Targeted imaging of the atypical chemokine receptor 3 (ACKR3/CXCR7) in human cancer xenografts

Babak Behnam Azad, Ala Lisok, Samit Chatterjee, John T. Poirier, Mrudula Pullambhatla, Gary D. Luker, Martin Gilbert Pomper, Sridhar Nimmagadda

Research output: Contribution to journalArticle

Abstract

The atypical chemokine receptor ACKR3 (formerly CXCR7), over-expressed 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 radio-labeled 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. Methods: ACKR3 expression data were extracted from Cancer Cell Line Encyclopedia, The Cancer Genome Atlas, and the Clinical Lung Cancer Genome Project. 89Zr-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 125I and evaluated by SPECT imaging and ex vivo biodistribution studies. Results: 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 89Zr-ACKR3-mAb was produced in 80% ± 5% radiochemical yields with greater than 98% radiochemical purity. In vitro cell uptake of 89Zr-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 89Zr-ACKR3-mAb uptake in high-ACKR3-expressing tumors. SPECT imaging of 125I-ACKR3-mAb showed the versatility of ACKR3-mAb for in vivo monitoring of ACKR3 expression. Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)981-988
Number of pages8
JournalJournal of Nuclear Medicine
Volume57
Issue number6
DOIs
StatePublished - Jun 1 2016

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Chemokine Receptors
Heterografts
Monoclonal Antibodies
Neoplasms
Lung Neoplasms
Esophageal Neoplasms
Genome
Lung
Atlases
Single-Photon Emission-Computed Tomography
Squamous Cell Carcinoma
Breast
Encyclopedias
Squamous Cell Neoplasms
Tumor Microenvironment
Radio
Disease Progression
Cell Survival
Flow Cytometry
Carcinogenesis

Keywords

  • Zr
  • Breast cancer
  • Esophageal cancer
  • Lung cancer
  • Molecular imaging
  • Tumor microenvironment

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging

Cite this

Targeted imaging of the atypical chemokine receptor 3 (ACKR3/CXCR7) in human cancer xenografts. / Behnam Azad, Babak; Lisok, Ala; Chatterjee, Samit; Poirier, John T.; Pullambhatla, Mrudula; Luker, Gary D.; Pomper, Martin Gilbert; Nimmagadda, Sridhar.

In: Journal of Nuclear Medicine, Vol. 57, No. 6, 01.06.2016, p. 981-988.

Research output: Contribution to journalArticle

Behnam Azad, Babak ; Lisok, Ala ; Chatterjee, Samit ; Poirier, John T. ; Pullambhatla, Mrudula ; Luker, Gary D. ; Pomper, Martin Gilbert ; Nimmagadda, Sridhar. / Targeted imaging of the atypical chemokine receptor 3 (ACKR3/CXCR7) in human cancer xenografts. In: Journal of Nuclear Medicine. 2016 ; Vol. 57, No. 6. pp. 981-988.
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T1 - Targeted imaging of the atypical chemokine receptor 3 (ACKR3/CXCR7) in human cancer xenografts

AU - Behnam Azad, Babak

AU - Lisok, Ala

AU - Chatterjee, Samit

AU - Poirier, John T.

AU - Pullambhatla, Mrudula

AU - Luker, Gary D.

AU - Pomper, Martin Gilbert

AU - Nimmagadda, Sridhar

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AB - The atypical chemokine receptor ACKR3 (formerly CXCR7), over-expressed 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 radio-labeled 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. Methods: ACKR3 expression data were extracted from Cancer Cell Line Encyclopedia, The Cancer Genome Atlas, and the Clinical Lung Cancer Genome Project. 89Zr-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 125I and evaluated by SPECT imaging and ex vivo biodistribution studies. Results: 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 89Zr-ACKR3-mAb was produced in 80% ± 5% radiochemical yields with greater than 98% radiochemical purity. In vitro cell uptake of 89Zr-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 89Zr-ACKR3-mAb uptake in high-ACKR3-expressing tumors. SPECT imaging of 125I-ACKR3-mAb showed the versatility of ACKR3-mAb for in vivo monitoring of ACKR3 expression. Conclusion: 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.

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