Skip to main content
SpringerLink
Log in

Pharmacokinetics and acute toxicology of intraventricular 131I-monoclonal antibody targeting disialoganglioside in non-human primates

  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Tumors metastatic to the leptomeninges are often incurable despitecurrent aggressive treatment modalities. Regional therapy by intrathecaladministration of monoclonal antibodies (MoAbs) can maximize theirconcentration to tumor sites while reducing systemic toxicities.Anti-GD2 antibody 3F8 has successfully targeted humanneuroectoderm derived tumors. Disialoganglioside GD2expression in the central nervous system is identical between humans andcynomolgus monkeys. We studied the pharmacokinetics and the acute andsubacute toxicities of intraventricular 131I-3F8 in 8cynomolgus monkeys. Four animals were purposely immunized with intravenous3F8 administered 2–4 weeks prior to injections. All animals remainedclinically stable. Toxicities included weight loss, fever and CSFleukocytosis. One animal developed a left-sided hemiparesis following hisseventh injection, presumably due to a local drug accumulation in thesetting of an intermittently patent catheter. The estimated radiation doseto the CSF was 19–48 Gy in the immunized monkeys and 19–82 Gy inthe nonimmunized monkeys, and to blood was 0.11–0.98 Gy and0.29–2.03 Gy, respectively. Histopathology revealed chronic reactivechanges adjacent to the region of catheter placement and a focal vasculitisin 2 animals. Peripheral blood counts and bone marrow examinations remainednormal. Because of the blood-brain barrier, CSF monkey-anti-mouse antibodytiters were less than 10 per cent of those in the serum. In contrast to theCSF radioactivity clearance which was similar in all animals, bloodclearance was substantially accelerated in 3F8-immunized animals versuscontrols. Correspondingly, the CSF to blood dose ratio was improved 1.3 to6.6 fold (mean 3.5). We conclude that intraventricular administration of131I-3F8 in primates is tolerable. It can deliver very highdoses of radiation to the CSF space with minimal toxicity to blood and bonemarrow. Serum anti-mouse antibody accelerates the clearance of131I-3F8 in blood and may improve the therapeutic index.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Pfeffer MR, Wygoda M, Siegal T: Leptomeningeal metastases treatment results in 98 consecutive patients. Isr J Med Sci 24: 611–618, 1988

    Google Scholar 

  2. Packer RJ, Siegel KR, Sutton LN, Litmann P, Bruce DA, Schut L: Leptomeningeal dissemination of primary central nervous system tumors in childhood. Ann Neurol 18: 217–221, 1985

    Google Scholar 

  3. Pinkerton CR, Chessells JM: Failed central nervous system prophylaxis in children with lymphoblastic leukemia: Treatment and outcome. Br J Hematol 57: 553–561, 1984

    Google Scholar 

  4. Land VJ, Thomas PRM, Boyett JM, Glicksman AS, Culbert S, Castleberry RP, Berry DH, Vats T, Humphrey GB: Comparison of maintenance treatment regimens for first central nervous system relapse in children with acute lymphocytic leukemia. Cancer 56: 81–87, 1985

    Google Scholar 

  5. Heideman RL, Packer RJ, Albright LA, Freeman CR, Rorke LB: Tumor of the central nervous system. In: Pizzo PA, Poplack DG (eds) Principles and Practice of Pediatric Oncology. 2nd edition. J.B. Lippincott Co., Philadelphia, 1993

    Google Scholar 

  6. Cheung NK, Saarinen UM, Neely JE, Landmeier B, Donovan D, Coccia PF: Monoclonal antibodies to a glycolipid antigen on human neuroblastoma. Can Res 45: 2642–2649, 1985

    Google Scholar 

  7. Miraldi FD, Nelson AD, Kraly C, Ellery S, Landmeier B, Coccia PF, Strandjord SE, Cheung NKV: Diagnostic imaging of human neuroblastoma with radiolabeled antibody. Radiology 161: 413–418, 1986

    Google Scholar 

  8. Bergman I, Arbit E, Rosenblum M, Larson SM, Heller G, Cheung NK: Treatment of spinal epidural neuroblastoma xenografts in rats using antiGD2 monoclonal antibody 3F8. J Neurooncol 15: 235–242, 1993

    Google Scholar 

  9. Berra B, Gaini SM, Riboni L: Correlation between ganglioside distribution and histologic grading of human astrocytomas. Int J Can 36: 363–366, 1985

    Google Scholar 

  10. Traylor TD, Hogan EL: Gangliosides of human cerebral astrocytomas. J Neurochem 34: 126–131, 1980

    Google Scholar 

  11. Ye JN, Cheung NKV: A novel O-acetylated ganglioside detected by anti-GD2 monoclonal antibodies. Int J Can 50: 197-201, 1992

    Google Scholar 

  12. Wikstrand CJ, Fredman P, Svennerholm L, Bigner SH, Vick W, Fuller G, Bigner DD: Expression of gangliosides GM 2 M GD2, GD3, 3-sioLM1 and 3,6-isoLD1 in CNS malignancies as defined by epitope-characterized monoclonal antibodies (Mabs). (Abstract). 9th International Congress on Brain Tumors Research and Therapy 1991

