Abstract
Lutetium (177Lu) lilotomab satetraxetan (177Lu-lilotomab) is a novel anti-CD37 radioimmunoconjugate (RIC) currently in Phase 2b clinical trial for treatment of non-Hodgkin lymphoma (NHL). The aim of the current study was to investigate tolerability and anti-tumor efficacy of multiple dosing of 177Lu-lilotomab in vivo. Nude mice with subcutaneous (s.c.) NHL (Ramos) xenografts were given 2, 3 or 4 weekly injections of 300 MBq/kg 177Lu-lilotomab or NaCl. Treatment tolerability was assessed by body weight, hematology and histopathological evaluation. A separate experiment in mice without xenografts was performed to collect long term toxicity data. Mice in this study were dosed more conservatively with the intention that all mice should survive until end of experiment and were administered 2 or 4 weekly injections of 200 MBq/kg 177Lu-lilotomab or NaCl. Total accumulated activity of 900 MBq/kg 177Lu-lilotomab given as three weekly injections was tolerated by nude mice with s.c. Ramos xenografts, which is 50 % higher than the maximum tolerated activity (MTA) of a single injection of 530-600 MBq/kg. In the long-term toxicity animals, the highest accumulated activity tested, 800 MBq/kg, was also well tolerated. Radioactivity-dependent transient reduction in white blood cell and platelet counts occurred in all treated groups, with nadir 1-3 weeks after last injection. This toxicity was radioactivity dependent and consistent with histopathological changes in hemolymphopoietic tissues. Significant tumor growth delay measured as time to reach 4 times intial tumor volume was observed in all groups given multiple injections of 300 MBq/kg 177Lu-lilotomab compared to NaCl control group (p<0.001). In conclusion, weekly injections of 177Lu-lilotomab increase the accumulated MTA from 530 to 900 MBq/kg in nude mice, allowing the total injected activity and hence the radiation dose to tumor to be increased without increasing the toxicity to normal tissues.
Highlights
Non-Hodgkin lymphoma (NHL) caused an estimated 200,000 cancer deaths worldwide in 2014 [1]
Survival of mice treated with multiple injections of 177Lu-lilotomab
No toxicity-related end point was met in the nonxenografted animals given weekly injections of 200 MBq/kg 177Lu-lilotomab (Figure 1a)
Summary
Non-Hodgkin lymphoma (NHL) caused an estimated 200,000 cancer deaths worldwide in 2014 [1]. The most common sub-type of NHL is follicular lymphoma (FL), which represents approximately 25% of all newly diagnosed cases of NHL and 70% of indolent lymphomas. The 5-year overall survival rates for rituximab-refractory FL patients and those with early disease progression are 58% and 50%, respectively, compared to approximately 90% for all FL patients [2,3,4]. Indolent NHLs are usually diagnosed in the advanced stage and require systemic therapy. While immuno-chemotherapy regimens are initially effective in inducing responses, most patients inevitably relapse, and the same therapies show decreasing efficacy with repeated administration [2,3]
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