Nuklearmedizin 1986; 25(06): 210-215
DOI: 10.1055/s-0038-1624344
Originalarbeiten — Original Articles
Schattauer GmbH

Specific Imaging of Human Brain Tumor Xenografts Utilizing Radiolabelled Monoclonal Antibodies (MAbs)[*]

D. E. Bullard
1   From the Departments of Surgery, Duke University Medical Center, Durham, North Carolina, USA
2   From the (Neurosurgery), Pathology, Duke University Medical Center, Durham, North Carolina, USA
,
C. J. Wikstrand
2   From the (Neurosurgery), Pathology, Duke University Medical Center, Durham, North Carolina, USA
,
P. A. Humphrey
2   From the (Neurosurgery), Pathology, Duke University Medical Center, Durham, North Carolina, USA
,
Y. S. Lee
2   From the (Neurosurgery), Pathology, Duke University Medical Center, Durham, North Carolina, USA
,
R. E. Coleman
3   From the Radiology, Duke University Medical Center, Durham, North Carolina, USA
,
M. Zalutsky
3   From the Radiology, Duke University Medical Center, Durham, North Carolina, USA
,
D. D. Bigner
1   From the Departments of Surgery, Duke University Medical Center, Durham, North Carolina, USA
2   From the (Neurosurgery), Pathology, Duke University Medical Center, Durham, North Carolina, USA
› Author Affiliations
This work was supported by Research Grants CA 11898 and CA32672 from the National Cancer Institute and PO1 NS0023 from the National Institutes of Neurological and Communicative Disorders and Stroke. Doctor Bullard holds the Teacher-Investigator Development Award 1KO N200800 from the National Institutes of Neurological and Communicative Disorders and Stroke. We would like to thank Mrs. Rose Hagan for editorial assistance and help in preparation of this manuscript and Ms. Nancy Storck and Mr. Thomas Hooyman for expert technical assistance.
Further Information

Publication History

Received: 04 July 1986

Publication Date:
20 January 2018 (online)

At the present time, specific imaging and treatment of central nervous system malignancies is not possible. The development of monoclonal hybridoma technology may provide the solution to this problem. We have utilized human glioma-derived cell lines (HGCL) transplanted subcutaneously and intracranially into athymic mice and rats to evaluate the imaging and localizing properties of a panel of MAbs. MAbs 81C6, C12, and D12 and 81C6 Fab have shown significant in vivo localization against HGCL D-54 MG and 81C6 against U-251 MG when compared to equivalent non-specific MAbs. In subcutaneous D-54 MG-induced xenografts, maximal localization indices (LI) of up to 15.0 for 81C6, 6.8 for 81C6 Fab, 6.48 for C12, and 4.47 for D12 have been seen. The tumor-tissue ratios for normal brain have ranged from 235 for 81C6 to 167 for D12. The total percent injected dose for 81C6 was nearly 5% in U-251 MG tumors and 10% of the initial dose in D-54 tumors, while the percent injected dose for control MAb were 1.9% and 2.8%, respectively. Four subcutaneously growing U-251 MG tumors were clearly imaged using 1311-81C6. With intracranial growing D-54 MG,1311-81C6 provided external imaging of intracranial tumors at sizes as small as 20 mg while 131l-45.6, a non-specific MAb, provided imaging only when tumors achieved sizes greater than 300 mg. These data indicate that operationally specific MAbs and MAb Fab can specifically localize and be used to image human tumors transplanted into immunocompromised animals. The animal models described in this paper provide a sensitive method of evaluating MAbs in pre-human trials.

