WO1993006233A1 - Immunotherapie contre les tumeurs utilisant un procede permettant de vaincre la resistance d'une tumeur en croissance progressive - Google Patents

Immunotherapie contre les tumeurs utilisant un procede permettant de vaincre la resistance d'une tumeur en croissance progressive Download PDF

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WO1993006233A1
WO1993006233A1 PCT/US1992/008013 US9208013W WO9306233A1 WO 1993006233 A1 WO1993006233 A1 WO 1993006233A1 US 9208013 W US9208013 W US 9208013W WO 9306233 A1 WO9306233 A1 WO 9306233A1
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tumor
human
antibody
host
cells
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PCT/US1992/008013
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Lionel A. Manson
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Manson Lionel A
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • 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
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • 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

Definitions

  • Tumor immunotherapy utilizing a method of overcoming the resistance of a progressively growing tumor.
  • the MAbs that have been used clinically with human patients were generated by immunizing mice with human tumor tissue and choosing those mouse MAbs that preferentially reacted with human tumor tissue compared to their reactivity with normal human tissue, and as a consequence not likely to be directed against the molecules expressed on the surface of the tumor cells that the immune systems of the autochthonous host recognize as tumor-specific during progressive tumor growth (EATI) , each such antigenic determinant is referred to in this application as an "oncotope", as described in detail herein.
  • EATI tumor-specific during progressive tumor growth
  • the discoveries made in this laboratory demonstrate that some virus-induced and carcinogen-induced progressively- growing tumors trigger in the tumor-bearing host both a B- cell and a T-cell immune response.
  • the B-cell response resulted in the production of anti-tumor antibodies that coated the tumor cells without harming them or interfering with their rate of growth, but made them resistant to the "killer cells" (T-cell response) that coexisted in the host.
  • a method of overcoming the resistance of a progressively growing tumor in a host to lymphocytotoxic effector cells conferred by an anti-tumor polyclonal antibody response induced in the host comprises the steps of obtaining a sample of the progressively growing tumor from the host, generating at least one human monoclonal antibody directed against at least one oncotope of the progressively growing tumor, subjecting the human monoclonal antibody to an analysis to make a determination of the therapeutic value of the human monoclonal antibody, generating a blocking human antibody which blocks anti-oncotope monoclonal antibodies; and delivering a therapeutic amount of the blocking human antibody to the host to permit the tumor to expose uncovered oncotopes thereby becoming sensitive to lymphocytotoxic effector cells.
  • Fig. 1 shows the prophylactic effect of anti-EATI.
  • a hypertonic salt eluate of 14-day old EL4 tumors (grown in C57BL/6 mice from a subcutaneous inoculation of 5 x 10 4 cultured EL4) was made, centrifuged at 100,000 x g. , dialyzed overnight against PBS-azide, centrifuged after dialysis and concentrated to a volume of 1 ml/gm of original tumor. It contained 7.4 ⁇ g/ml of specific binding Ig when assayed on
  • DBA/2 mice injected with PBS, served as controls.
  • All animals received a challenge dose of 1 x 10 4 P815Y cultured cells inoculated i.p. All ascites were removed on day 15 after tumor challenge and the total number obtained plotted in the graph;
  • Fig. 2 exemplifies a direct radioimmunoassay for anti-membrane Ig.
  • the solid phase in this assay were filter- paper discs, 3/16 in diameter, (542 Whatman paper activated with cyanogen bromide and to which had been coupled either L5178Y MLP or thoroughly washed membrane preparations, of lysed sheep red blood cells (SRBC) ) .
  • the SRBC membrane discs and a highly affinity-purified anti-SRBC Ig preparation were used to standardize the 125I-anti FAB used in the assay.
  • This assay was run in parallel with the L5178Y MLP discs and the
  • M24F antiserum C57BL/6 anti-L5178Y (H-2 ) serum
  • M24F serum C57BL/6 anti-L5178Y (H-2 ) serum
  • Fig. 3 is an antigen inhibition assay. A 1:100 dilution of the M24F serum in PBS was incubated with the indicated amounts of either the syngeneic MLP (EL4) or the allogeneic MLP (L5178Y) . The MLP is particulate, thus easily pelleted by centrifugation at 100,000 x g. for 10 min. The supernatant fluid was then titered as indicated in Fig. 2.
