Immuno-PET imaging of CD30 positive lymphoma using 89Zr-DFO-AC-10

The CD30-specific antibody-drug conjugate, brentuximab vedotin (BV), is approved for the treatment of relapsed, refractory Hodgkin lymphomas, and systemic anaplastic large T-cell lymphomas. Multiple ongoing clinical trials investigate BV efficacy in other CD30 positive hematologic malignancies. Since CD30 expression varies among different types of lymphoma, and can also change during the course of treatment, companion diagnostic imaging of CD30 could be a valuable tool in optimizing patient-specific BV treatment regimens. Methods: The mouse anti-human CD30 antibody AC-10 was radiolabeled with the positron-emitting radionuclide ⁸⁹Zr. The stability and specificity of ⁸⁹Zr-DFO-AC-10 was evaluated in vitro. The pharmacokinetics of ⁸⁹Zr-DFO-AC-10 was studied in Balb/c nude mice bearing subcutaneous human Karpas 299 tumors (CD30 (+) model) or A-431 tumors (CD30(-) model) using PET/CT imaging, biodistribution studies and autoradiography. Results: AC-10 was conjugated with a desferrioxamine B (DFO) chelator and radiolabeled with ⁸⁹Zr to give formulated ⁸⁹Zr-DFO-AC-10 with a radiochemical yield of 80%, radiochemical purity >99% and specific activity of 111-148 MBq/mg. ⁸⁹Zr-DFO-AC-10 was stable in mouse and human serum, and preserved the immunoreactivity towards CD30. Biodistribution data showed the highest tissue accumulation of ⁸⁹Zr-DFO-AC-10 in CD30(+) tumors with 37.9±8.2 %IA/g at 72 h post injection (p.i), whereas uptake in CD30(-) tumors was 11.0±0.4 %IA/g. The specificity of ⁸⁹Zr-DFO-AC-10 binding to CD30 in vivo was confirmed by blocking studies. Based on time-activity curves, tumor-to-muscle ratios increased from 18.9 to 51.8 between 24 and 144 h p.i. in the CD30(+) model, and from 4.8 to 8.7 in the CD30(-) model. Tumor-to-blood ratios also increased from 3.2 to 13.6 in CD30(+) and from 1 to 2 in CD30(-) model. Conclusion: Our results demonstrate that ⁸⁹Zr-DFO-AC-10 can be used as a sensitive PET imaging agent for measuring CD30 expression with high tumor-to-normal tissue contrast. ⁸⁹Zr-DFO-AC-10 is a promising radiotracer for clinical translation of imaging CD30 in various lymphoma patients and in other pathologies.

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