Automated light-induced synthesis of (89)Zr-radiolabeled antibodies for immuno-positron emission tomography

Clinical production of (89)Zr-radiolabeled antibodies ((89)Zr-mAbs) for positron emission tomography imaging relies on the pre-conjugation of desferrioxamine B (DFO) to the purified protein, followed by isolation and characterization of the functionalized intermediate, and then manual radiosynthesis. Although highly successful, this route exposes radiochemists to a potentially large radiation dose and entails several technological and economic hurdles that limit access of (89)Zr-mAbs to just a specialist few Nuclear Medicine facilities worldwide. Here, we introduce a fully automated synthesis box that can produce individual doses of (89)Zr-mAbs formulated in sterile solution in < 25 min starting from [(89)Zr(C(2)O(4))(4)](4–) ((89)Zr-oxalate), our good laboratory practice-compliant photoactivatable desferrioxamine-based chelate (DFO-PEG(3)-ArN(3)), and clinical-grade antibodies without the need for pre-purification of protein. The automated steps include neutralization of the (89)Zr-oxalate stock, chelate radiolabeling, and light-induced protein conjugation, followed by (89)Zr-mAb purification, formulation, and sterile filtration. As proof-of-principle, (89)ZrDFO-PEG(3)-azepin-trastuzumab was synthesized directly from Herceptin in < 25 min with an overall decay-corrected radiochemical yield of 20.1 ± 2.4% (n = 3), a radiochemical purity > 99%, and chemical purity > 99%. The synthesis unit can also produce (89)Zr-mAbs via the conventional radiolabeling routes from pre-functionalized DFO-mAbs that are currently used in the clinic. This automated method will improve access to state-of-the-art (89)Zr-mAbs at the many Nuclear Medicine and research institutions that require automated devices for radiotracer production.