title: Radioimmunotherapy of solid tumors by targeting extra domain B fibronectin: identification of the best-suited radioimmunoconjugate.
abstract: OBJECTIVE
  The expression of extra domain B (ED-B) fibronectin is always associated with angiogenic processes and can be exclusively observed in tissues undergoing growth and/or extensive remodeling. Due to this selective expression, ED-B fibronectin is an interesting target for radioimmunotherapy of malignant diseases. The aim of this study was to identify the most appropriate ED-B-targeting radioimmunoconjugate for the therapy of solid tumors.
  
  
  METHODS
  Three ED-B fibronectin-binding human antibody formats of L19 were investigated: dimeric single-chain Fv (approximately 50 kDa), "small immunoprotein" (SIP, approximately 80 kDa), and immunoglobulin G1 (IgG1, approximately 150 kDa). These L19 derivatives were either labeled with I-125 or with In-111 (using MX-diethylenetriaminepentaacetic acid, MX-DTPA). Pharmacokinetics and tumor accumulation of the radiolabeled immunoconjugates were investigated in F9 (murine teratocarcinoma) tumor-bearing mice. Subsequently, dosimetry for the corresponding therapeutic isotopes I-13-1 and Y-90 was done. After testing the myelotoxicity of I-131-L19-SIP and I-131-L19-IgG1 in non-tumor-bearing mice, the therapeutic efficacy of these iodinated antibody formats was finally investigated in F9 tumor-bearing mice.
  
  
  RESULTS
  The most favorable therapeutic index was found for I-131-L19-SIP followed by I-131-L19-IgG1. The therapeutic index of all In-111-labeled derivatives was significantly inferior. Considering the bone marrow as the dose-limiting organ, it was calculated that activities of 74 MBq I-131-L19-SIP and 25 MBq I-131-L19-IgG1 could be injected per mouse without causing severe myelotoxicity. The best therapeutic efficacy was observed using I-131-L19-SIP, resulting in significant tumor growth delay and prolonged survival after a single injection.
  
  
  CONCLUSIONS
  Compared with other L19-based radioimmunoconjugates, I-131-L19-SIP is characterized by superior antitumor efficacy and toxicity profile in the F9 teratocarcinoma animal model. These results indicate that ED-B fibronectin-targeted radioimmunotherapy using I-131-L19-SIP has potential to be applied to treatment of solid cancers.
authors.affiliation: Schering AG Research Laboratories, Berlin, Germany. dietmar.berndorff@schering.de
authors.forename: Dietmar
authors.initials: D
authors.lastname: Berndorff
authors.forename: Sandra
authors.initials: S
authors.lastname: Borkowski
authors.forename: Stephanie
authors.initials: S
authors.lastname: Sieger
authors.forename: Axel
authors.initials: A
authors.lastname: Rother
authors.forename: Matthias
authors.initials: M
authors.lastname: Friebe
authors.forename: Francesca
authors.initials: F
authors.lastname: Viti
authors.forename: Christoph S
authors.initials: CS
authors.lastname: Hilger
authors.forename: John E
authors.initials: JE
authors.lastname: Cyr
authors.forename: Ludger M
authors.initials: LM
authors.lastname: Dinkelborg
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D019281:Dimerization; D004591:Electrophoresis, Polyacrylamide Gel; D005353:Fibronectins / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry / Q000494:pharmacology*; D007128:Immunoglobulin Fragments / Q000737:chemistry; D007074:Immunoglobulin G / Q000737:chemistry; D008239:Lysine / Q000737:chemistry; D051379:Mice; D009369:Neoplasms / Q000628:therapy*; D004369:Pentetic Acid / Q000031:analogs & derivatives / Q000737:chemistry; D017434:Protein Structure, Tertiary; D016499:Radioimmunotherapy / Q000379:methods*; D011874:Radiometry; D013997:Time Factors
chemical_list: D005353:Fibronectins; D018796:Immunoconjugates; D007128:Immunoglobulin Fragments; D007074:Immunoglobulin G; C077295:2-(4-isothiocyanatobenzyl)-6-methyldiethylenetriaminepentaacetic acid; D004369:Pentetic Acid; D008239:Lysine