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Title: Alpha particle radioimmunotherapy: Animal models and clinical prospects

Abstract

Short-lived isotopes that emit alpha particles have a number of physical characteristics which make them attractive candidates for radioimmunotherapy. Among these characteristics are high linear energy transfer and correspondingly high cytotoxicity; particle range limited to several cell diameters from the parent atom; low potential for repair of alpha-induced DNA damage; and low dependence on dose rate and oxygen enhancement effects. This report reviews the synthesis, testing and use in animal models of an alpha particle emitting radioimmunoconjugate constructed via the noncovalent chelation of Bismuth-212 to a monoclonal IgM antibody specific for the murine T cells/neuroectodermal surface antigen, Thy 1.2. These {sup 212}Bi-anti-Thy 1.2 immunoconjugates are capable of extraordinary cytotoxicity in vitro, requiring approximately three {sup 212}Bi-labeled conjugates per target cell to suppress {sup 3}H-thymidine incorporation to background levels. The antigen specificity afforded by the monoclonal antibody contributes a factor of approximately 40 to the radiotoxicity of the immunoconjugate. Animals inoculated with a Thy 1.2+ malignant ascites were cured of their tumor in an antigen-specific fashion by intraperitoneal doses of approximately 200 microCi per mouse. Alpha particle emitting radioimmunoconjugates show great potential for regional and intracavitary molecular radiotherapy.

Authors:
; ; ; ; ; ;  [1]
  1. (Dana Farber Cancer Institute, Boston, MA (USA))
Publication Date:
OSTI Identifier:
5561418
Resource Type:
Journal Article
Resource Relation:
Journal Name: International Journal of Radiation Oncology, Biology and Physics; (USA); Journal Volume: 16:6
Country of Publication:
United States
Language:
English
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE; NEOPLASMS; RADIOIMMUNOTHERAPY; ALPHA PARTICLES; ANTIGENS; BIOLOGICAL MODELS; BISMUTH 212; EXPERIMENTAL NEOPLASMS; IN VITRO; MICE; MONOCLONAL ANTIBODIES; THYMIDINE; TRACER TECHNIQUES; TRITIUM COMPOUNDS; ALPHA DECAY RADIOISOTOPES; ANIMALS; ANTIBODIES; AZINES; BETA DECAY RADIOISOTOPES; BETA-MINUS DECAY RADIOISOTOPES; BISMUTH ISOTOPES; CHARGED PARTICLES; DISEASES; HEAVY NUCLEI; HETEROCYCLIC COMPOUNDS; HOURS LIVING RADIOISOTOPES; HYDROGEN COMPOUNDS; IMMUNOLOGY; IMMUNOTHERAPY; ISOTOPE APPLICATIONS; ISOTOPES; MAMMALS; MEDICINE; NUCLEAR MEDICINE; NUCLEI; NUCLEOSIDES; NUCLEOTIDES; ODD-ODD NUCLEI; ORGANIC COMPOUNDS; ORGANIC NITROGEN COMPOUNDS; PYRIMIDINES; RADIOIMMUNOLOGY; RADIOISOTOPES; RADIOLOGY; RADIOTHERAPY; RIBOSIDES; RODENTS; THERAPY; VERTEBRATES; 550604* - Medicine- Unsealed Radionuclides in Therapy- (1980-)

