title: Immuno-PET Imaging of CD30-Positive Lymphoma Using 89Zr-Desferrioxamine-Labeled CD30-Specific AC-10 Antibody.
abstract: The CD30-specific antibody-drug conjugate, brentuximab vedotin, is approved for the treatment of relapsed, refractory Hodgkin lymphomas and systemic anaplastic large T-cell lymphomas. Multiple ongoing clinical trials are investigating brentuximab vedotin efficacy in other CD30-positive hematologic malignancies. Because 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 brentuximab vedotin treatment regimens.
  
  
  METHODS
  The mouse antihuman CD30 antibody AC-10 was radiolabeled with the positron-emitting radionuclide (89)Zr. The stability and specificity of (89)Zr-desferrioxamine (DFO)-labeled CD30-specific AC-10 antibody ((89)Zr-DFO-AC-10) was evaluated in vitro. The pharmacokinetics of (89)Zr-DFO-AC-10 was studied in BALB/c nude mice bearing subcutaneous human Karpas 299 tumors (CD30-positive model) or A-431 tumors (CD30-negative model) using PET/CT imaging, biodistribution studies, and autoradiography.
  
  
  RESULTS
  AC-10 was conjugated with a DFO B chelator and radiolabeled with (89)Zr to give formulated (89)Zr-DFO-AC-10 with a radiochemical yield of 80%, radiochemical purity greater than 99%, and specific activity of 111-148 MBq/mg. (89)Zr-DFO-AC-10 was stable in mouse and human sera and preserved the immunoreactivity toward CD30. Biodistribution data showed the highest tissue accumulation of (89)Zr-DFO-AC-10 in CD30-positive tumors, with 37.9% ± 8.2% injected activity per gram of tissue at 72 h after injection, whereas uptake in CD30-negative tumors was 11.0% ± 0.4%. The specificity of (89)Zr-DFO-AC-10 binding to CD30 in vivo was confirmed by blocking studies. Time-activity curves showed that between 24 and 144 h after injection, tumor-to-muscle ratios increased from 18.9 to 51.8 in the CD30-positive model and from 4.8 to 8.7 in the CD30-negative model. Tumor-to-blood ratios also increased, from 3.2 to 13.6 and from 1 to 2 in the CD30-positive and -negative models, respectively.
  
  
  CONCLUSIONS
  Our results demonstrate that for measuring CD30 expression, (89)Zr-DFO-AC-10 is a sensitive PET agent with high tumor-to-normal-tissue contrast. (89)Zr-DFO-AC-10 is a promising CD30-imaging radiotracer for clinical translation in patients with various lymphomas and other diseases.
authors.affiliation: German Cancer Consortium, Heidelberg, Germany Department of Nuclear Medicine, University Hospital Freiburg, Freiburg, Germany German Cancer Research Center, Heidelberg, Germany; and svetlana.rylova@uniklinik-freiburg.de.
authors.forename: Svetlana N
authors.initials: SN
authors.lastname: Rylova
authors.affiliation: German Cancer Consortium, Heidelberg, Germany Department of Nuclear Medicine, University Hospital Freiburg, Freiburg, Germany German Cancer Research Center, Heidelberg, Germany; and.
authors.forename: Luigi
authors.initials: L
authors.lastname: Del Pozzo
authors.affiliation: German Cancer Consortium, Heidelberg, Germany German Cancer Research Center, Heidelberg, Germany; and Department of Internal Medicine I, University Hospital Freiburg, Freiburg, Germany.
authors.forename: Cathrin
authors.initials: C
authors.lastname: Klingeberg
authors.affiliation: Department of Nuclear Medicine, University Hospital Freiburg, Freiburg, Germany.
authors.forename: Roswitha
authors.initials: R
authors.lastname: Tönnesmann
authors.affiliation: German Cancer Consortium, Heidelberg, Germany German Cancer Research Center, Heidelberg, Germany; and Department of Internal Medicine I, University Hospital Freiburg, Freiburg, Germany.
authors.forename: Anna L
authors.initials: AL
authors.lastname: Illert
authors.affiliation: German Cancer Consortium, Heidelberg, Germany Department of Nuclear Medicine, University Hospital Freiburg, Freiburg, Germany.
authors.forename: Philipp T
authors.initials: PT
authors.lastname: Meyer
authors.affiliation: Department of Nuclear Medicine, University Hospital Freiburg, Freiburg, Germany.
authors.forename: Helmut R
authors.initials: HR
authors.lastname: Maecke
authors.affiliation: German Cancer Consortium, Heidelberg, Germany Department of Nuclear Medicine, University Hospital Freiburg, Freiburg, Germany German Cancer Research Center, Heidelberg, Germany; and.
authors.forename: Jason P
authors.initials: JP
authors.lastname: Holland
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000276:immunology* / Q000493:pharmacokinetics; D000918:Antibody Specificity; D045744:Cell Line, Tumor; D003676:Deferoxamine / Q000737:chemistry*; D004355:Drug Stability; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry / Q000276:immunology / Q000493:pharmacokinetics; D017730:Ki-1 Antigen / Q000276:immunology* / Q000378:metabolism; D008223:Lymphoma / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D049268:Positron-Emission Tomography / Q000379:methods*; D011854:Radiochemistry; D011868:Radioisotopes; D014018:Tissue Distribution; D015040:Zirconium
chemical_list: D000911:Antibodies, Monoclonal; D018796:Immunoconjugates; D017730:Ki-1 Antigen; D011868:Radioisotopes; D015040:Zirconium; D003676:Deferoxamine
keywords: 89Zr; CD30; PET/CT; antibody; brentuximab vedotin; lymphoma