title: Radioimmunotherapy of head and neck cancer xenografts using 131I-labeled antibody L19-SIP for selective targeting of tumor vasculature.
abstract: The extra domain B of fibronectin (ED-B) is a marker of tumor angiogenesis. The human monoclonal antibody (mAb) L19-SIP (approximately 80 kDa; SIP is "small immunoprotein") has been selected for targeting of ED-B. The aim of this study was to evaluate the potential of radioimmunotherapy (RIT) with L19-SIP, either alone or in combination with cetuximab, for treatment of head and neck squamous cell carcinoma (HNSCC). Combination with cetuximab was considered because this anti-EGFR (epidermal growth factor receptor) mAb has proven value for the treatment of HNSCC.
  
  
  METHODS
  HNSCC xenograft lines FaDu and HNX-OE were evaluated for ED-B and EGFR expression. L19-SIP was radiolabeled with 2 candidate radionuclides for RIT, 177Lu and 131I (or 125I as substitute). The biodistribution of coinjected 177Lu-L19-SIP and 125I-L19-SIP was assessed in FaDu-bearing nude mice, whereas 131I-L19-SIP was evaluated in both xenograft lines. After labeling with high-dose 131I (623-789 MBq/mg), the maximum tolerated dose (MTD) was assessed. The efficacy of RIT with injected 131I-L19-SIP, either alone or in combination with unlabeled cetuximab (1 mg 2 times a week intraperitoneally for 4 wk), was evaluated in both xenograft lines.
  
  
  RESULTS
  Xenograft lines expressed both antigens, with similar EGFR expression and the highest ED-B expression in FaDu. Radioiodinated L19-SIP performed better than 177Lu-L19-SIP and was further exploited. The biodistribution of 131I-L19-SIP was most favorable in FaDu-bearing mice, with tumor uptake values at 24, 48, and 72 h after injection of 8.6 +/- 1.6, 5.8 +/- 0.4, and 3.4 +/- 0.2 %ID/g (%ID/g is percentage injected dose per gram of tissue), respectively, and ratios of tumor to normal tissues that gradually increased in time, such as for blood from 4.4 +/- 1.8 at 24 h to 21.4 +/- 1.7 at 72 h, after injection. RIT at the MTD level of 74 MBq caused significant tumor growth delay and improved survival in both lines. Although FaDu was most sensitive for RIT, with size reduction of all tumors, HNX-OE was most sensitive for treatment with cetuximab. The best survival and cure rates were obtained, however, when RIT and cetuximab were combined.
  
  
  CONCLUSIONS
  RIT with 131I-L19-SIP appeared efficacious in HNSCC xenografts. The efficacy of RIT was enhanced by combination with cetuximab, without increase of toxicity.
authors.affiliation: Department of Otolaryngology/Head and Neck Surgery, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Bernard M
authors.initials: BM
authors.lastname: Tijink
authors.forename: Dario
authors.initials: D
authors.lastname: Neri
authors.forename: C René
authors.initials: CR
authors.lastname: Leemans
authors.forename: Marianne
authors.initials: M
authors.lastname: Budde
authors.forename: Ludger M
authors.initials: LM
authors.lastname: Dinkelborg
authors.forename: Marijke
authors.initials: M
authors.lastname: Stigter-van Walsum
authors.forename: Luciano
authors.initials: L
authors.lastname: Zardi
authors.forename: Guus A M S
authors.initials: GA
authors.lastname: van Dongen
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry; D002294:Carcinoma, Squamous Cell / Q000473:pathology* / Q000628:therapy*; D045744:Cell Line, Tumor; D006258:Head and Neck Neoplasms / Q000473:pathology* / Q000628:therapy*; D006801:Humans; D007457:Iodine Radioisotopes / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000098:blood supply / Q000473:pathology*; D009389:Neovascularization, Pathologic; D017434:Protein Structure, Tertiary; D016499:Radioimmunotherapy / Q000379:methods*
chemical_list: D000911:Antibodies, Monoclonal; D007457:Iodine Radioisotopes