89Zr-PET imaging to predict tumor uptake of 177Lu-NNV003 anti-CD37 radioimmunotherapy in mouse models of B cell lymphoma
Danique Giesen, Marjolijn N. Lub–de Hooge, Marcel Nijland, Helèn Heyerdahl, Jostein Dahle, Elisabeth G.E. de Vries, Martin Pool
Abstract
Abstract [ 177 Lu]Lu-DOTA-NNV003, a radioimmunoconjugate targeting CD37, is developed as novel radioimmunotherapy (RIT) treatment for patients with B cell non-Hodgkin’s lymphoma (NHL). Since patients are at risk for developing hematological toxicities due to CD37 expression on normal B cells, we aimed to develop 89 Zr-labeled NNV003 for positron emission tomography (PET) imaging as a surrogate tool to predict [ 177 Lu]Lu-DOTA-NNV003 RIT whole-body distribution and tumor uptake. NNV003 antibody was first radiolabeled with 89 Zr. [ 89 Zr]Zr- N -sucDf-NNV003 tumor uptake was evaluated by PET imaging of mice bearing human CD37-expressing REC1 B cell NHL or RAMOS Burkitt’s lymphoma xenograft tumors followed by ex vivo analysis. Finally, CD37-targeting of [ 89 Zr]Zr- N -sucDf-NNV003 and [ 177 Lu]Lu-DOTA-NNV003 RIT were compared. [ 89 Zr]Zr- N -sucDf-NNV003 accumulated in REC1 tumors over time, which was not observed for non-specific, 111 In-labeled IgG control molecule. In RAMOS tumor-bearing mice, [ 89 Zr]Zr- N -sucDf-NNV003 tumor uptake was higher than [ 111 In]In-DTPA-IgG at all tested tracer protein doses (10 µg, 25 µg and 100 µg; P < 0.01), further confirming [ 89 Zr]Zr- N -sucDf-NNV003 tumor uptake is CD37-mediated. [ 89 Zr]Zr- N -sucDf-NNV003 and [ 177 Lu]Lu-DOTA-NNV003 RIT showed similar ex vivo biodistribution and tumor uptake in the RAMOS tumor model. In conclusion, [ 89 Zr]Zr- N -sucDf-NNV003 PET imaging can serve to accurately predict CD37-targeting of [ 177 Lu]Lu-DOTA-NNV003. To enable clinical implementation, we established a good manufacturing practice (GMP)-compliant production process for [ 89 Zr]Zr- N -sucDf-NNV003.