Kinetics and dosimetry of MAb-170: Evaluation of possibilities for intraperitoneal radioimmunotherapy

Summary

The monoclonal antibody MAb-170 is directed against adenocarcinomas of different origin. Recent experience in radioimmunoscintigraphy revealed a positive uptake of this MAb in peritoneal metastases of ovarian carcinoma (FIGO lll/IV). Aim: The present investigation should clarify the question whether this antibody could be of use in an adjuvant intraperitoneal radioimmunotherapy (RIT) in patients with minimal residual disease after first-look surgery. Methods: Four patients underwent intraperitoneal application of Tc-99m MAb-170. Subsequent quantitative whole-body scintigraphy, serum and urine sampling were performed for a 48 h period. In one case tumour tissue specimen were sampled during the first surgical procedure 15 h p.L Results: The quantitative evaluation revealed no relevant accumulation in liver, spleen and bone marrow never exceeding 5 % of the whole-body activity. The critical organs are the kidneys that showed 8 to 11 % uptake at 24 h pi. The effective serum curve had a maximum at 24 h pi, the second phase gave a elimination half-time of 53 h. Assuming the worst case, the mean dose to red bone marrow was 0.3 Gy/370 MBq injected dose (ID). Conclusion: These results confirm that a RIT with Re-186 MAb-170 is feasible with activities of up to 3.7 GBq. A kit for labelling MAb-170 with Perrhenate is under investigation.

Zusammenfassung

Der monoklonale Antikörper MAb-170 ist gegen tumorassoziiertes Antigen von Adenokarzinomen gerichtet. Erste Erfahrungen in der Radioimmunszintigraphie (RIS) zeigen vielversprechende Ergebnisse in der Diagnostik von Ovarialkarzinomen. Ziel: Die durchgeführten Untersuchungen sollten klären, ob ein Einsatz dieses Antikörpers - nach Markierung mit Re-186 - zur adjuvanten intraperitonealen Radioimmuntherapie (RIT) von Patientinnen mit Peritonealkarzinose und »minimal residual disease« nach First-look-OP sinnvoll ist. Methoden: Bei 4 Patientinnen wurde Tc-99m MAb-170 intraperitoneal appliziert. Ganzkörperszintigramme, Urinausscheidung und Serumaktivitätskonzentration wurden anschließend über 48 h registriert. In einem Fall wurden 15 h nach Applikation im Rahmen der First-look-OP Gewebeproben gewonnen. Ergebnisse: Die Knochenmarkdosis betrug 0,35 Gy/370 MBq Re-186 MAb-170, die Nierendosis (kritisches Organ) 0,37 Gy. Die Akkumulation in Leber, Milz, Herz und Lunge war gering bis mäßig (<5,4 % ID), die mittlere Tumordosis wurde auf 25 Gy/370 MBq geschätzt. Der effektive Serumaktivitätsverlauf zeigte ein Maximum 24 h p.i., die Halbwertszeit der Eliminationphase betrug 53 Stunden. Schlussfolgerurig: Die vorliegenden Ergebnisse rücken eine RIT mit Re-186-markiertem MAb-170 in den Bereich des Möglichen mit Therapieaktivitäten bis 1,8 GBq.

Keywords

Radioimmunotherapy - monoclonal antibodies - ovarian cancer - peritoneal carcinosis - dosimetry

Schlüsselwörter

Radioimmuntherapie - monoklonale Antikörper - Ovarialkarzinom - Peritonealkarzinose - Dosimetrie

