Targeted Alpha Therapy with Ac-Macropa-Isatuximab for CD38-positive Hematological Malignancies

Abstract

BackgroundHematological malignancies include diverse cancers related to immune system cells and blood-forming tissue. Treatment resistance and relapse are common despite the introduction of novel therapeutics. Following the development of the PET probe [89Zr]Zr-DFO-isatuximab, targeting the overexpressed CD38 receptor, we developed [225Ac]Ac-Macropa-isatuximab for targeted alpha therapy in murine models of human multiple myeloma (MM) and lymphoma. MethodsIn vitro studies were performed using the CD38 expressing MM1.S (human MM) and Daudi (human lymphoma). Radiopharmaceutical therapy studies were performed in female NSG mice, and the disseminated disease models were established by intravenous injection of luciferase-transfected cells. Mice were randomized (n = 10 mice per cohort) and received a high activity (5.5 kBq) or low activity (2.7 kBq) of [225Ac]Ac-Macropa-Isatuximab in single or multiple cycles. Controls receiving untargeted [225Ac]Ac-Macropa-IgG or saline were included. Tumor burden was measured by bioluminescence imaging (BLI). Weight loss greater than 20% or leg paralysis were used as endpoints. Results[225Ac]Ac-Macropa-Isatuximab was obtained with high radiochemical yield and purity (>95%). It displayed high immunoreactivity and excellent stability in human serum over 10 days. The therapeutic effect of [225Ac]Ac-mcp-Isatuximab was significant for all the treatment cohorts compared to the saline control after administration of the first cycle. Low activities were better tolerated in general, resulting in extended median survivals. The most successful regimen in the MM model was the dual cycle of low activity, with a median survival of 60 days (P < 0.001). In the lymphoma model, the single high activity of 5.5 kBq and four low activity of 2.7 kBq resulted in similar median survivals of 143 days (P < 0.0001) and 147 days (P < 0.0001). These regimens resulted in complete responses with no detectable cancer cells in some cases. Remarkably, no significant kidney damage was observed in any of the models. Conclusion[225Ac]Ac-Macropa-Isatuximab selectively targets CD38, reducing tumor growth and, in some cases, tumor eradication, especially when applied in multiple cycles. Importantly, it has not been associated with significant toxicities at levels of administered activity required for therapeutic benefit, indicating its promise as a therapeutic option.