Radioimmunotherapy of lymphoma by ¹⁷⁷Lu-tetraxetan-tetulomab in nude mice with Ramos xenografts

Objectives To study the biodistribution, therapeutic and toxic effects of the novel anti-CD37 radioimmunoconjugate ¹⁷⁷Lu-tetraxetan-tetulomab in nude mice with Ramos xenografts and the in-vitro internalization of tetulomab in Ramos cells.

Methods Experiments were performed in nude mice with subcutaneous Ramos xenografts. Biodistribution of ¹⁷⁷Lu-tetraxetan-tetulomab was compared with that of ¹⁷⁷Lu-tetraxetan-rituximab for 1, 6, 24 and 48 hours and 5, 7 and 14 days after injection. Therapeutic and toxic effects of 50 to 1000 MBq/kg ¹⁷⁷Lu-tetraxetan-tetulomab were studied. Control groups were injected with 0.9 % NaCl or cold tetulomab or rituximab. Body weight, blood counts, clinical chemistry and tumor volume were measured regularly. Histology studies were performed in the 800 and 1000 MBq/kg and control groups. Internalization of tetulomab was studied in-vitro by incubating Ramos cells with tetulomab bound to Alexa Fluor 488 at 4°C for 1 h and 37°C for 18 h.

Results Biodistribution of ¹⁷⁷Lu-tetraxetan-tetulomab was promising and similar to the biodistribution of ¹⁷⁷Lu-tetraxetan-rituximab. Betalutin treatments of up to 400 MBq/kg did not present any signs of toxicity. 100% of the animals in the 1000 MBq/kg and 50% of the animals in the 800 MBq/kg group died of radiation toxicity, indicating a MTD between 400 and 800 MBq/kg. Main organs regarding safety of treatment with Betalutin were bone marrow and spleen. Treatment with 400 and 800 MBq/kg of Beatlutin extended mean survival of mice. There was no internalization of tetulomab at 4°C with 1 h of incubation time, while most of the tetulomab was internalized when incubated at 37°C for 18 h.

Conclusions ¹⁷⁷Lu-tetraxetan-tetulomab showed promising properties for radioimmunotherapy. The MTD was between 400 and 800 MBq/kg. Tetulomab was strongly internalized in cells after 18 h at 37°C, which could potentially enhance the effect of radioimmunotherapy in vivo, providing a residualizing radiolabel, such as ¹⁷⁷Lu, is used.