  • EL4 syngeneic MLP
  • L5178Y allogeneic MLP
  • Fig. 4 shows the immunoprecipitation studies with P815Y.
  • Tumor cells were grown in medium containing 3 H- glucocsa ine, 3 ⁇ Ci/ml for 3 days. At this time, greater than 70% of the isotope in the medium was incorporated into the growing cells. Cells were harvested, washed and lysed in o
  • Cowan I organisms After 2 hour incubation, the preparation was pelleted. The clear supernatant fluid was divided into 2 aliquots. One was precipitated with 2 ⁇ l. of D4 antiserum, the other with 2 ⁇ l. of a P815Y eluate. After overnight incubation, coated Staph. aureus pellets were added, and 2 hours later pelleted. To each supernatant fluid was added 2 ⁇ l. of D4 antiserum and the process repeated. To each of the four Staph. aureus pellets was added 0.2 ml. of a 2% sodium dodecyl sulfate-2% mercaptoethanol solution and the tubes placed in a boiling water bath for 3 minutes.
  • the eluates were then chromatographed on a 12% SDS-polyacrylamide discontinuous gel containing molecular weight markers as indicated in the figure, A was bovine serum albumin (68,000 kDa) B was egg albumin (48,000 kDa) and C was trypsinogen
  • HMAbs human monoclonal antibodies
  • HMAbs-2 sometimes referred to herein as human blocking antibodies
  • the source of immune B cells with these latter activities will again be B-cells of the tumor-bearing patient.
  • HMAbs directed against the oncotopes of various tumors will be immediately useful for classifying human tumors, will provide standardized reagents for diagnostic tests and be the primary reagents for biochemically describing EATI. Since they are specific for the oncotopes and should show little or no cross-reactivity for normal tissue, they should be ideal carriers for agents lethal to tumors, such as radioactive atoms and toxins (immunotoxins) .
  • the major advantage of this form of therapeutic intervention is that all of the effector reagents proposed to be used will act in a specific way on the immune systems of the host and therefore not interfere with the ability of the host immune systems to react against any non-tumor immunogens, such as bacteria, viruses and other infectious agents, and therefore not interfere with the capacity of the host immune systems to continue to act as a major defense system for the host.
  • the state of understanding at the present time of the immunological relationships between a host and the autochthonous tumor it may be bearing is in a state of disarray. There is no consensus that any or all such tumors in humans have triggered an immune response in the host during the time that the tumor has expanded from a single cell until the time that the tumor can be detected clinically (more than 10 cells) . The same can be said of the immune responses to tumors of experimental animals, be they autochthonous or transplantable.
  • tumor-specific antigens expressed on tumors, however there is no consensus as to what constitutes immunogenicity, what defines a tumor-specific antigen, what immune responses have taken place in the tumor- bearing host and are these responses compatible with progressive tumor growth.
  • the resistant cells were found to be covered with antibodies the host had synthesized, directed against the tumor-unique structures. These anti-tumor antibodies were found only on the growing tumor cells in the tumor-bearing host, and not in its serum. Since the host has a limited capacity to synthesize these antibodies, the tumor cells bind all that is made as soon as it is elaborated and therefore none was found in the serum.
  • mice normal mice were immunized with the antibody preparation eluted from in vivo grown tumor cells, as published by Manson, Transpl. Proc, Vol. 16, 524-527, (1984) .
  • Three mice were pre-immunized with one injection of 1 ⁇ g. of the eluted antibody each, then challenged six days later with 10 4 tumor cells. Fifteen days later, the number of tumor cells detectable in the ascites of these animals as well as three control animals was determined.
