G.T. et al . Proc Natl Acad Sci USA (1984) 8JL :2864-2867; Gorczynski, R.M. et al . , Cancer Res (1984) 4_4:3291-3298; Dunn, P.L. et al . , Immunol (1987) 60:181- 186) .
  • the paper also cites an additional report by Herlyn, D.A. et al.
  • the present invention concerns the use of anti- idiotypic antibodies to induce an antitumor T-cell response in tumor-bearing subjects.
  • the invention results from the recognition that the essential elements of the ability of anti-idiotypic antibodies to mediate antitumor activity in a subject resides in their ability to cause the subject to mount a T-cell response to a tumor associated antigen (TAA) .
  • TAA tumor associated antigen
  • the invention involves monitoring the T-cell response of the subject and in aiding the subject in mounting such a response by supplying the anti-id in conjunction with at least one adjuvant which stimulates T-cell response.
  • the invention is directed to a method to induce and monitor an antitumor T-cell mediated response in a tumor-bearing subject which method comprises administering an anti-idiotypic antibody to the subject.
  • the anti-idiotypic antibody has an internal image that mimics a tumor associated antigen characteristic of the tumor that afflicts the subject. The subject is monitored to ensure that a T-cell response is obtained and the protocol can then be adjusted accordingly.
  • the invention is directed to a composition which is useful to elicit an antitumor T-cell-mediated response.
  • the composition contains, in addition to at least one anti-idiotypic antibody with an internal image that mimics the relevant tumor associated antigen, an adjuvant which encourages a T-cell response in the subject.
  • the invention is directed to a method of treatment using these compositions.
  • anti-idiotypic antibody is used in its art-recognized sense.
  • antibodies capable of binding that antigen specifically do so because of a region of the antibody which is an "idiotype” unique to antibodies raised with regard to the stimulating antigen.
  • the conventional antibody-antigen specific immunoreactivity which is used to advantage, for example, in the conduct of immunoassays, relies on the ability of "idiotypic” antibodies to bind antigen.
  • the idiotypic region of the antibody is not perfectly coextensive with the "paratope", i.e., that region which is most complementary to the epitope residing on the antigen. However, the same general regions of the antibody are involved.
  • anti-idiotypic antibodies raised in response to the antigen immunization are themselves treated as antigens, either because they are deliberately administered, or by virtue of their generation in si tu in the first immunization, a secondary population of antibodies called "anti-idiotypic" antibodies is raised. These are antibodies which have unique regions by virtue of their ability to bind the idiotypic antibodies. A certain portion of these anti-idiotypic antibodies will mimic the structure of the epitope presented by the original antigen and to which the anti-ids bind. This subset of the anti-idiotypic population thus in effect behaves in a manner similar to the original antigen.
  • the anti-idiotypic antibodies of the invention are those which bear such an internal image--i.e., they mimic a tumor associated antigen which characterizes the tumor against which a T-cell response is to be mounted.
  • the idiotypic or anti-idiotypic regions of antibodies are located in the immunoreactive portions of the antibody molecule.
  • antibodies unless otherwise specified or evident from the context, are intended to include such immunologically reactive fragments, such as, most commonly, Fab, Fab' , and F(ab') 2 fragments. Ways to prepare both monoclonal and polyclonal anti- idiotypic antibodies which mimic tumor associated antigens is described in detail in U.S. Patent 5,053,224, the disclosure of which is incorporated herein by reference. Briefly, polyclonal anti-idiotypic antibodies may be produced by immunizing animals with monoclonal idiotypic antibodies and screening for antisera which react with idiotypic antibodies to tumor associated antigens. Preferably, a competition assay between the TAA and the antisera is employed; the anti-ids which mimic the antigen are successful competitors.
  • the antisera can be purified by sequential adsorption with immobilized antibody of the same isotype as the monoclonal idiotypic antibody but a different idiotype in order to remove antiisotypic antibodies from the antisera and then with the immobilized monoclonal idiotypic antibody to remove the remaining anti-ids.
  • the purified sera can then be again tested for their ability to bind idiotypic antibodies in competition with TAA.
