Cyclotron production of 58mCo for Auger electron-based targeted radioimmunotherapy and PET imaging post-therapy with the daughter 58gCo

Objectives : The absence of energetic gammas makes the Auger electron emitter ^58mCo (t_1/2=9.10 h, 100% IC) an ideal radionuclide for targeted therapy [Refs 1-3]. It decays to a positron-emitting daughter, ^58gCo (t_1/2=70.86 d, 14.9% β⁺), which can be readily detected by Positron Emission Tomography (PET) and hence can be employed to verify the biodistribution of the parent isotope post-treatment in vivo. In this work, we describe 1) the targetry and radiochemistry involved in the production of high specific activity ^58mCo; and 2) the results of a pilot radiotherapy study using a ^58mCo-labeled anti-CD105 antibody (TRC105) in a mouse model of mammary carcinoma.

Methods : Thick targets of 95.06% isotopically-enriched ⁵⁷Fe, electroplated over a silver disk, were irradiated with 60 μA of 8.2 MeV deuterons from a PETtrace cyclotron. The irradiated targets were dissolved in HCl and radiocobalt chromatographically purified using a combination of ion exchange and extraction chromatography. The method allowed the recovery of the expensive target material for re-electrodeposition. Production yields of ^58mCo were quantified via two methods: 1) indirectly via quantification of ^58gCo activity over time (E_γ = 811 keV) using an efficiency-calibrated high purity germanium (HPGe) detector, fitting the data points with the Bateman equation that contains the initial activities of the parent and daugher radionuclides; and 2) via direct quantification of ^58mCo (E_γ = 24.9 keV) using a low-energy HPGe detector. The reactivity of ^58mCo was evaluated by chelation with NOTA. For radiolabeling with ^58mCo, TRC105 was first conjugated to p-SCN-Bn-NOTA with a 25:1 NOTA:TRC105 ratio. Radiotherapy studies were carried out in BALB/c mice bearing 4T1 tumors, 11 days after subcutaneous implantation of cancer cells. A group of 4 tumor-bearing mice received 148±11 MBq injections of ^58mCo-NOTA-TRC105, and PET scans were acquired 48 h post-injection (p.i.) to quantify tumor uptake. A second therapeutic dose of 155±18 MBq was administered on day 5 after the first dose, and PET scans were performed at 48 h, 9 and 17 days p.i of the second dose. For each mouse, tumor growth and body weight was monitored for a period of 3 weeks. The efficacy of the treatment was determined by comparing treated mice with a non-treated control group (n=4) that received two injections of non-radioactive TRC105 (140 μg). The dosimetric burden of ^58gCo to a standard adult male was estimated after processing the biodistribution data with the software OLINDA/EXM [Ref 4].

Results /b>: ^58mCo and ^58gCo yields at end of irradiation were 14.4±3.3 and 0.13±0.03 MBq/μAh, respectively (n=3). Cobalt separation efficiency was 96±2%, with a ⁵⁷Fe recycling efficiency of 94±3%. Reactivity with NOTA was 26±7 GBq/μmol, which allowed for high labeling yields (65%) with a ratio of 25 μg of NOTA-TRC105 per mCi of ^58mCo. PET scans at 48 h p.i. of the first dose revealed elevated tumor uptake of 13.3±1.5 % of the ^58gCo injected dose per gram (%ID/g). At day 17 p.i. of the second dose, the %ID/g values were 4.1±2.7, 1.0±0.8, 1.2±0.3, 0.8±0.6, 1.1±0.5 and 0.3±0.2 for the tumor, heart, liver, lung, spleen and muscle, respectively, which demonstrates the clearance of ^58gCo from normal tissue. The effective dose to an adult male is 0.489 mSv/MBq of ^58gCo. No significant difference in tumor growth rate was observed between the treated and non-treated groups after 22 days p.i. of the first dose.

Conclusions We have developed an efficient method for the production of hundreds of MBq of the Auger emitter ^58mCo with high specific activity. Its application in a radiotherapy study demonstrates the feasibility to perform targeted radioimmunotherapy with this radionuclide, and the potential of ^58gCo-based PET scans to assess the biodistribution of the ^58mCo-labeled agent in vivo.

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