  13. Longee DC, Wilkstrand CT, Mansson JE, He X, Fuller GN, Bigner SH, Fredman P, Svennerholm L, Bigner DD: Disialoganglioside GD2 in human neuroectodermal tumor cell lines and gliomas. Acta Neuropath 82: 45–54, 1991

    Google Scholar 

  14. Cheung NK, Lazarus H, Miraldi FD, Abramowsky CR, Kallick S, Saarinen UM, Spitzer T, Strandjord SE, Coccia PF, Berger NA: Ganglioside GD2 specific monoclonal antibody 3F8: A phase I study in patients with neuroblastoma and malignant melanoma. J Clin Oncol 5: 1430–1440, 1987

    Google Scholar 

  15. Houghton AN, Chapman PB, Bajorin DF: Antibodies in cancer therapy: Melanoma. In: Devita VT (ed) Biologic Therapy of Cancer. 1st edition. J.B. Lippincott Co., Philadelphia, 1991

    Google Scholar 

  16. Handgretinger R, Anderson K, Lang P: A phase I study of human/mouse chimeric antiganglioside GD2 antibody ch14.18 in patients with neuroblastoma. (Abstract). Eur J Can 31A: 261–267, 1995

    Google Scholar 

  17. Miraldi F, Nelson AD, Kraly C, Ellery S, Landmeier B, Coccia PF, Strandjord SE, Cheung NKV: Diagnostic imaging of human neuroblastoma with radiolabeled antitumor antibody. (Abstract). Radiology 153: 148, 1984

    Google Scholar 

  18. Cheung NK, Yeh SDJ, Gulati S, Kushner BH, Burch L, Larson S: 131I-3F8 targeted radiotherapy of neuroblastoma (NB): A phase I clinical trial. (Abstract). Proc Am Assoc Cancer Res 31: 284, 1990

    Google Scholar 

  19. Arbit AE, Cheung NK, Yeh SDJ, Daghighian F, Zhang JJ, Cordon-Cardo C, Canete A, Pentlow K, Finn R, Larson SM: Quantitative studies of monoclonal antibody targeting to disialoganglioside GD2 in human brain tumors. Eur J Nuc Med 22: 419–426, 1995

    Google Scholar 

  20. Zalutsky MR, Garg PK, Schuster JM, Garg S, Archer GE, Fuchs HE, Bigner DD: Effective treatment of experimental human neoplastic meningitis (NM) with intrathecal astatine-211 monoclonal antibody (Mab). (Abstract). J Nucl Med 31: 922, 1990

    Google Scholar 

  21. Schold SC, Zalutsky MR, Coleman RE, Glantz MJ, Friedman AH, Jaszczak RJ, Bigner SH, Bigner DD: Distribution and dosimetry of 123I labeled monoclonal antibody 81C6 in patients with anaplastic glioma. Invest Radiol 28: 488–496, 1993

    Google Scholar 

  22. Mosely RP, Davies AG, Richardson RB, Zalutsky M, Carrell S, Fabre J, Slack N, Bullimore J, Pizer B, Papanastassiou V, Kemshead JT, Coakham HB, Lashford LS: Intrathecal administration of 131I radiolabelled monoclonal antibody as a treatment for neoplastic meningitis. B J Cancer 62: 637–642, 1990

    Google Scholar 

  23. Pizer B, Papanastassiou V, Hancock J, Cassano W, Coakham H, Kemshead J: A pilot study of monoclonal antibody targeted radiotherapy in the treatment of central nervous system leukaemia in children. Br J Haem 77: 466–472, 1991

    Google Scholar 

  24. Pizer BL, Papanastassiou V, Mosely R, Tzanis S, Hancock JP, Kemshead JT, Coakham HB: Meningeal leukemia and medulloblastoma: Preliminary experience with intrathecal radioimmunotherapy. Antibody Immunocon Radiopharm 4: 753–761, 1991

    Google Scholar 

  25. Kemshead JT, Papanastassiou V, Coakham HB, Pizer BL: Monoclonal antibodies in the treatment of central nervous system malignancies. Eur J Cancer 28: 511–513, 1992

    Google Scholar 

  26. Dippold WG, Bernhard H, Meyer zum Buschenfelde KH: Immunological response to intrathecal GD3ganglioside antibody treatment in cerebral fluid melanosis. In: Oettgen HF (ed) Gangliosides and Cancer. VCH Publishers, New York 240, 1990

    Google Scholar 

  27. Malkin MG: Phase I study of intraventricular R24 mouse monoclonal antibody in patients with primary or disseminated R24-positive leptomeningeal neoplasms. (in press)

  28. Lammie GA, Cheung NKV, Gerald W, Rosenblum M, Cordon-Cardo C: Ganglioside GD2 expression in the human nervous system and in neuroblastomas–an immunohistochemical study. Int J Oncol 3: 909–915, 1993

