Abstract
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Objectives To explore the internalization, biodistribution, therapeutic and toxic effects of the novel anti-CD37 radioimmunoconjugate 177Lu-tetraxetan-tetulomab.
Methods Biodistribution of 177Lu-tetraxetan-tetulomab was compared with 177Lu-labeled-rituximab and -isotype control antibody 24, 48 and 120 h after injection in nude mice with subcutaneous Ramos lymphoma xenografts. Therapeutic and toxic effects of 300 to 540 MBq/kg 177Lu-tetraxetan-tetulomab and 177Lu-labeled-rituximab and -isotype control antibody were studied. Control mice recieved 0.9 % NaCl or cold tetulomab. Body weight, blood counts and tumor volume were monitored. Binding and internalization of Alexa-647-labeled tetulomab and rituximab in Ramos cells was visualized by fluorescence microscopy.
Results The uptake of 177Lu-tetraxetan-tetulomab and -rituximab in key organs/tissues was similar to the uptake of 177Lu-labeled isotype control. The uptake in blood was slightly higher for the isotype control. The uptake in tumor was significantly higher for 177Lu-tetraxetan-tetulomab and -rituximab (max. 16 and 18 %I.D./g respectively) than for the isotype control (max. 2 %ID/g). Mice treated with doses of 177Lu-tetraxetan-tetulomab of up to 530 MBq/kg did not present signs of severe toxicity. However, 6 out of 10 mice treated with 530 MBq/kg of 177Lu-tetraxetan-rituximab showed severe symptoms of radiation toxicity (WBC < 0.8 109/l, PLT < 130 109/l) and had to be euthanized between 11 and 18 days after treatment. Treatments with 400 MBq/kg or higher doses of 177Lu-tetraxetan-tetulomab showed a significantly delayed tumor growth compared to all other treatments, except 177Lu-tetraxetan-rituximab. Tetulomab was internalized faster and to a higher degree than rituximab.
Conclusions 177Lu-tetraxetan-tetulomab was more effective and less toxic than 177Lu-tetraxetan-rituximab, which might be explained by the internalization of 177Lu-tetraxetan-tetulomab.