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Apr 1 – 5, 2019
Fairmont Château Laurier Hotel
UTC timezone

212Pb-NNV003 as a novel targeted alpha therapy for CD37 positive B-cell chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL)

Not scheduled
Fairmont Château Laurier Hotel

Fairmont Château Laurier Hotel



Dr Amal SAIDI (Orano Med)


**Background** Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults in western countries, accounting for approximately one quarter of all leukemias and Non-Hodgkin lymphoma (NHL) caused an estimated 200,000 cancer deaths worldwide in 2014. More than 90,000 cases of chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL) are expected in the US each year. Immuno-chemotherapy using anti-CD20 monoclonal antibodies (mAb) in combination with DNA alkylating agents is the front-line therapy of CLL and NHL. Despite promising initial results, relapses after repeated administration of immuno-chemotherapy are frequent and relapsed/refractory patients show poor prognosis. As CD37 is strongly and selectively expressed on the surface of mature B lymphocytes and B-cell malignancies, the development of new therapies targeting CD37 expressing cells may prove useful for relapsed or refractory patients as an alternative to CD20 targeting agents. We have developed a targeted alpha therapy (TAT) where the CD37-specific antibody NNV003 is coupled to the *in-vivo* alpha-particle-generator, 212Pb. When treated with alpha radiation, targeted cancer cells are exposed to high linear energy transfer (LET). LET acts over a short range (50–100 µm), causing double strand breaks in the DNA of targeted cells while sparing adjacent normal tissues **Materials and Methods** The efficacy of a single escalating 212Pb-NNV003 administration was evaluated on disseminated models of human Burkitt’s lymphoma (Daudi) and CLL (MEC-2). 10 million Daudi cells or 2.5 million MEC-2 cells were intravenously injected in CB17-SCID or R2G2 mice and 212Pb-NNV003 was given two days later. Unspecific, 212Pb-labeled antibody was used as control. Dose range finding and tolerability studies were performed in CB17-SCID and R2G2 tumor-free mice to define the maximum tolerated dose prior to the efficacy studies. **Results** 212Pb-NNV003 displays a favorable toxicity profile after a single intravenous injection in tumor-free mice. No acute hematological toxicity was observed, and animals presented only a slight initial reduction in their platelets (PLT) counts which was fully recovered 4-weeks after injection. A single intravenous dose of 10, 15 or 20 µCi of 212Pb-NNV003 led to 70 %, 90 % and 100 % of mice injected with MEC-2 cells being tumor free 20 weeks post cell injection. Control animals that received saline, cold antibody or 212Pb-cetuximab presented a median survival of 4.9, 5.4 and 9.3 weeks, respectively. A single intravenous dose of 2.5, 5 and 7.5 µCi 212Pb-NNV003 led to over 80% tumor-free mice injected with Daudi cells 15 weeks post cell injection. Control animals that received saline, cold antibody or 212Pb-cetuximab presented a median survival of 7, 7.8 and 7.7 weeks, respectively. **Conclusion** The results of preclinical studies suggest that TAT using 212Pb-NNV003 may have positive clinical implication for the treatment of CD37 positive CLL and NHL.
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Presentation Type Contributed Oral

Primary author

Dr Amal SAIDI (Orano Med)


Dr Astri MAALAND (Nordic Nanovector) Dr Helen HEYERDAHL (Nordic Nanovector) Dr Jostein DAHLE (Nordic Nanovector) Dr Julien TORGUE (Orano Med)

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