Therapy of human carcinoma xenografts with antibodies to EGFr and HER-2 conjugated to radionuclides emitting low-energy electrons.
OBJECTIVE
Low-energy electrons (10-50 keV) can be effective and specific cytotoxic agents when delivered to the cell surface by antibodies, because their path length in tissue is comparable to a cell diameter. In this study, we have begun to evaluate the therapeutic potential of antibodies (Abs) conjugated to (111)In against carcinoma xenografts in nude mice.


METHODS
Abs to EGFr or HER-2 were labeled with (111)In to a high specific activity of approximately 1.48 GBq/mg (40 mCi/mg). They were injected into nude mice 5-6 days after inoculation of human carcinoma cells, either A431 or SK-OV-3, and tumor growth was monitored. In preliminary in vitro experiments, we calculated the cumulative decays per cell, estimated the centigray dose delivered to the nucleus, and related this to the fraction surviving.


RESULTS
Abs to both antigens provided significant protection in nude mouse xenograft models (p values ranging from <0.05 to <0.001). Some mice appeared to be cured, but most had delayed tumor growth. The specificity of the effect was demonstrated by testing non-reactive Abs labeled in the same way. The radioactivity was required, because unconjugated Abs had no therapeutic effect. The maximum tolerated dose was required in order for therapy to be effective, but most of the treated mice had no significant weight loss or other overt signs of toxicity.


CONCLUSIONS
Abs labeled with nuclides emitting low-energy electrons, such as (111)In, can be effective therapeutic agents against microscopic s.c. tumors. This strategy should be considered for clinical applications.
Mattes
M Jules
MJ
Garden State Cancer Center at the Center for Molecular Medicine and Immunology, 520 Belleville Avenue, Belleville, NJ 07109, USA. mjmattes@gscancer.org
Goldenberg
David M
DM
D000818:Animals; D000912:Antibodies, Neoplasm / Q000097:blood / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D004583:Electrons / Q000627:therapeutic use; D066246:ErbB Receptors / Q000276:immunology*; D005260:Female; D006801:Humans; D007205:Indium Radioisotopes / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000532:radiotherapy*; D016499:Radioimmunotherapy / Q000379:methods*; D019275:Radiopharmaceuticals / Q000627:therapeutic use; D011879:Radiotherapy Dosage; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*; D014183:Transplantation, Heterologous
D000912:Antibodies, Neoplasm; D066246:ErbB Receptors; D007205:Indium Radioisotopes; D019275:Radiopharmaceuticals; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human