Zusammenfassung

Zum gegenwärtigen Zeitpunkt ist eine spezifische Abbildung und Behandlung von Malignomen des zentralen Nervensystems nicht möglich. Die Entwicklung der monoklonalen Hybridoma- Technologie könnte die Lösung des Problems bringen. Wir haben vom menschlichen Gliom abgeleitete Zellinien (HGCL), die subkutan und intrakraniell in athymische Mäuse und Ratten transplantiert wurden, be- nutzt, um die Bildgebungs- und Lokalisierungseigenschaften einer Reihe von MAbs zu überprüfen. Die MAbs 81C6, C12 und D12 und 81C6 Fab zeigten eine signifikante In-vivo-Lokalisation gegen HGCL D-54 MG und 81C6 gegen U-251 MG im Vergleich zu entsprechenden unspezifischen MAbs. In subkutan D-54 MG induzierten Xenotransplantaten wurden maximale Lokalisationsindices (LI) bis zu 15.0 für 81C6, 6.8 für 81C6 Fab, 6.48 für C12 und 4.47 für D12 gesehen. Die Tumor-zu-Gewebe-Verhältnisse reichten für normales Gehirn von 235 für 81C6 bis zu 167 für D12. Der Gesamtprozentsatz der injizierten Dosis war für 81C6 nahezu 5% in U- 252-MG-Tumoren und 10% der Anfangsdosis in D-54-Tumoren, während der Prozentsatz der injizierten Dosis für die Kontroll-MAbs 1,9% bzw. 2,8% betrug. 4 subkutan wachsende U-251-MG-Tumore wurden bei Anwendung von 131J-81C6 deutlich abgebildet. Beim intrakraniell wachsenden D-54 MG gewährleistete 131J-81C6 von außen eine Abbildung intrakranieller Tumoren bis herab zu einer Größe von 20 mg, während 131J-45.6, ein unspezifischer MAb, nur dann eine Abbildung ermöglichte, wenn die Tumoren eine Größe von mehr als 300 mg erreichten. Diese Daten zeigen, daß funktionsfähige spezifische MAbs und MAb Fab sich spezifisch anreichern können und für die Abbildung menschlicher Tumore, die in immunologisch kompromittierte Tiere transplantiert wurden, herangezogen werden können. Das Tiermodell, das in dieser Arbeit beschrieben wird, liefert ein empfindliches Verfahren für die Beurteilung von MAbs in der vorklinischen Prüfung.

* Presented at the Symposion on “Monoclonal Antibodies in Nuclear Medicine” in Freiburg i.Br., May 1-3, 1986.


