Clinical Experience with α-Particle–Emitting ²¹¹At: Treatment of Recurrent Brain Tumor Patients with ²¹¹At-Labeled Chimeric Antitenascin Monoclonal Antibody 81C6

Abstract

a-Particle-emitting radionuclides, such as 211 At, with a 7.2-h half-life, may be optimally suited for the molecularly targeted radiotherapy of strategically sensitive tumor sites, such as those in the central nervous system. Because of the much shorter range and more potent cytotoxicity of a-particles than of b-particles, 211 At-labeled agents may be ideal for the eradication of tumor cells remaining after surgical debulking of malignant brain tumors. The main goal of this study was to investigate the feasibility and safety of this approach in patients with recurrent malignant brain tumors. Methods: Chimeric antitenascin monoclonal antibody 81C6 (ch81C6) (10 mg) was labeled with 71-347 MBq of 211 At by use of N-succinimidyl 3-[ 211 At]astatobenzoate. Eighteen patients were treated with 211 At-labeled ch81C6 ( 211 At-ch81C6) administered into a surgically created resection cavity (SCRC) and then with salvage chemotherapy. Serial g-camera imaging and blood sampling over 24 h were performed. Results: A total of 96.7% 6 3.6% (mean 6 SD) of 211 At decays occurred in the SCRC, and the mean blood-pool percentage injected dose was #0.3. No patient experienced dose-limiting toxicity, and the maximum tolerated dose was not identified. Six patients experienced grade 2 neurotoxicity within 6 wk of 211 At-ch81C6 administration; this neurotoxicity resolved fully in all but 1 patient. No toxicities of grade 3 or higher were attributable to the treatment. No patient required repeat surgery for radionecrosis. The median survival times for all patients, those with glioblastoma multiforme, and those with anaplastic astrocytoma or oligodendroglioma were 54, 52, and 116 wk, respectively. Conclusion: This study provides proof of concept for regional targeted radiotherapy with 211 At-labeled molecules in oncology. Specifically, the regional administration of 211 At-ch81C6 is feasible, safe, and associated with a promising antitumor benefit in patients with malignant central nervous system tumors.

Anti-CD45 radioimmunotherapy using 211At with bone marrow transplantation prolongs survival in a disseminated murine leukemia model

“…Conversely, a-emitting radionuclides have the potential to deliver improved therapeutic ratios of absorbed radioactivity with less nonspecific toxicity because of their very short path lengths (;60-80 mm), making them attractive candidates for therapy of leukemias and elimination of minimal residual disease. [12][13][14][15][16] Differences in path lengths dictate that b emitters rely on the cross-fire effect, irradiating bystander cells without the need to deliver the radionuclide directly to each malignant cell. The cross-fire effect from a emitters is confined to smaller volumes, resulting in a cytotoxic effect in short-range tracks near cells binding the radionuclide via the mAb.…”

Targeted use of Alpha Particles: Current Status in Cancer Therapeutics

“…Ra in a phase one trial addressing safety and tolerability [60]. Pain relief was reported by 52%, 60%, and 56% of the patients after 7 days, 4 weeks and 8 weeks, respectively.…”

Application of Radionuclides and Antibody-Drug Conjugates to Target Cancer

“…44 Currently several preclinical trails include the biovectors: Monoclonal antibody C595 labelled with bismuth-213 to target MUC1 gene expressed by the prostate; 45 PA12 human recombinant protein to target urokinase-type Plasminogen Activator (uPA) system which is expressed in several types of cancer (e.g. breast cancer); 46 Monoclonal antibody J591 to target the Prostate Specific Membrane Antigen (PSMA) 47 and Bevacizumab (Avastin ® ) in the treatment of recurrent glioblastoma.…”