Targeted alpha therapy with 212Pb-NNV003 for the treatment of CD37 positive B-cell chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL)

Background: Each year more than 90,000 cases of chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL) are expected in the US. The standard of care includes immuno-chemotherapy with alkylating agents in combination with an anti-CD20 monoclonal antibody, in addition to targeted therapies such as Bruton's tyrosine kinase inhibitors. While immuno-chemotherapy regimens are initially effective in inducing responses, most patients inevitably relapse and the same therapies show decreasing efficacy with repeated administration. In recent years, CD37 has emerged as a new therapeutic target for B-cell malignancies. CD37 is highly and selectively expressed on the surface of mature B lymphocytes and B-cell malignancies. Therapies targeting CD37-expressing cells may become a useful alternative to CD20 targeting agents, due to the emergence of resistance to anti-CD20 therapies over time. Alpha-emitting radionuclides have demonstrated good potential for cancer targeted therapies because of efficient energy deposition along the short alpha track (50-100 µm). The absorbed energy causes irreparable DNA double-strand breaks and localized cytotoxicity while sparing surrounding healthy tissues. We have developed a targeted alpha therapy (TAT) where the CD37-specific antibody NNV003 is coupled to the alpha-particle-emitting radioisotope 212Pb. We recently showed that 212Pb-NNV003 is highly effective in animal models of Burkitt's lymphoma and CLL (Saidi et al., Blood, 2018, 132: 4422). A clinically relevant SA is expected to be 0.1-0.2 µCi/µg based on receptor occupancy calculations. To support the selection of SA for a clinical trial, the therapeutic effect of a range of specific activities were compared in this study in a preclinical model of CLL. Methods: The efficacy and tolerability of different activity levels and different SA of a single-dose 212Pb-NNV003 treatment were evaluated using escalating activity levels in human disseminated models of Burkitt's lymphoma (Daudi) and CLL (MEC-2). 10 million Daudi cells or 2.5 million MEC-2 cells were intravenously injected into CB17-SCID or R2G2 mice, respectively on day 0, and a single intravenous dose of 212Pb-NNV003 was given two days later (n=9-12 per group). 212Pb-cetuximab (unspecific isotype control), unlabeled NNV003 and NaCl were used as controls. Results: A single intravenous dose of 2.5, 5 and 7.5 µCi 212Pb-NNV003 lead to survival of 91%, 73% and 67% of mice injected with Daudi cells 26 weeks post cell injecti