  • Fig. 1 In Fig. 1 are shown the results, the three controls showed normal ascites growth of tumor, whereas two of the three animals given anti-tumor antibody showed no significant tumor growth. It was concluded that an anti-idiotype response was most probably responsible for the rejection of the tumor, i.e. the rate of formation of the blocking antibody was interfered with whereas the rate of formation of the "killer cells" was not affected by the treatment, thus leading to the elimination of the challenge tumor dose.
  • EATI emergence-associated tumor immunogens
  • the gene product of Class I genes is a glycoprotein, 46-49 kDa in size, with multiple antigenic determinants (epitopes) in the molecule.
  • epitopes multiple antigenic determinants (epitopes) in the molecule.
  • inbred mice the large polymorphism seen with respect to these epitopes (more than one hundred) have been organized into two types, those that are specific for a single strain of mouse ("private") and those that are found in several different mouse strains (“public”) .
  • a similar system has been found with human tissue-typing data, namely a large degree of polymorphism that can be observed as "public” and "private” epitopes, a combination of which constitute the Class 1 antigens of the human MHC (HLA) .
  • the reagents which made this classification possible in humans and in mice are antibodies directed against these epitopes which describe this polymorphism.
  • Private oncotopes - each tumor may have a unique oncotope, characteristic of that tumor, and different from that found in every other tumor;
  • HMAbs human hybridomas secreting monoclonal antibodies directed against such oncotopes with a variety of malignant tumors.
  • the objective will be to develop a panel of such HMAbs for diagnostic studies, classification of tumors and ultimately for therapeutic purposes as will be described in this application.
  • the individual whole tumor line cells will be used as the solid-phase immunoadsorbent in the enzyme-linked immunoadsorbent assay (ELISA) and as a source of cell-free membrane particulates ( icrosomal lipoproteins, MLP) which are bound to filter paper discs that become the solid phase immunoadsorbent in the radioimmunoassay (RIA) to detect, assay and quantify a polyclonal anti-tumor antibody as well as HMAbs. Only small amounts of tissue will be required to initiate such cultures. It may be possible to use a portion of the sample removed from the patient at the initial biopsy for diagnostic purposes as a source for tissue culture-grown cells.
  • ELISA enzyme-linked immunoadsorbent assay
  • MLP cell-free membrane particulates
  • RIA radioimmunoassay
  • Successful cultures have also been developed by dissociating solid tumors, carcinomas and sarcomas with a mixture of enzymes (deoxyribonuclease, hyaluronidase and a bacterial collagenase) .
  • a goodly proportion of the tumor cells survive the dissociating protocols and will then grow as adherent cultures on plastic surfaces with normal tissue culture media.
  • enzymes have been used to dissociate the tumor cells, it is essential that the cells undergo several days growth in culture in order to re-express the oncotopes on the surface membranes of the cells. It is also essential that the cells be removed from the plastic surfaces by scraping, enzymes should not be used.
  • Radioimmunoassay RIA
  • MLP particles are prepared from tumor cells grown in culture or normal tissues such as spleen, liver, kidneys as described by Manson & al, J. Cell Comp. Physiol. Vol. 61, 109-118 (1963). These MLP particles, microsomal in size, were shown to be complete histocompatibility and tumor immunogens by Manson & al, Transpl. Proc, Vol. 7, 161-164 (1975).
  • the cell-free particles are covalently bound to cyanogen-treated filter paper discs, 3/16 in, diameter (Whatman No. 52) , 2 ⁇ g protein per disc.
  • MLP discs are placed in flat- bottom wells of a 96-well Microtiter plate. A dilution containing 0.5-2 ng. of specific antibody is added to the well (diluted in PBS buffer which contains 0.2% bovine serum albumin and 2% horse serum) and incubated at room temperature overnight. The wells are washed and an 125I-labelled anti- immunoglobulin is added and the plates incubated again overnight. The discs are washed, dried and counted in a gamma-spectrometer. As indicated in Fig. 2, a linear relationship was observed between the 125I bound to the disc and the original anti-membrane antibody added to the discs.
  • FIG. 3 is an example of such an assay.
