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

ABSTRACT: Clinical production of ⁸⁹Zr-radiolabeled antibodies (⁸⁹Zr-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 ⁸⁹Zr-mAbs to just a specialist few Nuclear Medicine facilities worldwide. Here, we introduce a fully automated synthesis box that can produce individual doses of ⁸⁹Zr-mAbs formulated in sterile solution in < 25 min starting from [⁸⁹Zr(C₂O₄)₄]^4- (⁸⁹Zr-oxalate), our good laboratory practice-compliant photoactivatable desferrioxamine-based chelate (DFO-PEG₃-ArN₃), and clinical-grade antibodies without the need for pre-purification of protein. The automated steps include neutralization of the ⁸⁹Zr-oxalate stock, chelate radiolabeling, and light-induced protein conjugation, followed by ⁸⁹Zr-mAb purification, formulation, and sterile filtration. As proof-of-principle, ⁸⁹ZrDFO-PEG₃-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 ⁸⁹Zr-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 ⁸⁹Zr-mAbs at the many Nuclear Medicine and research institutions that require automated devices for radiotracer production.

SUBMITTER: Klingler S

PROVIDER: S-EPMC8758695 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Selection of the right drug for the right patient is a promising approach to increase clinical benefit of targeted therapy with monoclonal antibodies (mAbs). Assessment of in vivo biodistribution and tumor targeting of mAbs to predict toxicity and efficacy is expected to guide individualized treatment and drug development. Molecular imaging with positron emission tomography (PET) using zirconium-89 ((89)Zr)-labeled monoclonal antibodies also known as (89)Zr-immuno-PET, visualizes and quantifies uptake of radiolabeled mAbs. This technique provides a potential imaging biomarker to assess target expression, as well as tumor targeting of mAbs. In this review we summarize results from initial clinical trials with (89)Zr-immuno-PET in oncology and discuss technical aspects of trial design. In clinical trials with (89)Zr-immuno-PET two requirements should be met for each (89)Zr-labeled mAb to realize its full potential. One requirement is that the biodistribution of the (89)Zr-labeled mAb (imaging dose) reflects the biodistribution of the drug during treatment (therapeutic dose). Another requirement is that tumor uptake of (89)Zr-mAb on PET is primarily driven by specific, antigen-mediated, tumor targeting. Initial trials have contributed toward the development of (89)Zr-immuno-PET as an imaging biomarker by showing correlation between uptake of (89)Zr-labeled mAbs on PET and target expression levels in biopsies. These results indicate that (89)Zr-immuno-PET reflects specific, antigen-mediated binding. (89)Zr-immuno-PET was shown to predict toxicity of RIT, but thus far results indicating that toxicity of mAbs or mAb-drug conjugate treatment can be predicted are lacking. So far, one study has shown that molecular imaging combined with early response assessment is able to predict response to treatment with the antibody-drug conjugate trastuzumab-emtansine, in patients with human epithelial growth factor-2 (HER2)-positive breast cancer. Future studies would benefit from a standardized criterion to define positive tumor uptake, possibly supported by quantitative analysis, and validated by linking imaging data with corresponding clinical outcome. Taken together, these results encourage further studies to develop (89)Zr-immuno-PET as a predictive imaging biomarker to guide individualized treatment, as well as for potential application in drug development.

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

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