Pre-clinical investigation of astatine-211-parthanatine for high-risk neuroblastoma

Abstract

Astatine-211-parthanatine ([²¹¹At]PTT) is an alpha-emitting radiopharmaceutical therapeutic that targets poly(adenosine-diphosphate-ribose) polymerase 1 (PARP1) in cancer cells. High-risk neuroblastomas exhibit among the highest PARP1 expression across solid tumors. In this study, we evaluated the efficacy of [²¹¹At]PTT using 11 patient-derived xenograft (PDX) mouse models of high-risk neuroblastoma, and assessed hematological and marrow toxicity in a CB57/BL6 healthy mouse model. We observed broad efficacy in PDX models treated with [²¹¹At]PTT at the maximum tolerated dose (MTD 36 MBq/kg/fraction x4) administered as a fractionated regimen. For the MTD, complete tumor response was observed in 81.8% (18 of 22) of tumors and the median event free survival was 72 days with 30% (6/20) of mice showing no measurable tumor >95 days. Reversible hematological and marrow toxicity was observed 72 hours post-treatment at the MTD, however full recovery was evident by 4 weeks post-therapy. These data support clinical development of [²¹¹At]PTT for high-risk neuroblastoma.

Fig. 1. Anti-tumor efficacy of [²¹¹At]PTT in high-risk neuroblastoma patient-derived xenograft models.

a Trial design for evaluation of [²¹¹At]PTT efficacy in high-risk neuroblastoma patient-derived tumor models (n = 11 PDX models). b Genetic signatures associated with PDX models. c Tumor response waterfall plot for all dose levels evaluated. Each bar denotes a single treated subject. Significant differences in response were found between 36 MBq/kg/fraction x 4 and lower dose levels (paired-model T-test; p-value = * <0.05). d Event free survival (EFS) for PDX tumors treated with [²¹¹At]PTT at 12, 24, 36 MBq/kg/fraction x 4, or saline control. Significant differences in EFS were found between control and all dose levels analyzed (paired-model ANOVA analysis; p-value = *0.013, **0.0019, ****<0.0001). e Tumor growth curves for PDX models treated with 24 MBq/kg/fraction x 4 and re-challenged at the same dose level at the time of tumor progression. Dotted lines indicate dose-fractionation schedule. f Mouse weight over time for all control and treated mice. Blue line represents NB-EBC1x (n = 1) mouse removed from study due to weight loss after re-challenge at 24 MBq/kg level. Salmon lines represent NB-1643x (n = 1) and COG-N-471x (n = 1) mice removed from study due to weight loss >50 days post-treatment at 36 MBq/kg dose level. * Mice removed from study due to weight loss >20% from study initiation → Mice were tumor free at end of study.

Fig. 2. Testing for contributing factors of [²¹¹At]PTT response.

a Linear regression plot for EFS vs. PARP1 mRNA (p value = 0.8). b Grouped response for genetic signatures in PDX models. Lines represent models with 1 or more genetic signatures.

Fig. 3. Safety profile of [²¹¹At]PTT.

a Tolerability studies to determine hematological and marrow toxicity of [²¹¹At]PTT in CB57BL6 mice. b Complete blood counts and c marrow progenitor colony formation at 72 hours post-treatment after dose escalation. Mice received either 36, 48, or 60 MBq/kg/fraction twice weekly for a total of 4 dose fractions. d Marrow progenitor colony formation was assessed at 72 hours, 2 and 4 weeks post treatment for 2 dose fractions at the 36 MBq/kg/fraction dose level. Statistical analysis was performed by ordinary one-way ANOVA comparison between the mean of control and test groups. p-value denoted as * <0.05, ** <0.01, ***<0.001, ****<0.0001. PLT platelets, WBC white blood cells, LY lymphoctyes, NE neutrrophils, GEMM-early progenitor cell, GM granulocyte and macrophage progenitor cells.