  • An assay such as this was used to detect the presence of materials in sera obtained from women with metastatic mammary cancer that might be cross-reactive to epitopes found on mouse mammary tumor virus, using a panel of MAbs developed against mouse mammary tumor virus, as published by Manson & al, in Current Controversies in Breast Cancer, ed. by Ames & al. p.425-431, University of Texas Press, Austin (1984).
  • Tumor cells (0.5-1.0 x 10 per well) are attached to the bottom of flat-bottom 96-well polyvinyl chloride Microtiter plates, treated with poly-1- lysine. The cells are lightly fixed and covalently-bound to the PLL layer with glutaraldehyde. Antibody dilutions are then assayed by being adsorbed onto the cells in the well, which are then reacted with a purified anti-immunoglobulin reagent that has been conjugated to an enzyme, such as horseradish peroxidase, alkaline phosphatase or ⁇ - galactosidase. After an appropriate period of time, the conjugate is washed out and substrate for the enzyme added.
  • an enzyme such as horseradish peroxidase, alkaline phosphatase or ⁇ - galactosidase.
  • ELISA test is much more rapid than the RIA, but not as sensitive.
  • a sensitivity approaching that seen in the RIA has been obtained using 0-galactosidase and a fluorescent substrate, methylumbelliferyl galactoside and a fluorescence plate reader.
  • MLP Membrane Fractions Rich In EATI
  • Washed cultured cells are suspended in a hypotonic medium containing a variable amount of sucrose (0-0.18 M, depending on the particular cell that is being used) but always 0.01 M in Mg + .
  • the cells are homogenized in a nitrogen decompression apparatus, which results in complete breakage of the cells but very little breakage of nuclei.
  • the homogenate is then fractionated by differential centrifugation, the fraction sedimenting after 10' at 5000 x g is discarded, whereas the pellet obtained after 1 hour at 100,000 x g is retained
  • microsomes This pellet is suspended in a ground-glass homogenizer in 2 M sucrose, and centrifuged in a swinging bucket rotor overnight. The pellicle floating at the top of each tube is suspended in distilled water and preserved at either 0"C or -20°C as is required.
  • the usual yield of MLP per gram of tissue used is 2-4 mg. of protein as assayed in a fluorescent protein assay using BSA as a standard.
  • B cells A significant percentage of the lymphoid cells found in the peripheral circulation are B cells (15-30%) .
  • the amount of anti-EATI that will be produced in such cultures is expected to be small. It is intended to cryopreserve these cultures at this stage to permit these to be used as starting preparations for developing anti-tumor HMAbs.
  • Tumor Tissue Immune B cells may be isolated from the tumor itself taken from the tumor bearing patient during a biopsy or surgery. Solid tumors are relatively easily dissociated with enzymes as has already been described. The tumor cells will most likely be adherent to plastic, whereas lymphoid cells are not, and therefore easily removed from such cultures. These lymphoid cultures will then be immortalized with EBV as described above and cryopreserved.
  • MLP can act as a complete immunogen in vitro and in vivo as reviewed by Manson &
  • EBV immortalization procedure works best with resting B cells, thus cultures stimulated with MLP will be allowed to rest before EBV treatment.
  • the first step will be to obtain immune B cells from the patient and immortalize them with EBV as described above.
  • the EBV transformed cultures are known to be polyclonal. Procedures will be used to enhance antibody production to permit isolating hybridomas secreting HMAbs.
  • lymphoid cells To 10 lymphoid cells are added an equal number of log phase growing SP2/0-Agl4 myeloma cells (drug-marked, nonsecretory; ATCC #CRL 1581) . The cell mixture is centrifuged. To the well- drained pellet, warmed to 37°C is added drop-wise 1 ml. of 50% PEG, also warmed to 37°C. All subsequent reactions are carried out at 37°C. One milliliter of serum-free medium is added slowly over a period of 1 min. This step is then repeated. Next is added 7 ml. of serum-free medium over 2-3 min., after which time the cells are pelleted. To the pellet is added 30 ml.
  • samples of the supernatant fluid are tested in either the RIA or ELISA for reactivity against cell surface oncotopes. Those that test positively are then tested for lack of reactivity against a cell line, also grown in culture, that does not express the oncotope.