 
  • REFERENCES

  • 1 Adams C. J, Bullard D. E, Bigner S. H, Bigner D. D. Intracerebral transplantation of D-54 MG human glioma line in immunosuppressed rats. In: Biology of Brain Tumors. Walker M. D, Thomas D. G. T. eds. 97-105 Martinus Nijhoff: Boston; 1986
  • 2 Allan P. M, Garson J. A, Harper E. I. et al. Biological characterization in clinical applications of a monoclonal antibody recognizing an antigen restricted to neuroectodermal tissue. Intern. J. Cancer 1983; 31: 591-8.
  • 3 Bauer F. K, Tubis M, Thomas H. B. Accumulation of homologous radioiodinated albumin in experimental tumors. Proc. Soc. exp. Biol. Med 1955; 90: 140-2.
  • 4 Bigner D. D, Bigner S. N, Ponten J. et al. Heterogeneity of genotypic and phenotypic characteristics of fifteen permanent cell lines derived from human gliomas. J. Neuropathol. exp. Neurol 1981; 40: 201-29.
  • 5 Bourdon M. A, Wikstrand C. J, Furthmayr H. et al. Human glioma-mesenchymal extracellular matrix antigen defined by monoclonal antibody. Cancer Res 1983; 43: 2796-805.
  • 6 Bullard D. E, Adams C. J, Coleman R. E, Bigner D. D. In vivo imaging of intracranial human glioma xenografts comparing specific with nonspecific radiolabeled monoclonal antibodies. J. Neurosurg 1986; 64: 257-62.
  • 7 Bullard D. E, Bigner D. D. Applications of monoclonal antibodies in the diagnosis and treatment of primary brain tumors. J. Neurosurg 1985; 63: 2-16.
  • 8 Bullard D. E, Bourdon M, Bigner D. D. Comparison of various methods of delivering radiolabeled monoclonal antibodies to normal rat brain. J. Neurosurg 1984; 61: 901-11.
  • 9 Bullard D. E, Schold S. C, Bigner S. H, Bigner D. D. Growth and chemotherapeutic response in athymic mice of tumors arising from human glioma-derived cell lines. J. Neuropathol. exp. Neurol 1981; 40: 410-27.
  • 10 Carrell S, Accola R. S, Karmenyola A. L, Mach J. T. Common human melanoma associated antigen(s) detected by monoclonal antibodies. Cancer Res 1980; 40: 2523-8.
  • 11 Coakham H. B, Garson J. A, Allan P. M. et al. Immunohistological diagnosis of central nervous system tumors using a monoclonal antibody panel. J. clin. Path 1985; 38: 165-73.
  • 12 Conover W. J. Practical Nonparametric Statistics. 2nd ed. 216 John Wiley and Sons; New York: 1980
  • 13 Davies A. G, Richardson R. B, Bourne S. P. et al. Immunolocalization of human brain tumors. In: Tumors of the Brain. Blechan N. ed. Springer; New York: 1986
  • 14 Duran-Reynals F. Studies on the localization of dyes and foreign proteins in normal and malignant tissues. Amer. J. Cancer 1931; 35: 98-107.
  • 15 Epenetos A. A, Courtenay-Luck N, Pickering D. et al. Antibody-guided irradiation of brain glioma by arterial infusion of radioactive monoclonal antibody against epidermal growth factor receptor and blood group A antigen. Brit. med. J 1985; 200: 1463-6.
  • 16 Farrands P, Pimm M. B, Embleton J. J. et al. Radioimmunodetection of human colorectal cancers by anti-tumor monoclonal antibody. Lancet 1982; 02: 397-400.
  • 17 Green S. B, Byar D. P, Walker M. D. et al. Comparisons of carmustine, procarbazine, and high-dose methylprednisolone as additions to surgery and radiotherapy for the treatment of malignant glioma. Cancer Treatm. Rep 1983; 67: 121-32.
  • 18 Humphrey P. A, Pegra C. N, Wikstrand C. J, Bullard D. E, Bigner D. D. Utilization of purified, radiolabeled monoclonal antibodies Fab fragments for in vivo localization in malignant gliomas. J. Neuro-Oncol. In press.
  • 19 Lamoyi E. Preparation of F(ab’)2 fragments from mouse IgG of various subclasses. Methods Enzymol 1986; 121: 652-63.
  • 20 Levy R, Miller R. A. Tumor therapy with monoclonal antibodies. Fed. Proc 1983; 42: 1650-2656.
  • 21 Mann B. D, Cohen M. B, Saxton R. E. et al. Imaging of human tumor xenografts in nude mice with radiolabeled monoclonal antibodies. Limitations of specificity due to nonspecific uptake of antibody. Cancer 1984; 54: 1318-27.
  • 22 Moshakas et al. 1981; Schold Jr. S. C, Bullard D. E, Bigner S. H. et al. Growth, morphology, and serial transplantation of anaplastic human gliomas in athymic mice. J. Neuro-Oncol 1983; 01: 5-14.
  • 23 Parham P. The fragmentation of monoclonal IgGl, IgG2a, and IgG2b from BALB/c mice. J. Immunol 1983; 131: 2895-902.
  • 24 Wikstrand C. J, McLendon R. E, Bullard D. E. et al. Production and characterization of two human glioma xenografts - localizing monoclonal antibodies (MAbs). (Submitted 1986).
  • 25 Zimmerman H. M. Brain tumors: Their incidence in classification in man in their experimental production. Ann. N. Y. Acad. Sei 1969; 159: 337-59.