PET imaging to non-invasively study immune activation leading to antitumor responses with a 4-1BB agonistic antibody

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• 作者：Helena Escuin-Ordinas (1)
  Mark W Elliott (2)
  Mohammad Atefi (1)
  Michelle Lee (2)
  Charles Ng (1)
  Liu Wei (3)
  Bego?a Comin-Anduix (4) (5)
  Encarnacion Montecino-Rodriguez (6)
  Earl Avramis (4)
  Caius Radu (3) (5)
  Leslie L Sharp (2) (7)
  Antoni Ribas (1) (3) (5) (8)
  
• 关键词：4 ; 1BB ; CD137 ; Immune activating antibodies ; PET imaging ; Colon cancer
• 刊名：Journal for Immunotherapy of Cancer
• 出版年：2013
• 出版时间：December 2013
• 年：2013
• 卷：1
• 期：1
• 全文大小：771KB
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• 作者单位：Helena Escuin-Ordinas (1)
  Mark W Elliott (2)
  Mohammad Atefi (1)
  Michelle Lee (2)
  Charles Ng (1)
  Liu Wei (3)
  Bego?a Comin-Anduix (4) (5)
  Encarnacion Montecino-Rodriguez (6)
  Earl Avramis (4)
  Caius Radu (3) (5)
  Leslie L Sharp (2) (7)
  Antoni Ribas (1) (3) (5) (8)
  
  1. Department of Medicine (Division of Hematology-Oncology) at David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, USA
  2. Pfizer Worldwide Research and Development, Oncology Research Unit, San Diego, CA, USA
  3. Ahmanson Translational Imaging Division, Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, USA
  4. Department of Surgery (Division of Surgical-Oncology), UCLA, Los Angeles, USA
  5. Jonsson Comprehensive Cancer Center (JCCC), Los Angeles, USA
  6. Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, USA
  7. Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Dr, San Diego, CA, 92121, USA
  8. Department of Medicine, Division of Hematology-Oncology, Jonsson Comprehensive Cancer Center at UCLA, 11-934 Factor Building, 10833 Le Conte Avenue, Los Angeles, CA, 90095-1782, USA
  
• ISSN：2051-1426

文摘

Background Molecular imaging with positron emission tomography (PET) may allow the non-invasive study of the pharmacodynamic effects of agonistic monoclonal antibodies (mAb) to 4-1BB (CD137). 4-1BB is a member of the tumor necrosis factor family expressed on activated T cells and other immune cells, and activating 4-1BB antibodies are being tested for the treatment of patients with advanced cancers. Methods We studied the antitumor activity of 4-1BB mAb therapy using [18 F]-labeled fluoro-2-deoxy-2-D-glucose ([18 F]FDG) microPET scanning in a mouse model of colon cancer. Results of microPET imaging were correlated with morphological changes in tumors, draining lymph nodes as well as cell subset uptake of the metabolic PET tracer in vitro. Results The administration of 4-1BB mAb to Balb/c mice induced reproducible CT26 tumor regressions and improved survival; complete tumor shrinkage was achieved in the majority of mice. There was markedly increased [18?F]FDG signal at the tumor site and draining lymph nodes. In a metabolic probe in vitro uptake assay, there was an 8-fold increase in uptake of [3H]DDG in leukocytes extracted from tumors and draining lymph nodes of mice treated with 4-1BB mAb compared to untreated mice, supporting the in vivo PET data. Conclusion Increased uptake of [18?F]FDG by PET scans visualizes 4-1BB agonistic antibody-induced antitumor immune responses and can be used as a pharmacodynamic readout to guide the development of this class of antibodies in the clinic.