  • fibroblast cultures will be derived from scrapings taken from inside the check or surgically removed from the patient's skin, as described by Sly and Grubb,
  • a first objective will be to find a continuously-growing cell line that may act as a negative control cell for RIA and
  • Equal aliquots of the treated cell extract were allowed to react with 2 ⁇ l each of the P815Y-eluate or D-4 antiserum (an antiserum obtained from the Transplantation Immunology Branch of the National Institute of Allergy and Infectious Diseases of the National Institutes of Health in Bethesda, MD) specifically directed against the #4 specificity of the Major Histocompatibility Complex Class I gene product, a private specificity for the H-2 haplotype. Both supernatant fluids obtained from this immunoprecipitation step were treated with the D4 antiserum. The four pellets that were obtained were subjected to sodium dodecyl sulfate gel electrophoresis with internal molecular weight standards.
  • HMAb As soon as HMAb is obtained, it will be possible to screen the immortalized and cryopreserved polyclonal B cell populations for their capacity to elaborate anti-HMAb activity. Since the original immortalized populations will be secreting polyclonal anti-EATI, it may not be possible to detect the presence of a clone that has the capacity to synthesize HMAb-2 and secrete it into the supernatant fluid. Such molecules will be neutralized by the polyclonal anti- EATI and their presence would not be detectable in an ELISA.
  • a B cell which is secreting anti-EATI should also have a surface im unoglobulin with the same anti- EATI idiotype. Two procedures will be used to take advantage of this fact. In one, it should be possible to allow the immortalized B cells to adsorb onto live cultures of the tumor line, expecting that they would attach themselves to the EATI molecules of the tumor cells. If the immortalized B cells obtained from the patient contain B cell secreting anti-idiotype immunoglobulin, they would have an idiotype that mimics the three-dimensional structure of EATI and therefore would not bind to the tumor cell monolayer. Thus, after a suitable adsorption period at 37°C, the non-adsorbed lymphoid population will be removed and cultured separately.
  • the supernatant fluid elaborated by such cultures will be assayed in an ELISA or RIA.
  • the solid phase will be a plastic surface to which will first be attached a mixture of rabbit anti-human Fc purified IgG, rabbit anti- human IgM and rabbit anti-human IgA.
  • the rabbit immunoglobulin will bind all the human immunoglobulin secreted by the purified population of immortalized B cells.
  • the surface will then be reacted with an 125I-culture supernatant fluid from the original immortalized B cell cultures. If any anti- idiotype immunoglobulins are being produced by the frac ⁇ tionated B cell populations, they should bind 125 I-anti-EATI present in the culture fluids. A positive result will be an indication to continue to process this population of B cells into the human-mouse hybrid stage to be a source of mRNA for HMAb-2 production, and for significant quantities of HMAb-2.
  • the affinity binding constant of avidin with biotin is several orders of magnitude higher than that of antibodies combining with their antigens.
  • the developers propose to biotinylate an antibody which will bind uniquely with a subpopulation of cells, then pass the mixture of cells, some coated with biotmylated antibody, the majority free, through a solid phase bead column to which has been bound avidin covalently.
  • HMAb anti-oncotope antibody
  • HMAb-2 anti-oncotope idiotype
  • HMAb and HMAb-2 Large scale production of HMAb and HMAb-2 Some experience has been obtained with commercially-developed methods for production of milligram quantities of mouse Mabs that may prove useful in obtaining larger quantities of HMAbs or HMAbs-2.
  • One such procedure, developed by Damon Corp. involved encapsulating hybridoma cells in Ca-alginate "microcapsules".
  • the anti-MMTV gp-52 Mab VE7 was encapsulated and the capsules incubated in an appropriate medium for 7 days. At the end of this time, the capsules were harvested and their contents liberated into 5 ml of saline. The yield of material, as assayed by RIA, was 5.6 mg. of VE7 per ml starting with 2 x
  • Another apparatus that used in the laboratory to obtain milligram amounts of Mab was the Amicon Vitafiber artificial capillary unit.
