Strong anti-tumor effect of ¹⁷⁷Lu-tetraxetan-tetulomab in nude mice with Ramos xenografts

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.