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Targeted alpha therapy with astatine-211-labeled anti-PSCA A11 minibody shows antitumor efficacy in prostate cancer xenografts and bone microtumors

Artikel i vetenskaplig tidskrift
Författare Tom Bäck
Karin Jennbacken
Malin Hagberg Thulin
Sture Lindegren
H. Jensen
T. Olafsen
P. J. Yazaki
Stig Palm
Per Albertsson
Jan-Erik Damber
A. M. Wu
Karin Welén
Publicerad i Ejnmmi Research
Volym 10
Nummer/häfte 1
Sidor 12
ISSN 2191-219X
Publiceringsår 2020
Publicerad vid Institutionen för kliniska vetenskaper, Avdelningen för radiofysik
Institutionen för kliniska vetenskaper, Avdelningen för onkologi
Institutionen för kliniska vetenskaper, Avdelningen för urologi
Sidor 12
Språk en
Länkar dx.doi.org/10.1186/s13550-020-0600-...
Ämnesord Metastatic prostate cancer, Targeted alpha therapy, Alpha particles, Alpha-radioimmunotherapy, Astatine-211, Prostate stem cell antigen, Intratibial microtumors, stem-cell antigen, dosimetry estimate, membrane antigen, long-term, radioimmunotherapy, camera, micrometastases, quantification, expression, Radiology, Nuclear Medicine & Medical Imaging
Ämneskategorier Cancer och onkologi, Klinisk medicin

Sammanfattning

Purpose Targeted alpha therapy (TAT) is a promising treatment for micrometastatic and minimal residual cancer. We evaluated systemic alpha-radioimmunotherapy (alpha-RIT) of metastatic castration-resistant prostate cancer (mCRPC) using the alpha-particle emitter At-211-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 alpha-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 mu 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 At-211-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 mm(3) versus 3.79 +/- 1.24 mm(3) (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 alpha-RIT with At-211-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 At-211-labeled PSCA-directed vectors. Such studies should include methods to improve the therapeutic window, e.g., by implementing a pretargeted regimen of alpha-RIT or by altering the size of the targeting vector.

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