  • a culture was initiated with 1 x 10 7 cells of VE7 and culture continued in the apparatus for 14 days. At the end of that time the contents of the chamber were removed.
  • Hasemann and Capra Proc. Nat. Acad. Sci. USA, Vol. 87, 3942-3946, (1990) describe the successful production of a mouse Mab by a baculovirus expression system using, as a vector, a double-recombinant virus containing both the immunoglobulin heavy and light chain cDNA.
  • a major advantage of using this insect system is that late in virus infection as much as 50-75% of total cellular protein is claimed to be the foreign protein.
  • the authors claim that the rig produced in culture is identical to that produced by the parent Mab grown in mouse ascites using a variety of functional tests.
  • lymphoid lines used in my laboratory such as P815Y, P815-X2, L5178Y, EL4 or L1210.
  • L5178Y have been grown under chemostat conditions in 8L stirred vessels and achieved higher than 6 xlO cells per ml. over a number of days. All of the cell lines are immunoglobulin-negative and therefore may prove useful as hosts for recombinant immunoglobulin production.
  • lymphoblastoid cell lines utilized are easily grown in large quantities also in other commercial apparatuses.
  • the antibody combining site for EATI or for anti-EATI are the functional molecules aimed for, since they should have equal blocking and combining capacity to the entire Ig molecule.

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Abstract

Procédé permettant de vaincre la résistance d'une tumeur, en croissance progressive dans un individu, aux cellules effecteurs lymphocytotoxiques développées au cours d'une réaction aux anticorps polyclonaux antitumoraux induite dans l'individu. Le procédé consiste à prélever sur le sujet un échantilon de la tumeur en croissance progressive, à produire au moins un anticorps monoclonal humain dressé contre au moins un oncotope de la tumeur, à soumettre cet anticorps monoclonal humain à une analyse pour en déterminer la valeur thérapeutique, à produire un anticorps humain bloquant les anticorps monoclonaux antioncotopes, et à administrer au sujet une quantité thérapeutique de l'anticorps bloquant, afin que la tumeur expose des oncotopes découverts, devenant ainsi sensible aux cellules effecteurs lymphocytotoxiques.
PCT/US1992/008013 1991-09-19 1992-09-15 Immunotherapie contre les tumeurs utilisant un procede permettant de vaincre la resistance d'une tumeur en croissance progressive WO1993006233A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0325847A1 (fr) * 1987-11-30 1989-08-02 Idec Pharmaceuticals Corporation Procédé pour la sélection d'anticorps anti-idiotypiques, et leur utilisation pour le diagnostic, la surveillance, et le traitement de maladie

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0325847A1 (fr) * 1987-11-30 1989-08-02 Idec Pharmaceuticals Corporation Procédé pour la sélection d'anticorps anti-idiotypiques, et leur utilisation pour le diagnostic, la surveillance, et le traitement de maladie

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
BIOESSAYS vol. 8, no. 2, 1988, CAMBRIDGE UK pages 74 - 78 VERHOEYEN M. ET ALL 'Engineering of antibodies' *
CANCER DETECTION AND PREVENTION vol. SUP.1, 1987, NEW YORK pages 111 - 120 MANSON, L.A. 'Novel tumor-specific antigen(s) response observed in a syngeneic lymphoma-bearing host' cited in the application *
FASEB JOURNAL vol. 2, no. 6, 25 March 1988, BETHESDA, MD US page A1836 L.A.MANSON 'The role that an antitumor antibody plays during progressive growth of P815Y in syngeneic host' *
IMMUNOLOGY TODAY vol. 10, no. 2, February 1989, AMSTERDAM page 36 MANSON L.A. 'Tumor immunotherapy' *
JOURNAL OF IMMUNOLOGICAL METHODS vol. 100, 1987, AMSTERDAM pages 5 - 40 KEITH JAMES 'Human monoclonal antibody production. Current status and future prospects' *
TRANSPLANTATION PROCEEDINGS vol. 16, no. 2, April 1984, NEW YORK pages 524 - 527 L.A.MANSON 'The role of anti-tumor antibody in progressive tumor growth' cited in the application *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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

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