• Literatur

• 1 Alexander C, Villena-Heinsen CE, Schaefer A. et al. MAb-170 for immunoscintigraphic detection of ovarian tumors. Am J Obstet Gynecol 1999; 181: 513-7.
• 2 Alvarez RD, Partridge EE, Khazaeli MB. et al. Intraperitoneal radioimmunotherapy of ovarian cancer with ^l77Lu-CC49: a phase I/II study. Gynecologic Oncology 1997; 65: 94-101.
• 3 Behr TM, Sharkey RM, Juweid MI. et al. Factors influencing the pharmacokinetics, dosimetry, and diagnostic accuracy of radio-immunodetection and radioimmunotherapy of carcinoembryonic antigen-expressing tumors. Cancer Research 1996; 56: 1805-16.
• 4 Behr TM, Sharkey RM, Juweid ME. et al. Variables influencing tumor dosimetry in radioimmunotherapy of CEA-expressing cancers with anti-CEA and antimucin monoclonal antibodies. J Nucl Med 1997; 38: 409-18.
• 5 Bombardieri E, Ferrari L, Spinelli A. et al. Radioimmunotherapy of ovarian cancer with radiolabeled monoclonal antibodies: biological basis, present status and future perspectives. Anticancer Research 1997; 17: 1719-30.
• 6 Breitz HB, Durham JS, Fisher DR. et al. Pharmacokinetics and normal organ dosimetry following intraperitoneal Rhenium-186-labeled monoclonal antibody. J Nucl Med 1995; 36: 754-61.
• 7 Buijs WC, Tibben JG, Boerman OC. et al. Dosimetric analysis of chimeric monoclonal antibody cMOvl8 IgG in ovarian carcinoma patients after intraperitoneal and intravenous administration. Eur J Nucl Med 1998; 25: 1552-61.
• 8 Chatal JF, Saccavini JC, Gestin JF. et al. Biodistribution of Indium-ll 1-labelled OC125 monoclonal antibody intraperitoneally injected into patients operated for ovarian carcinomas. Cancer Research 1989; 49: 3087-94.
• 9 DeNardo SJ, Richman C, O’Donnell RT. et al. Treatment of metastatic breast and prostate cancer with In-11 l/Y-90 MAbl70: pharmacokinetic and therapy dosimetry. Eur J Nucl Med 2000; 27: 951. (abstr.)
• 10 Juweid M, Sharkey RM, Alavi A. et al. Regression of advanced refractory ovarian cancer treated with iodine-131-labeled anti-CEA monoclonal antibody. J Nucl Med 1997; 38: 257-60.
• 11 Juweid M, Swayne LC, Sharkey RM. et al. Prospects of radioimmunotherapy in epithelial ovarian cancer: results with iodine-131 -labeled murine and humanized MN-14 anti-carcinoem-bryonic antigen monoclonal antibodies. Gynecologic oncology 1997; 67: 259-71.
• 12 Mahé MA, Fumoleau P, Fabbro M. et al. A phase II study of intraperitoneal radioimmunotherapy with iodine-131-labeled monoclonal antibody OC-125 in patients with residual ovarian carcinoma. Clinical Cancer Research 1999; 5: 3249s-53s.
• 13 Maraveyas A, Snook D, Hird V. et al. Pharmacokinetics and toxicity of an yttrium-90-CITC-DTPA-HMFG1 radioimmunoconjugate for intraperitoneal radioimmunotherapy of ovarian cancer. Cancer 1994; 73 (Suppl. 03) 1067-75.
• 14 Meredith RF, Partridge EE, Alvarez RD. et al. Intraperitoneal radioimmunotherapy of ovarian cancer with lutetium-177-CC49. J Nucl Med 1996; 37: 1491-6.
• 15 Muto MG, Kassis AI. Monoclonal antibodies used in the detection and treatment of epithelial ovarian cancer. Cancer 1995; 76: 2016-27.
• 16 Rosenblum MG, Verschraegen CF, Murray JL. et al. Phase I study of ⁹⁰Y-labeled B72.3 intraperitoneal administration in patients with ovarian cancer: effect of dose and EDTA coadministration on pharmacokinetics and toxicity. Clinical Cancer Research 1999; 5: 953-61.
• 17 Wissenschaftliche Tabellen Geigy, Teilband Somatometrie und Biochemie, 8. Auflage. Basel: Ciba-Geigy; 1982