    Google Scholar 

  29. Cheung NK, Landmeier B, Neely J, Nelson D, Abramowsky C, Ellery S, Adams R, Miraldi FD: Complete tumor ablation with iodine 131I-radiolabeled disialoganglioside GD2 specific monoclonal antibody against human neuroblastoma xenografted in nude mice. J Natl Can Inst 77: 739–745, 1986

    Google Scholar 

  30. Loeb WF: In: Loeb WF, Quimbly FW (eds) Clinical Chemistry in Laboratory Animals. Pergamon Press, New York, NY, 1989

    Google Scholar 

  31. Foster WG, McMahon A, Younglai EV: Reproductive endocrine effects of chronic lead exposure on the male cynomolgus monkey. Reprod Toxicol 7: 203–209, 1993

    Google Scholar 

  32. Cornelius CE: The use of non-human primates in the study of bilirubin metabolism and bile secretions. Am J Primatol 2: 343–354, 1982

    Google Scholar 

  33. Strauss LG, Conti PS: The application of PET in clinical oncology. J Nucl Med 32: 623–648, 1991

    Google Scholar 

  34. Wagner HN: Clinical PET: Its time has come. J Nucl Med 32: 561–564, 1991

    Google Scholar 

  35. Cheung NK, Cheung IY, Canete A, Yeh SJ, Kushner B, Bonilla MA, Heller G, Larson SM: Antibody response to murine anti GD2 monoclonal antibodies: Correlation with patient survival. Can Res 54: 2228–2233, 1994

    Google Scholar 

  36. Kun LE, Moulder J: General principles of radiation therapy. In: Pizzo PA, Poplack DG (eds) Principles and Practice of Pediatric Oncology. J.B. Lippincott Co., Philadelphia 291, 1993

    Google Scholar 

  37. Humm JL, Cobb LM: Nonuniformity of tumor dose in radioimmunotherapy. J Nucl Med 31: 75–83, 1990

    Google Scholar 

  38. Papanastassiou V, Pizer BL, Coakham HB, Bullimore J, Zananiri A, Kemshead JT: Treatment of recurrent and cystic malignant gliomas by a single intracavitary injection of 131Imonoclonal antibody: Feasibility, pharmacokinetics and dosimetry. Br J Can 67: 144–151, 1993

    Google Scholar 

  39. O’Donoghue JA, Bardies M, Wheldon TE: Relationships between tumor size and curability for uniformly targeted therapy with beta-emitting radionuclides. J Nucl Med 36: 1902–1909, 1995

    Google Scholar 

  40. Humm JL: Dosimetric aspects of radiolabeled antibodies for tumor therapy. J Nucl Med 27: 1490–1497, 1986

    Google Scholar 

  41. Vaidynanathan G, Zalutsky MR: Meta-(211-A) astatobenzylguanine synthesis via astatodemetallation and preliminary in vitroand in vivoevaluation. Bioconjug Chem 3: 499–503, 1992

    Google Scholar 

  42. Zalutsky MR, Moseley RP, Coakman HB, Coleman RE, Bigner DD: Pharmacokinetics and tumor localization of 131Ilabeled anti-tenascin monoclonal antibody 81C6 in patients with gliomas and other intracranial malignancies. Can Res 49: 2807–2813, 1989

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York Hospital-Cornell Medical College, New York, USA

    Kim Kramer, Nai-Kong V. Cheung & Alfred P. Gillio

  2. Department of Medical Physics, New York Hospital-Cornell Medical College, New York, USA

    John Humm & Ronald Finn

  3. Department of Nuclear Medicine, New York Hospital-Cornell Medical College, New York, USA

    Gene DiResta & Steven Larson

  4. Department of the Departments of Neurosurgery, New York Hospital-Cornell Medical College, New York, USA

    Ehud Arbit

  5. Department of Pathology, New York Hospital-Cornell Medical College, New York, USA

    Marc Rosenblum

  6. Department of Veterinary Medicine, New York Hospital-Cornell Medical College, New York, USA

    Hai Nguyen

  7. Department of Pediatric Bone Marrow Transplantation, New York Hospital-Cornell Medical College, New York, USA

    George Gonzalez & Alfred P. Gillio

  8. Department of the Neuroblastoma Research Laboratory, New York Hospital-Cornell Medical College, New York, USA

    Kim Kramer, Nai-Kong V. Cheung, Chongjuan Liu & Yu-Fang Yang

  9. Department of the Departments of Ophthalmology, New York Hospital-Cornell Medical College, New York, USA

    Mary E. Mendelsohn

Authors
  1. Kim Kramer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nai-Kong V. Cheung
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. John Humm
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gene DiResta
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ehud Arbit
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Steven Larson
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ronald Finn
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Marc Rosenblum
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hai Nguyen
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. George Gonzalez
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Chongjuan Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Yu-Fang Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Mary E. Mendelsohn
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Alfred P. Gillio
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kramer, K., Cheung, NK.V., Humm, J. et al. Pharmacokinetics and acute toxicology of intraventricular 131I-monoclonal antibody targeting disialoganglioside in non-human primates. J Neurooncol 35, 101–112 (1997). https://doi.org/10.1023/A:1005822524905

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1005822524905

Search

Navigation