Kjenpemelding😃
Her er komplett abstract:
Sunday, October 13, 2019, 14:30 - 16:00 Lecture Hall 111
OP-134
Targeted alpha therapy with 212Pb-NNV003 is efficient in treatment of ibrutinib-resistant chronic lymphocytic leukaemia in preclinical models
A. Saidi1, H. Heyerdahl2, A. Maaland2, J. Torgue3, J. Dahle2; 1Orano Med SAS, Paris La Défense, FRANCE, 2Nordic Nanovector ASA, Oslo, NORWAY, 3Orano Med LLC,
Plano, TX, UNITED STATES OF AMERICA.
Aim/Introduction: Approximately 90,000 cases of chronic lymphocytic leukaemia (CLL) and non-Hodkgin’s lymphoma (NHL) are expected annually in the US. Standard of care includes chemotherapy combined with anti-CD20 antibodies and Bruton’s tyrosine kinase inhibitor ibrutinib. While these therapies are initially effective, most patients inevitably relapse. CD37 is under clinical evaluation as a therapeutic target for B-cell malignancies. Alpha-emitting radionuclides have demonstrated potential for targeted therapies due to the short alpha track, causing localized cytotoxicity. Orano Med and Nordic Nanovector developed a targeted alpha therapy combining the CD37-specific antibody NNV003 with the alpha-particle- emitting radioisotope 212Pb. We previously reported that 212Pb-NNV003 is effective in disseminated animal models using CD37- expressing NHL and CLL cell lines (1). Here we compare the efficacy of 212Pb-NNV003 with ibrutinib in a disseminated mouse model using the ibrutinib-resistant cell line MEC-2. Materials and Methods: The efficacy and tolerability of a single dose 212Pb- NNV003 treatment were evaluated in disseminated models using human CLL (MEC-2) and Burkitt’s lymphoma (Daudi) cells. Comparison to therapeutic doses of ibrutinib was investigated in the MEC-2 model. R2G2 or CB17-SCID mice were injected intravenously with 2.5×106 MEC-2 or 10×106 Daudi cells on day 0, followed by intravenous injection of 212Pb-NNV003 (2.5, 5 or 7.5 μCi in Daudi model and 5, 10, 15 or 20 μCi in MEC-2 model) or daily oral administration of ibrutinib (12.5 or 25 mg/kg) starting on day 2 (n=10-12 per group). 212Pb-cetuximab (unspecific isotype control), unlabelled NNV003 and NaCl were used as controls. Results: 212Pb-NNV003 treatments resulted in survival of 67-91% of the mice 26 weeks after Daudi cell injection, and 30-90% of the mice 27 weeks after MEC-2 cell injection. Control mice presented a median survival of 7-8 weeks in the Daudi model and 4.9-9.3 weeks in the MEC-2 model. 212Pb-NNV003 showed a significantly prolonged survival compared to ibrutinib and controls (p <0.0001). 15 and 20 μCi 212Pb-NNV003 resulted in survival of 100% and 70% of mice 15 weeks after MEC-2 cell injection. Ibrutinib treated animals presented a median survival of 4.3-4.4 weeks, comparable to the NNV003 and saline groups (4.1 and 4.4 weeks). Mice receiving 212Pb-cetuximab presented a median survival of 7 weeks. Conclusion: The study shows that a single injection 212Pb-NNV003 is safe and effective for the treatment of CD37 positive CLL and NHL in preclinical models, with promising efficacy in an ibrutinib-resistant CLL model. Further clinical testing is warranted. References: 1. Saidi
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