Targeting and therapy of human glioma xenografts in vivo utilizing radiolabeled antibodies.
Radiolabeled antibodies provide a potential basis for selective radiotherapy of human gliomas. We have measured tumor targeting by radiolabeled monoclonal antibodies directed against neuroectodermal and tumor-associated antigens in nude mice bearing human glioma xenografts. Monoclonal P96.5, a mouse IgG2a immunoglobulin, defines an epitope of a human melanoma cell surface protein and specifically binds the U-251 human glioma as measured by immunoperoxidase histochemistry. IIIIn-radiolabeled P96.5 specifically targets the U-251 human glioma xenograft and yields 87.0 microCi of tumor activity/g/100 microCi injected activity compared to 4.5 microCi following administration of 100 microCi radiolabeled irrelevant monoclonal antibody. Calculations of targeting ratios demonstrate the deposited dose to be 11.6 times greater with radiolabeled P96.5 administration compared to irrelevant monoclonal antibody. The dose found in normal organs is less than 20% of that in the tumor, further supporting specific targeting of the human glioma xenograft by this antibody. Monoclonal antibody ZME018, which defines a second melanoma-associated antigen, demonstrates positive immunoperoxidase staining of the tumor, but comparatively decreased targeting. To test the therapeutic potential of 90Y-radiolabeled P96.5 and ZME018, tumors and normal sites were implanted with miniature thermoluminescent dosimeters. Average absorbed doses of 3770 +/- 445 (SEM) and 645 +/- 48 cGy in tumor, 353 +/- 41 and 222 +/- 13 cGy in a contralateral control i.m. site, 980 +/- 127 and 651 +/- 63 cGy in liver, and 275 +/- 14 and 256 +/- 18 cGy in total body were observed 7 days following administration of 100 microCi 90Y-radiolabeled P96.5 and ZME018, respectively. Calculations of absorbed dose by the medical internal radiation dose method confirmed thermoluminescent dosimeter absorbed dose measurements. To test the therapeutic potential, tumor-bearing nude mice were given intracardiac injections of either buffer or 90Y-radiolabeled P96.5 or ZME018. Tumor regression was measured in 1 of 12, 9 of 10, and 12 of 12 compared to 0 of 10, 1 of 10, and 2 of 10 animals following administration of 50, 100, or 200 microCi 90Y-labeled P96.5 and ZME018, respectively. Average maximal decreases in tumor volume were 42.7 +/- 11.9 and 94.2 +/- 3.3% 28 and 58 days following 100 and 200 microCi 90Y-radiolabeled P96.5 administration, respectively. In contrast, no average decrease in tumor volume was noted following 50, 100, or 200 microCi 90Y-labeled ZME018.(ABSTRACT TRUNCATED AT 400 WORDS)
Division of Radiation Oncology, Johns Hopkins Oncology Center, Baltimore, Maryland 21205.
J A
JA
Williams
B W
BW
Wessels
J A
JA
Edwards
K A
KA
Kopher
P M
PM
Wanek
M D
MD
Wharam
S E
SE
Order
J L
JL
Klein
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000951:Antigens, Neoplasm / Q000276:immunology; D004307:Dose-Response Relationship, Radiation; D005910:Glioma / Q000000981:diagnostic imaging / Q000628:therapy*; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008545:Melanoma / Q000276:immunology; D051379:Mice; D009368:Neoplasm Transplantation; D011829:Radiation Dosage; D011877:Radionuclide Imaging; D014183:Transplantation, Heterologous; D015021:Yttrium Radioisotopes / Q000627:therapeutic use*
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D015021:Yttrium Radioisotopes