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The ?-emitter astatine-211 targeted to CD38 can eradicate multiple myeloma in a disseminated disease model.

ABSTRACT: Minimal residual disease (MRD) has become an increasingly prevalent and important entity in multiple myeloma (MM). Despite deepening responses to frontline therapy, roughly 75% of MM patients never become MRD-negative to ?10-5, which is concerning because MRD-negative status predicts significantly longer survival. MM is highly heterogeneous, and MRD persistence may reflect survival of isolated single cells and small clusters of treatment-resistant subclones. Virtually all MM clones are exquisitely sensitive to radiation, and the ?-emitter astatine-211 (211At) deposits prodigious energy within 3 cell diameters, which is ideal for eliminating MRD if effectively targeted. CD38 is a proven MM target, and we conjugated 211At to an anti-CD38 monoclonal antibody to create an 211At-CD38 therapy. When examined in a bulky xenograft model of MM, single-dose 211At-CD38 at 15 to 45 µCi at least doubled median survival of mice relative to untreated controls (P < .003), but no mice achieved complete remission and all died within 75 days. In contrast, in a disseminated disease model designed to reflect low-burden MRD, 3 studies demonstrated that single-dose 211At-CD38 at 24 to 45 µCi produced sustained remission and long-term survival (>150 days) for 50% to 80% of mice, where all untreated mice died in 20 to 55 days (P < .0001). Treatment toxicities were transient and minimal. These data suggest that 211At-CD38 offers the potential to eliminate residual MM cell clones in low-disease-burden settings, including MRD. We are optimistic that, in a planned clinical trial, addition of 211At-CD38 to an autologous stem cell transplant (ASCT) conditioning regimen may improve ASCT outcomes for MM patients.

SUBMITTER: O'Steen S

PROVIDER: S-EPMC6788008 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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The α-emitter astatine-211 targeted to CD38 can eradicate multiple myeloma in a disseminated disease model.

O'Steen Shyril S Comstock Melissa L ML Orozco Johnnie J JJ Hamlin Donald K DK Wilbur D Scott DS Jones Jon C JC Kenoyer Aimee A Nartea Margaret E ME Lin Yukang Y Miller Brian W BW Gooley Theodore A TA Tuazon Sherilyn A SA Till Brian G BG Gopal Ajay K AK Sandmaier Brenda M BM Press Oliver W OW Green Damian J DJ

Blood 20191001 15

Minimal residual disease (MRD) has become an increasingly prevalent and important entity in multiple myeloma (MM). Despite deepening responses to frontline therapy, roughly 75% of MM patients never become MRD-negative to ≤10-5, which is concerning because MRD-negative status predicts significantly longer survival. MM is highly heterogeneous, and MRD persistence may reflect survival of isolated single cells and small clusters of treatment-resistant subclones. Virtually all MM clones are exquisite ...[more]

