title: PET-based compartmental modeling of (124)I-A33 antibody: quantitative characterization of patient-specific tumor targeting in colorectal cancer.
abstract: OBJECTIVE
  The molecular specificity of monoclonal antibodies (mAbs) directed against tumor antigens has proven effective for targeted therapy of human cancers, as shown by a growing list of successful antibody-based drug products. We describe a novel, nonlinear compartmental model using PET-derived data to determine the "best-fit" parameters and model-derived quantities for optimizing biodistribution of intravenously injected (124)I-labeled antitumor antibodies.
  
  
  METHODS
  As an example of this paradigm, quantitative image and kinetic analyses of anti-A33 humanized mAb (also known as "A33") were performed in 11 colorectal cancer patients. Serial whole-body PET scans of (124)I-labeled A33 and blood samples were acquired and the resulting tissue time-activity data for each patient were fit to a nonlinear compartmental model using the SAAM II computer code.
  
  
  RESULTS
  Excellent agreement was observed between fitted and measured parameters of tumor uptake, "off-target" uptake in bowel mucosa, blood clearance, tumor antigen levels, and percent antigen occupancy.
  
  
  CONCLUSIONS
  This approach should be generally applicable to antibody-antigen systems in human tumors for which the masses of antigen-expressing tumor and of normal tissues can be estimated and for which antibody kinetics can be measured with PET. Ultimately, based on each patient's resulting "best-fit" nonlinear model, a patient-specific optimum mAb dose (in micromoles, for example) may be derived.
authors.affiliation: Department of Medical Physics, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10021, USA. zanzonip@mskcc.org.
authors.forename: Pat
authors.initials: P
authors.lastname: Zanzonico
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Jorge A
authors.initials: JA
authors.lastname: Carrasquillo
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Neeta
authors.initials: N
authors.lastname: Pandit-Taskar
authors.affiliation: Department of Medical Physics, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10021, USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: O'Donoghue
authors.affiliation: Department of Medical Physics, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10021, USA.
authors.forename: John L
authors.initials: JL
authors.lastname: Humm
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.|Departments of Psychiatry and Radiology, Stony Brook School of Medicine, Stony Brook, NY, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Smith-Jones
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Shutian
authors.initials: S
authors.lastname: Ruan
authors.affiliation: Columbia University Medical Center, New York, NY, USA.
authors.forename: Chaitanya
authors.initials: C
authors.lastname: Divgi
authors.affiliation: Olivia Newton-John Cancer Research Institute, La Trobe University, Melbourne, Australia.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Scott
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Kemeny
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.|Department of Surgery, City of Hope, Duarte, CA, USA.
authors.forename: Yuman
authors.initials: Y
authors.lastname: Fong
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Douglas
authors.initials: D
authors.lastname: Wong
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: David
authors.initials: D
authors.lastname: Scheinberg
authors.affiliation: Ludwig Institute for Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Gerd
authors.initials: G
authors.lastname: Ritter
authors.affiliation: Ludwig Institute for Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Achem
authors.initials: A
authors.lastname: Jungbluth
authors.affiliation: Ludwig Institute for Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Lloyd J
authors.initials: LJ
authors.lastname: Old
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Larson
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007457:Iodine Radioisotopes; D007700:Kinetics; D051379:Mice; D008954:Models, Biological; D058990:Molecular Targeted Therapy; D049268:Positron-Emission Tomography; D057285:Precision Medicine
chemical_list: D000911:Antibodies, Monoclonal; D007457:Iodine Radioisotopes