Radioimmunotherapy of human colonic cancer xenografts with 90Y labeled monoclonal antibodies to carcinoembryonic antigen.
Monoclonal antibodies (MAbs) to carcinoembryonic antigen (CEA) or alpha-fetoprotein (AFP) were conjugated with diethylenetriaminepentaacetic acid and radiolabeled with 90Y at a specific activity of 4.0-6.0 mCi/mg. Approximately 50% of the radiolabeled anti-CEA antibody (90Y-labeled NP-2) bound to an immunoadsorbent containing CEA while analysis by high performance liquid chromatography revealed that 95-98% of the 90Y was associated with immunoglobulin. Less than 5% of the 90Y dissociated from either MAb after incubation in plasma for 48 h at 37 degrees C. After injection into nude mice, 98% of the circulating radioactivity remained associated with antibody and no loss of immunoreactivity was observed at 3 days. To evaluate 90Y-labeled NP-2 as a therapeutic agent, varied doses (10-100 microCi) were administered as a single i.v. injection into groups of nude mice bearing s.c. implants (0.3-0.4 g) of a CEA-producing human colonic cancer xenograft, GW-39. At the 10-microCi dose, no inhibition of tumor growth was observed. After 28 days, tumor growth was inhibited by as much as 77% in mice treated with 50 microCi of 90Y-labeled NP-2 as compared to tumor growth in control animals given 90Y-labeled anti-AFP. Doses higher than 50 microCi (75 and 100 microCi) were toxic to most of the animals, killing them within 2-3 weeks after administration. Marked suppression of circulating leukocytes was observed with 20 and 50 microCi by 1-2 weeks postinjection, but they returned to normal levels 3-4 weeks later. These studies show that treatment with 90Y-labeled MAbs against CEA can produce significant antitumor effects. However, toxicity to the bone marrow may limit the therapeutic efficacy of systemically administered 90Y-labeled MAbs.
Sharkey
R M
RM
Center for Molecular Medicine and Immunology, Newark, New Jersey 07103.
Kaltovich
F A
FA
Shih
L B
LB
Fand
I
I
Govelitz
G
G
Goldenberg
D M
DM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D002272:Carcinoembryonic Antigen / Q000276:immunology*; D002460:Cell Line; D003110:Colonic Neoplasms / Q000473:pathology / Q000532:radiotherapy / Q000628:therapy*; D005260:Female; D006801:Humans; D007167:Immunotherapy; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D014018:Tissue Distribution; D014183:Transplantation, Heterologous; D015019:Yttrium / Q000493:pharmacokinetics / Q000627:therapeutic use*
D000911:Antibodies, Monoclonal; D002272:Carcinoembryonic Antigen; D015019:Yttrium