  • Monoclonal antibody preparations from such animals may also be prepared using standard techniques of immortalizing the antibody secreting cells of the animal and screening the cultures with idiotypic antibodies in competition with TAA. Human or murine monoclonals are preferred; polyclonal preparations in a variety of mammalian systems may also be used.
  • anti-idiotypic antibodies of the invention and the immunologically reactive fragments thereof may also be produced using recombinant techniques provided the relevant portions are sequenced so as to permit the construction of suitable variable regions. Recombinant production of such antibodies or fragments permits the use of chimeric antibodies as well as those natively produced.
  • the anti-idiotypic antibodies are administered for both prevention and treatment of malignancy including solid tumors, for example, tumors located in the lung, colon, rectum, stomach, breast, prostate, pancreas, uterus, ovary, urinary tract, skin, oral cavity, liver, bone, brain, endocrine glands, connective tissue, esophagus, eye and melanoma as well as malignancies of the blood and lymph nodes such as leukemia, lymphoma, and multiple myeloma.
  • malignancy including solid tumors, for example, tumors located in the lung, colon, rectum, stomach, breast, prostate, pancreas, uterus, ovary, urinary tract, skin, oral cavity, liver, bone, brain, endocrine glands, connective tissue, esophagus, eye and melanoma as well as malignancies of the blood and lymph nodes such as leukemia, lymphoma, and multiple myeloma.
  • the anti-idiotypic antibodies of the invention are administered as antitumor vaccines to subjects at risk for the development of malignancy or showing a diagnosis thereof.
  • the compositions are formulated for parenteral administration or for aerosol administration using formulations appropriate to the administration route, such as those described in Remington's Pharmaceutical Sciences, latest edition, Mack Publishing Company, Easton, PA.
  • Suitable routes for parenteral administration include injection, including intraperitoneal, intramuscular, intravenous, and subcutaneous injection.
  • the antibodies are generally formulated in a suitable liquid such as Hank's solution or Ringer's solution, along with suitable excipients providing buffering, stabilizing, and other desirable characteristics, as well as additional components if desired as further described below.
  • Alternative routes for parenteral administration include transmucosal and transdermal administration, generally involving excipients which enhance permeation such as bile salts, fusidic acids, detergents, and the like.
  • additional components for stabilizing the aerosol may also be included.
  • liposomes are desirably used as a carrier to direct the product to the immune system as disclosed in copending application 07/800,474, the disclosure of which is incorporated herein by reference.
  • the dosage range for the antibodies of the invention is of the order of 0.01 ⁇ g-100 mg per dose, preferably 0.1 ⁇ g-10 mg per dose, and more preferably 1 mg-5 mg per dose.
  • Suitable volumes for parenteral administration are about 0.1-5 ml.
  • the antibodies of the invention are administered, generally, in multiple doses typically once per week for one or two months and with decreasing frequency thereafter for a period extending about one year.
  • booster inoculations may be given every two months to five years. Alternate protocols may be appropriate in individual instances.
  • viral vectors are described, for example, by Hruby, D.E., Vet Parasitol (1988) 21:281-282, and by Iiu, S.-I., in "AIDS Research Reviews,” Dekker, Inc., (1991) . 1:403- 416.
  • the viral vectors may be administered in the traditional manner via a skin scratch, or may be included in a liposome injectable as described above.
  • antibodies of the invention may be administered alone, it is a further feature of the invention that these antibodies are administered along with adjuvants which enhance the cellular immune response to the anti-idiotypic antibody.
  • adjuvants include, but are not limited to, Freund' s Complete Adjuvant, Bacillus Calmette-Guerin (BCG) and other bacteria, adjuvant polysaccharides such as glucan, acemannan, lentinan; saponins, detoxified endotoxin (DETOX) , muramyl tripeptide, muramyl dipeptide and their derivatives, SAF1, lymphokines and cytokines such as IL-2 and interferon as well as colony stimulating factors such as GM-CSF, lipid A, monophosphoryl lipid A, alum or immune stimulating complexes in general (ISCOMS) .
  • the efficacy of the treatment is monitored using measurements of the cellular immune response.