PMID: 31395601

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Project description:PURPOSE:Targeted alpha therapy (TAT) is a promising treatment for micrometastatic and minimal residual cancer. We evaluated systemic ?-radioimmunotherapy (?-RIT) of metastatic castration-resistant prostate cancer (mCRPC) using the ?-particle emitter 211At-labeled to the anti-PSCA A11 minibody. A11 is specific for prostate stem cell antigen (PSCA), a cell surface glycoprotein which is overexpressed in more than 90% of both localized prostate cancer and bone metastases. METHODS:PC3-PSCA cells were implanted subcutaneously (s.c.) and intratibially (i.t) in nude mice. Efficacy of ?-RIT (two fractions-14-day interval) was studied on s.c. macrotumors (0, 1.5 and 1.9?MBq) and on i.t. microtumors (~100-200??m; 0, 0.8 or 1.5?MBq) by tumor-volume measurements. The injected activities for therapies were estimated from separate biodistribution and myelotoxicity studies. RESULTS:Tumor targeting of 211At-A11 was efficient and the effect on s.c. macrotumors was strong and dose-dependent. At 6?weeks, the mean tumor volumes for the treated groups, compared with controls, were reduced by approximately 85%. The separate myelotoxicity study following one single fraction showed reduced white blood cells (WBC) for all treated groups on day 6 after treatment. For the 0.8 and 1.5?MBq, the WBC reductions were transient and followed by recovery at day 13. For 2.4?MBq, a clear toxicity was observed and the mice were sacrificed on day 7. In the long-term follow-up of the 0.8 and 1.5?MBq-groups, blood counts on day 252 were normal and no signs of radiotoxicity observed. Efficacy on i.t. microtumors was evaluated in two experiments. In experiment 1, the tumor-free fraction (TFF) was 95% for both treated groups and significantly different (p < 0.05) from the controls at a TFF of 66%). In experiment 2, the difference in TFF was smaller, 32% for the treated group versus 20% for the controls. However, the difference in microtumor volume in experiment 2 was highly significant, 0.010 ± 0.003?mm3 versus 3.79 ± 1.24?mm3 (treated versus controls, respectively), i.e., a 99.7% reduction (p < 0.001). The different outcome in experiment 1 and 2 is most likely due to differences in microtumor sizes at therapy, or higher tumor-take in experiment 2 (where more cells were implanted). CONCLUSION:Evaluating fractionated ?-RIT with 211At-labeled anti-PSCA A11 minibody, we found clear growth inhibition on both macrotumors and intratibial microtumors. For mice treated with multiple fractions, we also observed radiotoxicity manifested by progressive loss in body weight at 30 to 90?days after treatment. Our findings are conceptually promising for a systemic TAT of mCRPC and warrant further investigations of 211At-labeled PSCA-directed vectors. Such studies should include methods to improve the therapeutic window, e.g., by implementing a pretargeted regimen of ?-RIT or by altering the size of the targeting vector.

Project description:PurposeCluster of differentiation 38 (CD38) is a promising therapeutic target in multiple myeloma (MM) patients and has resulted in the development of several CD38 immunotherapies. Current methods to evaluate CD38 expression in the preclinical setting include ex vivo flow cytometry and immunohistochemistry, which can be cumbersome and do not give whole-body information. In vivo imaging technologies such as positron emission tomography rely on decay of radioisotopes, limiting the number of molecular interactions observed at any given time point. Here, we demonstrate the use of near-infrared (NIR) fluorescence imaging for spatiotemporal monitoring of CD38 expression in preclinical MM using the anti-CD38 daratumumab (DARA) conjugated to the NIR fluorophore IRDye800CW (DARA-IRDye800).ProceduresStability studies with human serum and binding assays with human myeloma cells were performed with DARA-IRDye800. Immunocompromised mice with intra- and extramedullary tumors (n = 5/group) were administered with DARA-IRDye800 for in vivo imaging up to 7 days after injection. Ex vivo biodistribution and flow cytometry studies were performed to validate in vivo imaging results. A separate therapy study was performed in mice with intramedullary tumors that were treated and not treated with DARA at a therapeutic dose (n = 7/group). DARA-IRDye800 was administered for subsequent in vivo and ex vivo imaging in both cohorts of mice.ResultsDARA-IRDye800 maintained stability and had high affinity for CD38 (KD = 3.5 ± 0.05 nM). DARA-IRDye800 demonstrated a 5- and 18-fold increase in contrast in tumor-bearing regions of mice with extra- and intramedullary MM. Finally, mice treated with therapeutic doses of DARA and imaged with DARA-IRDye800 showed an 11-fold decrease in fluorescence intensities in vivo compared with untreated controls.ConclusionsOur studies establish DARA-IRDye800 as a promising contrast agent for preclinical evaluation of CD38 expression and for further investigating myeloma engraftment and kinetics in relation to anti-CD38 therapies.

Dataset Information

The ?-emitter astatine-211 targeted to CD38 can eradicate multiple myeloma in a disseminated disease model.

Publications

The α-emitter astatine-211 targeted to CD38 can eradicate multiple myeloma in a disseminated disease model.

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