title: Targeted Imaging of the Atypical Chemokine Receptor 3 (ACKR3/CXCR7) in Human Cancer Xenografts.
abstract: The atypical chemokine receptor ACKR3 (formerly CXCR7), overexpressed in various cancers compared with normal tissues, plays a pivotal role in adhesion, angiogenesis, tumorigenesis, metastasis, and tumor cell survival. ACKR3 modulates the tumor microenvironment and regulates tumor growth. The therapeutic potential of ACKR3 has also been demonstrated in various murine models of human cancer. Literature findings underscore the importance of ACKR3 in disease progression and suggest it as an important diagnostic marker for noninvasive imaging of ACKR3-overexpressing malignancies. There are currently no reports on direct receptor-specific detection of ACKR3 expression. Here we report the evaluation of a radiolabeled ACKR3-targeted monoclonal antibody (ACKR3-mAb) for the noninvasive in vivo nuclear imaging of ACKR3 expression in human breast, lung, and esophageal squamous cell carcinoma cancer xenografts.
  
  
  
  ACKR3 expression data were extracted from Cancer Cell Line Encyclopedia, The Cancer Genome Atlas, and the Clinical Lung Cancer Genome Project. (89)Zr-ACKR3-mAb was evaluated in vitro and subsequently in vivo by PET and ex vivo biodistribution studies in mice xenografted with breast (MDA-MB-231-ACKR3 [231-ACKR3], MDA-MB-231 [231], MCF7), lung (HCC95), or esophageal (KYSE520) cancer cells. In addition, ACKR3-mAb was radiolabeled with (125)I and evaluated by SPECT imaging and ex vivo biodistribution studies.
  
  
  
  ACKR3 transcript levels were highest in lung squamous cell carcinoma among the 21 cancer type data extracted from The Cancer Genome Atlas. Also, Clinical Lung Cancer Genome Project data showed that lung squamous cell carcinoma had the highest CXCR7 transcript levels compared with other lung cancer subtypes. The (89)Zr-ACKR3-mAb was produced in 80% ± 5% radiochemical yields with greater than 98% radiochemical purity. In vitro cell uptake of (89)Zr-ACKR3-mAb correlated with gradient levels of cell surface ACKR3 expression observed by flow cytometry. In vivo PET imaging and ex vivo biodistribution studies in mice with breast, lung, and esophageal cancer xenografts consistently showed enhanced (89)Zr-ACKR3-mAb uptake in high-ACKR3-expressing tumors. SPECT imaging of (125)I-ACKR3-mAb showed the versatility of ACKR3-mAb for in vivo monitoring of ACKR3 expression.
  
  
  
  Data from this study suggest ACKR3 to be a viable diagnostic marker and demonstrate the utility of radiolabeled ACKR3-mAb for in vivo visualization of ACKR3-overexpressing malignancies.
authors.affiliation: Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Babak
authors.initials: B
authors.lastname: Behnam Azad
authors.affiliation: Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Ala
authors.initials: A
authors.lastname: Lisok
authors.affiliation: Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Samit
authors.initials: S
authors.lastname: Chatterjee
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: John T
authors.initials: JT
authors.lastname: Poirier
authors.affiliation: Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Mrudula
authors.initials: M
authors.lastname: Pullambhatla
authors.affiliation: Department of Radiology, University of Michigan, Ann Arbor, Michigan; and.
authors.forename: Gary D
authors.initials: GD
authors.lastname: Luker
authors.affiliation: Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, Maryland Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Martin G
authors.initials: MG
authors.lastname: Pomper
authors.affiliation: Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, Maryland Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland snimmag1@jhmi.edu.
authors.forename: Sridhar
authors.initials: S
authors.lastname: Nimmagadda
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000276:immunology / Q000378:metabolism / Q000493:pharmacokinetics; D001692:Biological Transport; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D005260:Female; D006801:Humans; D051379:Mice; D057054:Molecular Imaging / Q000379:methods*; D049268:Positron-Emission Tomography; D011868:Radioisotopes; D054387:Receptors, CXCR / Q000276:immunology / Q000378:metabolism*; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon; D015040:Zirconium / Q000737:chemistry
chemical_list: C501896:ACKR3 protein, human; D000911:Antibodies, Monoclonal; D011868:Radioisotopes; D054387:Receptors, CXCR; D015040:Zirconium
keywords: 89Zr; breast cancer; esophageal cancer; lung cancer; molecular imaging; tumor microenvironment