  • Such monitoring permits adjustment of the protocol to enhance the effectiveness of the drugs .
  • the assessment of T-cell response is conducted, first, immediately before the start of the protocol in order to establish a baseline; and then determinations are made weekly, biweekly or monthly after the start of the protocol for about 6 months and at decreased frequency thereafter.
  • any convenient timing strategy appropriate to the individual case may be used.
  • a number of methods for monitoring cellular immune response are available.
  • test reaction which is a classic measure of cellular activity which is described in detail as applied to patient testing by Spitler, L.E., in "Manual of Clinical Immunology", Rose, N.R. et al . , eds. , Am Soc Microbiol, Washington, D.C. (1976) pgs. 53-63.
  • a test antigen is injected intradermally in about 0.1 ml saline or other isotonic solvent and the reaction is read 24-48 hours after injection.
  • the reaction consists of the development of erythema and induration at the test site with associated characteristic histopathological changes. These changes may be demonstrated by biopsy.
  • the immunizing antibody cannot be used as the test antigen since positive response would simply reflect reactivity to the murine component of the immunogen.
  • Tumor cells or their extracts or pure tumor antigens should be used as the test antigen.
  • Controls include injection of the solvent alone to rule out nonspecific dermal reactivity or injection of unrelated tumor cells or antigen to demonstrate specificity.
  • Another test for cellular response comprises lymphocyte stimulation. In this approach, the response of the patient's lymphocytes to the test antigens and suitable controls is measured in vitro.
  • the toxicity of the subject's peripheral blood or lymph node lymphocytes to tumor cells can be measured ex vivo in a standard radioactive chromium release assay as described by Yanelli, J.R. et al. , J Immunol (1985) 135:900-905.
  • Purified lymphocytes from the test subject are cultured with 51 Cr tagged tumor cells; varying numbers of effector cells are added to the tumor cells in microtiter plates and the plates are incubated for sufficient time to release label into the supernatant. The supernatants are then removed and counted.
  • cytolytic lymphocyte precursors can be conducted.
  • This method which is more sensitive than the lymphocyte toxicity method of the previous paragraph involves restimulation of lymphocytes in the peripheral blood by tumor cells or antigen in vi tro. This causes proliferation of the target cell as described by Vose, B.M. et al . , Int J Cancer (1982) 3_0:135-142 and by Mitchell, M.S. et al. , Cancer Res (1988) 48 . :5883-5893.
  • the method measures both precursors of cytolytic lymphocytes and mature effector cells .
  • Purified peripheral blood lymphocytes from the test subject are cultured with irradiated tumor cells, using appropriate controls.
  • the tumor cells are labeled with radioactive chromium and added to the cultured lymphocyte/tumor cell mixture. Results are assessed by determining the radioactive chromium release after an additional period of culture.
  • the specificity of the cytolytic reaction can be determined by using different target cell lines such as irrelevant tumors of the same and different histological types as that represented by the immunizing antibody.
  • interleukin-2 in plasma can be used as an index in vivo of T-cell activation. Plasma levels of IL- 2 can be measured conveniently using standard ELISA assays, for example. One such assay is described by Robins, R.A. et al. , Cancer Res (1991) 51:5425-5429.

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PCT/US1993/008163 1992-08-31 1993-08-31 Stimulation of an antitumor t-cell response using anti-idiotypic antibodies WO1994005329A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP6507378A JPH08502954A (ja) 1992-08-31 1993-08-31 抗−イディオタイプ抗体を用いた抗腫瘍ｔ細胞応答の刺激
EP93920425A EP0666761A4 (en) 1992-08-31 1993-08-31 STIMULATION OF AN ANTI-TUMOR RESPONSE OF T-LYMPHOCYTES USING ANTI-IDIOTYPIC ANTIBODIES.
