title: Theranostic pretargeted radioimmunotherapy of colorectal cancer xenografts in mice using picomolar affinity ⁸⁶Y- or ¹⁷⁷Lu-DOTA-Bn binding scFv C825/GPA33 IgG bispecific immunoconjugates.
abstract: OBJECTIVE
  GPA33 is a colorectal cancer (CRC) antigen with unique retention properties after huA33-mediated tumor targeting. We tested a pretargeted radioimmunotherapy (PRIT) approach for CRC using a tetravalent bispecific antibody with dual specificity for GPA33 tumor antigen and DOTA-Bn-(radiolanthanide metal) complex.
  
  
  METHODS
  PRIT was optimized in vivo by titrating sequential intravenous doses of huA33-C825, the dextran-based clearing agent, and the C825 haptens (177)Lu-or (86)Y-DOTA-Bn in mice bearing the SW1222 subcutaneous (s.c.) CRC xenograft model.
  
  
  RESULTS
  Using optimized PRIT, therapeutic indices (TIs) for tumor radiation-absorbed dose of 73 (tumor/blood) and 12 (tumor/kidney) were achieved. Estimated absorbed doses (cGy/MBq) to tumor, blood, liver, spleen, and kidney for single-cycle PRIT were 65.8, 0.9 (TI 73), 6.3 (TI 10), 6.6 (TI 10), and 5.3 (TI 12), respectively. Two cycles of PRIT (66.6 or 111 MBq (177)Lu-DOTA-Bn) were safe and effective, with a complete response of established s.c. tumors (100 - 700 mm(3)) in nine of nine mice, with two mice alive without recurrence at >140 days. Tumor log kill in this model was estimated to be 2.1 - 3.0 based on time to 500-mm(3) tumor recurrence. In addition, PRIT dosimetry/diagnosis was performed by PET imaging of the positron-emitting DOTA hapten (86)Y-DOTA-Bn.
  
  
  CONCLUSIONS
  We have developed anti-GPA33 PRIT as a triple-step theranostic strategy for preclinical detection, dosimetry, and safe targeted radiotherapy of established human colorectal mouse xenografts.
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.|Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, 415 E. 68th Street, Z-2064, New York, NY, 10065, USA.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Cheal
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Hong-Fen
authors.initials: HF
authors.lastname: Guo
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.|Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, 415 E. 68th Street, Z-2064, New York, NY, 10065, USA.
authors.forename: Sang-Gyu
authors.initials: SG
authors.lastname: Lee
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.|Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, 415 E. 68th Street, Z-2064, New York, NY, 10065, USA.
authors.forename: Blesida
authors.initials: B
authors.lastname: Punzalan
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Sandhya
authors.initials: S
authors.lastname: Chalasani
authors.affiliation: Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, 415 E. 68th Street, Z-2064, New York, NY, 10065, USA.|Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Edward K
authors.initials: EK
authors.lastname: Fung
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Achim
authors.initials: A
authors.lastname: Jungbluth
authors.affiliation: Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Pat B
authors.initials: PB
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 Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: O'Donoghue
authors.affiliation: Department of Psychiatry and Behavioral Science, Stony Brook University, Stony Brook, NY, USA.|Department of Radiology, Stony Brook University, Stony Brook, NY, USA.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Smith-Jones
authors.affiliation: Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.|Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.|Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: K Dane
authors.initials: KD
authors.lastname: Wittrup
authors.affiliation: Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, 415 E. 68th Street, Z-2064, New York, NY, 10065, USA.|Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Nai-Kong V
authors.initials: NV
authors.lastname: Cheung
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. larsons@mskcc.org.|Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, 415 E. 68th Street, Z-2064, New York, NY, 10065, USA. larsons@mskcc.org.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Larson
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000276:immunology / Q000627:therapeutic use*; D000915:Antibody Affinity; D015179:Colorectal Neoplasms / Q000000981:diagnostic imaging* / Q000532:radiotherapy; D018796:Immunoconjugates / Q000276:immunology / Q000627:therapeutic use*; D007074:Immunoglobulin G / Q000276:immunology; D008187:Lutetium / Q000627:therapeutic use; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D016499:Radioimmunotherapy; D019275:Radiopharmaceuticals / Q000276:immunology / Q000627:therapeutic use*; D057127:Single-Chain Antibodies / Q000276:immunology / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays; D015021:Yttrium Radioisotopes / Q000627:therapeutic use
chemical_list: D018033:Antibodies, Bispecific; C504395:Gpa33 protein, mouse; D018796:Immunoconjugates; D007074:Immunoglobulin G; D008562:Membrane Glycoproteins; D019275:Radiopharmaceuticals; D057127:Single-Chain Antibodies; D015021:Yttrium Radioisotopes; D008187:Lutetium
keywords: Bispecific antibodies; GPA33; Multistep targeting; Pretargeting; Radioimmunotherapy