Citation Formats

Macklis, R.M., Kaplan, W.D., Ferrara, J.L., Atcher, R.W., Hines, J.J., Burakoff, S.J., and Coleman, C.N. Alpha particle radioimmunotherapy: Animal models and clinical prospects. United States: N. p., 1989. Web. doi:10.1016/0360-3016(89)90938-3.
Macklis, R.M., Kaplan, W.D., Ferrara, J.L., Atcher, R.W., Hines, J.J., Burakoff, S.J., & Coleman, C.N. Alpha particle radioimmunotherapy: Animal models and clinical prospects. United States. doi:10.1016/0360-3016(89)90938-3.
Macklis, R.M., Kaplan, W.D., Ferrara, J.L., Atcher, R.W., Hines, J.J., Burakoff, S.J., and Coleman, C.N. 1989. "Alpha particle radioimmunotherapy: Animal models and clinical prospects". United States. doi:10.1016/0360-3016(89)90938-3.
@article{osti_5561418,
title = {Alpha particle radioimmunotherapy: Animal models and clinical prospects},
author = {Macklis, R.M. and Kaplan, W.D. and Ferrara, J.L. and Atcher, R.W. and Hines, J.J. and Burakoff, S.J. and Coleman, C.N.},
abstractNote = {Short-lived isotopes that emit alpha particles have a number of physical characteristics which make them attractive candidates for radioimmunotherapy. Among these characteristics are high linear energy transfer and correspondingly high cytotoxicity; particle range limited to several cell diameters from the parent atom; low potential for repair of alpha-induced DNA damage; and low dependence on dose rate and oxygen enhancement effects. This report reviews the synthesis, testing and use in animal models of an alpha particle emitting radioimmunoconjugate constructed via the noncovalent chelation of Bismuth-212 to a monoclonal IgM antibody specific for the murine T cells/neuroectodermal surface antigen, Thy 1.2. These {sup 212}Bi-anti-Thy 1.2 immunoconjugates are capable of extraordinary cytotoxicity in vitro, requiring approximately three {sup 212}Bi-labeled conjugates per target cell to suppress {sup 3}H-thymidine incorporation to background levels. The antigen specificity afforded by the monoclonal antibody contributes a factor of approximately 40 to the radiotoxicity of the immunoconjugate. Animals inoculated with a Thy 1.2+ malignant ascites were cured of their tumor in an antigen-specific fashion by intraperitoneal doses of approximately 200 microCi per mouse. Alpha particle emitting radioimmunoconjugates show great potential for regional and intracavitary molecular radiotherapy.},
doi = {10.1016/0360-3016(89)90938-3},
journal = {International Journal of Radiation Oncology, Biology and Physics; (USA)},
number = ,
volume = 16:6,
place = {United States},
year = 1989,
month = 6
}
  • Anti-Tac, a monoclonal antibody directed to the human interleukin 2 (IL-2) receptor, has been successfully conjugated to the alpha-particle-emitting radionuclide bismuth-212 by use of a bifunctional ligand, the isobutylcarboxycarbonic anhydride of diethylenetriaminepentaacetic acid. The physical properties of 212Bi are appropriate for radioimmunotherapy in that it has a short half-life, deposits its high energy over a short distance, and can be obtained in large quantities from a radium generator. Antibody specific activities of 1-40 microCi/microgram (1 Ci = 37 GBq) were achieved. Specificity of the 212Bi-labeled anti-Tac was demonstrated for the IL-2 receptor-positive adult T-cell leukemia line HUT-102B2 by protein synthesismore » inhibition and clonogenic assays. Activity levels of 0.5 microCi or the equivalent of 12 rad/ml of alpha radiation targeted by anti-Tac eliminated greater than 98% the proliferative capabilities of HUT-102B2 cells with more modest effects on IL-2 receptor-negative cell lines. Specific cytotoxicity was blocked by excess unlabeled anti-Tac but not by human IgG. In addition, an irrelevant control monoclonal antibody of the same isotype labeled with 212Bi was unable to target alpha radiation to cell lines. Therefore, 212Bi-labeled anti-Tac is a potentially effective and specific immunocytotoxic reagent for the elimination of IL-2 receptor-positive cells. These experiments thus provide the scientific basis for use of alpha-particle-emitting radionuclides in immunotherapy.« less
  • Alpha particles are energetic short-range ions whose higher linear energy transfer produces extreme cytotoxicity. An ..cap alpha..-particle-emitting radioimmunoconjugate consisting of a bismuth-212-labeled monoclonal immunoglobulin M specific for the murine T cell/neuroectodermal surface antigen Thy 1.2 was prepared. Analysis in vitro showed that the radioimmunoconjugate was selectively cytotoxic to a Thy 1.2/sup +/ EL-4 murine tumor cell line. Approximately three bismuth-212-labeled immunoconjugates per target cell reduced the uptake of (/sup 3/H)thymidine by the EL-4 target cells to background levels. Mice inoculated intraperitoneally with EL-4 cells were cured of their ascites after intraperitoneal injection of 150 microcuries of the antigen-specific radioimmunoconjugate, suggestingmore » a possible role for such conjugates in intracavitary cancer therapy. 18 references, 3 figures.« less
  • For comparison of cytotoxicity from alpha-particle irradiation with that from conventional x-irradiation, /sup 212/Bi, an alpha-emitting radionuclide, was attached to a monoclonal antibody that recognizes a cell surface antigen on human pancreatic carcinoma cells. For a given level of survival, the /sup 212/Bi-antibody complex was found to be approximately 20 times more efficient in cell killing than x-irradiation and 5 times more cytotoxic when compared with the cytotoxicity of an antigen-negative cell line or an isotype-matched control antibody. High linear energy transfer radioimmunotherapy using alpha emitters linked to monoclonal antibodies may be useful in vivo and in vitro for selectivelymore » killing target cell populations, especially those resistant to other forms of treatment.« less
  • Based on radioimmunoimaging for HCC using /sup 131/I-anti HCC isoferritin IgG, the experimental and clinical studies on radioimmunotherapy for HCC were reported. Thirty-six nude mice bearing human HCC were used for the study of labeled IgG, pure /sup 131/NaI and pure IgG. In the labeled IgG group, the tumor inhibition rate was significantly higher than that in other groups (81%, 60%, and 18%, respectively, p less than 0.05). The tumor cell DNA analysis showed the tumor cell was inhibited in the S stage of the cell cycle. Twenty pathologically proven unresectable HCC patients were treated by /sup 131/I-antihuman HCC isoferritinmore » IgG 20-55mCi monthly for 1-3 times (via hepatic arterial catheter or intravenously). The short-term response was promising, a decline in AFP level and shrinkage of tumor were observed in 80% (12/15) and 65% (13/20) of patients respectively. Sequence resection was successful in five patients (5/20) after radioimmunotherapy. No marked toxic effects were noted in our limited experience, but some problems remain to be discussed.« less
  • Radiolabeled antibodies that target hematologic disease often exhibit a highly variable as well as non-uniform spatial distribution within the marrow. Mean marrow absorbed dose estimates obtained using a single S-value to represent the absorbed dose per unit cumulated activity for the whole marrow may not adequately reflect potential normal marrow morbidity or tumor cytotoxicity in different marrow regions. New, region-specific, S-factors for marrow, developed at the Oak Ridge National Laboratory, were used to calculate the absorbed dose to three different marrow regions in 9 leukemia patients that were administered trace-labeled I-131-HuM195, the humanized version of (anti-CD33) M195 antibody. Time-activity curvesmore » for each marrow region were obtained by drawing contours around: the head and neck of both femurs, both humeral heads, and the third and fourth lumbar vertebra, in each of four daily conjugate-view images that were collected starting the day of the infusion. Based on data gathered in the regions over the spine and femur, we predict absorbed doses to the active marrow for various regions of the skeleton ranging from 0.16-0.63 mGy/MBq, with a region-weighted average of 0.46 mGy/MBq. This compares with estimates mGy/MBq, respectively. Analysis of marrow dosimetry by region and in a dose-volume histogram format will provide a more reliable dosimetry picture for the clinician than provided by the single dose estimates available previously.« less