AU50973/93A AU5097393A (en) 1992-08-31 1993-08-31 Stimulation of an antitumor t-cell response using anti-idiotypic antibodies

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US93807992A 1992-08-31 1992-08-31
US07/938,079 1992-08-31

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996001126A1 (en) * 1994-07-06 1996-01-18 Immunomedics, Inc. Multi-stage cascade boosting vaccine
EP1032583A1 (en) * 1998-03-06 2000-09-06 Imclone Systems, Inc. Active immunization against angiogenesis-associated antigens
WO2001012674A1 (en) * 1999-08-13 2001-02-22 Molecular Discoveries, L.L.C. Ovarian cancer cell and myeloma cell surface glycoproteins, antibodies thereto, and uses thereof
US6949244B1 (en) 1995-12-20 2005-09-27 The Board Of Trustees Of The University Of Kentucky Murine monoclonal anti-idiotype antibody 11D10 and methods of use thereof
US7090842B1 (en) 1994-12-28 2006-08-15 Board Of Trustees Of The University Of Kentucky Murine monoclonal anti-idiotype antibody 3H1 sequences for human carcinoembryonic antigen
US7226750B1 (en) 2000-08-08 2007-06-05 Molecular Discoveries, Inc. Ovarian cancer cell and myeloma cell surface glycoproteins, antibodies thereto, and uses thereof
US7354587B1 (en) 1994-07-06 2008-04-08 Immunomedics, Inc. Use of immunoconjugates to enhance the efficacy of multi-stage cascade boosting vaccines
US7901680B2 (en) 2005-10-19 2011-03-08 Ibc Pharmaceuticals, Inc. Dock-and-lock (DNL) vaccines for cancer therapy
US8435539B2 (en) 2004-02-13 2013-05-07 Immunomedics, Inc. Delivery system for cytotoxic drugs by bispecific antibody pretargeting
US8551480B2 (en) 2004-02-13 2013-10-08 Immunomedics, Inc. Compositions and methods of use of immunotoxins comprising ranpirnase (Rap) show potent cytotoxic activity
US8562988B2 (en) 2005-10-19 2013-10-22 Ibc Pharmaceuticals, Inc. Strategies for improved cancer vaccines
US8652484B2 (en) 2004-02-13 2014-02-18 Immunomedics, Inc. Delivery system for cytotoxic drugs by bispecific antibody pretargeting
US9481878B2 (en) 2004-02-13 2016-11-01 Immunomedics, Inc. Compositions and methods of use of immunotoxins comprising ranpirnase (Rap) show potent cytotoxic activity

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
Ann. Surg., Volume 202, No. 1, issued July 1985, W.H. COLE et al., "Need for Immunologic Stimulators During Immunosuppression Produced by Major Cancer Surgery", pages 9-20, see entire document. *
E. HARLOW et al., "Antibodies a Laboratory Manual", published 1988 by Cold Spring Harbor Laboratory, see pages 96-97. *
J. Clin. Invest., Volume 80, issued November 1987, R.C. KENNEDY et al., "Possible Role of Anti-Idiotypic Antibodies in the Induction of Tumor Immunity", pages 1217-1224, see entire document. *
J. Immunol., Volume 137, No. 5, issued 01 September 1986, S. RAYCHAUDHURI et al., "Tumor-Specific Idiotype Vaccines", pages 1743-1749, see entire document. *
J. Immunol., Volume 142, No. 3, issued 01 February 1989, Y. SAEKI et al., "Characterization of Regulatory Idiotope-Specific T Cell Clones to a Monoclonal Anti-Idiotypic Antibody Mimicking a Tumor-Associated Antigen (TAA)", pages 1046-1052, see entire document. *
Proc. Natl. Acad. Sci., Volume 81, issued January 1984, H. KOPROWSKI et al., "Human Anti-Idiotype Antibodies in Cancer Patients: Is the Modulation of the Immune Response Beneficial for the Patient?", pages 216-219, see entire document. *
Science, Volume 232, issued 04 April 1986, D. HERLYN et al., "Anti-Idiotypic Antibodies Bear the Internal Image of a Human Tumor Antigen", pages 100-102, see entire document. *
See also references of EP0666761A4 *
