89Zr-PET imaging to predict tumor uptake of 177Lu-NNV003 anti-CD37 radioimmunotherapy in mouse models of B cell lymphoma

Abstract

[¹⁷⁷Lu]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 ⁸⁹Zr-labeled NNV003 for positron emission tomography (PET) imaging as a surrogate tool to predict [¹⁷⁷Lu]Lu-DOTA-NNV003 RIT whole-body distribution and tumor uptake. NNV003 antibody was first radiolabeled with ⁸⁹Zr. [⁸⁹Zr]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 [⁸⁹Zr]Zr-N-sucDf-NNV003 and [¹⁷⁷Lu]Lu-DOTA-NNV003 RIT were compared. [⁸⁹Zr]Zr-N-sucDf-NNV003 accumulated in REC1 tumors over time, which was not observed for non-specific, ¹¹¹In-labeled IgG control molecule. In RAMOS tumor-bearing mice, [⁸⁹Zr]Zr-N-sucDf-NNV003 tumor uptake was higher than [¹¹¹In]In-DTPA-IgG at all tested tracer protein doses (10 µg, 25 µg and 100 µg; P < 0.01), further confirming [⁸⁹Zr]Zr-N-sucDf-NNV003 tumor uptake is CD37-mediated. [⁸⁹Zr]Zr-N-sucDf-NNV003 and [¹⁷⁷Lu]Lu-DOTA-NNV003 RIT showed similar ex vivo biodistribution and tumor uptake in the RAMOS tumor model. In conclusion, [⁸⁹Zr]Zr-N-sucDf-NNV003 PET imaging can serve to accurately predict CD37-targeting of [¹⁷⁷Lu]Lu-DOTA-NNV003. To enable clinical implementation, we established a good manufacturing practice (GMP)-compliant production process for [⁸⁹Zr]Zr-N-sucDf-NNV003.