Veterinary Parasitology, Volume 29, issued November 1988, D.E. HRUBY, "Present and Future Applications of Vaccinia Virus as a Vector", pages 281-292, see entire document. *

Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8163887B2 (en) 1994-07-06 2012-04-24 Immunomedics, Inc. Use of immunoconjugates to enhance the efficacy of multi-stage cascade boosting vaccines
US5798100A (en) * 1994-07-06 1998-08-25 Immunomedics, Inc. Multi-stage cascade boosting vaccine
US7354587B1 (en) 1994-07-06 2008-04-08 Immunomedics, Inc. Use of immunoconjugates to enhance the efficacy of multi-stage cascade boosting vaccines
US6132718A (en) * 1994-07-06 2000-10-17 Immunomedics, Inc. Multi-stage cascade boosting vaccine
WO1996001126A1 (en) * 1994-07-06 1996-01-18 Immunomedics, Inc. Multi-stage cascade boosting vaccine
US7090842B1 (en) 1994-12-28 2006-08-15 Board Of Trustees Of The University Of Kentucky Murine monoclonal anti-idiotype antibody 3H1 sequences for human carcinoembryonic antigen
US7083943B1 (en) 1995-01-29 2006-08-01 Malaya Chatterjee Polynucleotides related to murine anti-idiotype antibody 11D10 and methods of use thereof
US7399849B2 (en) 1995-01-29 2008-07-15 University Of Kentucky Research Foundation Murine monoclonal anti-idiotype antibody 11D10 and methods of use thereof
US6949244B1 (en) 1995-12-20 2005-09-27 The Board Of Trustees Of The University Of Kentucky Murine monoclonal anti-idiotype antibody 11D10 and methods of use thereof
EP1032583A4 (en) * 1998-03-06 2005-02-02 Imclone Systems Inc Active immunization against angiotens
EP1032583A1 (en) * 1998-03-06 2000-09-06 Imclone Systems, Inc. Active immunization against angiogenesis-associated antigens
US6986891B2 (en) 1999-08-13 2006-01-17 Molecular Discoveries, L.L.C. Myeloma cell and ovarian cancer cell surface glycoproteins, antibodies thereto, and uses thereof
WO2001012674A1 (en) * 1999-08-13 2001-02-22 Molecular Discoveries, L.L.C. Ovarian cancer cell and myeloma cell surface glycoproteins, antibodies thereto, and uses thereof
US7498129B2 (en) 1999-08-13 2009-03-03 Immunocellular Therapeutics, Ltd. Myeloma cell and ovarian cancer cell surface glycoproteins, antibodies thereto, and uses thereof
US7691376B2 (en) 1999-08-13 2010-04-06 Immunocellular Therapeutics, Ltd. Ovarian cancer cell and myeloma cell surface glycoproteins, antibodies thereto, and uses thereof
US7226750B1 (en) 2000-08-08 2007-06-05 Molecular Discoveries, Inc. Ovarian cancer cell and myeloma cell surface glycoproteins, antibodies thereto, and uses thereof
US8435539B2 (en) 2004-02-13 2013-05-07 Immunomedics, Inc. Delivery system for cytotoxic drugs by bispecific antibody pretargeting
US8551480B2 (en) 2004-02-13 2013-10-08 Immunomedics, Inc. Compositions and methods of use of immunotoxins comprising ranpirnase (Rap) show potent cytotoxic activity
US8652484B2 (en) 2004-02-13 2014-02-18 Immunomedics, Inc. Delivery system for cytotoxic drugs by bispecific antibody pretargeting
US9352036B2 (en) 2004-02-13 2016-05-31 Immunomedics, Inc. Delivery system for cytotoxic drugs by bispecific antibody pretargeting
US9481878B2 (en) 2004-02-13 2016-11-01 Immunomedics, Inc. Compositions and methods of use of immunotoxins comprising ranpirnase (Rap) show potent cytotoxic activity
US7901680B2 (en) 2005-10-19 2011-03-08 Ibc Pharmaceuticals, Inc. Dock-and-lock (DNL) vaccines for cancer therapy
US8562988B2 (en) 2005-10-19 2013-10-22 Ibc Pharmaceuticals, Inc. Strategies for improved cancer vaccines

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EP0666761A1 (en) 1995-08-16
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AU5097393A (en) 1994-03-29
EP0666761A4 (en) 1996-07-17

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