title: The strength of small: improved targeting of insulin-like growth factor-1 receptor (IGF-1R) with F(ab')₂-R1507 fragments in Ewing sarcomas.
abstract: OBJECTIVE
  To investigate whether F(ab')₂-fragments of the monoclonal Insulin-like Growth Factor-1 Receptor (IGF-1R) antibody R1507 (F(ab')₂-R1507) can successfully target IGF-1R in Ewing sarcomas (ES).
  
  
  METHODS
  BALB/c nude mice were subcutaneously implanted with IGF-1R-expressing human ES xenografts (EW-5 and EW-8) which previously showed heterogeneous or no uptake of indium-111-labelled R1507 IgG ((111)In-R1507), respectively. Mice were injected with (111)In-F(ab')₂-R1507 or (111)In-R1507 as a reference. Biodistribution and immuno-SPECT/computed tomography (CT) imaging studies were carried out 2, 4, 8 and 24 h post-injection (p.i.) for (111)In-F(ab')₂-R1507 and 24 h p.i. for (111)In-R1507.
  
  
  RESULTS
  Biodistribution studies showed specific accumulation of (111)In-F(ab')₂-R1507 in EW-5 xenografts from t=2 h p.i. onwards (3.6 ± 0.2%ID/g at t = 24 h p.i.) and (111)In-F(ab')₂-R1507 immuno-SPECT showed almost homogeneous intratumoural distribution at t=24h p.i. Tumour-to-blood ratios of (111)In-F(ab')₂-R1507 were significantly higher than those of (111)In-R1507 at t=24 h p.i. (2.4 ± 0.4 versus 0.5 ± 0.1, respectively; p<0.05). More importantly, (111)In-F(ab')₂-R1507 also specifically accumulated in EW-8 tumours (3.7 ± 0.7%ID/g at t = 24 h p.i). In both EW-5 and EW-8 tumours, there was a good spatial correlation between IGF-1R expression and (111)In-F(ab')₂-R1507 tumour distribution.
  
  
  CONCLUSIONS
  (111)In-F(ab')₂-R1507 fragments can successfully target IGF-1R in ES models and have superior tumour penetrating and IGF-1R-targeting properties as compared to (111)In-R1507. This suggests that anti-IGF-1R therapies in ES and other tumours may be improved by using smaller therapeutic compounds, although further in vivo studies addressing this topic are warranted.
authors.affiliation: Department of Medical Oncology, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands. E.Fleuren@onco.umcn.nl
authors.forename: Emmy D G
authors.initials: ED
authors.lastname: Fleuren
authors.forename: Yvonne M H
authors.initials: YM
authors.lastname: Versleijen-Jonkers
authors.forename: Sandra
authors.initials: S
authors.lastname: Heskamp
authors.forename: Melissa H S
authors.initials: MH
authors.lastname: Roeffen
authors.forename: Wilbert H
authors.initials: WH
authors.lastname: Bouwman
authors.forename: Janneke D M
authors.initials: JD
authors.lastname: Molkenboer-Kuenen
authors.forename: Hanneke W M
authors.initials: HW
authors.lastname: van Laarhoven
authors.forename: Wim J G
authors.initials: WJ
authors.lastname: Oyen
authors.forename: Otto C
authors.initials: OC
authors.lastname: Boerman
authors.forename: Winette T A
authors.initials: WT
authors.lastname: van der Graaf
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D005260:Female; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D007275:Injections, Intravenous; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D017526:Receptor, IGF Type 1 / Q000276:immunology*; D012512:Sarcoma, Ewing / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon; D014057:Tomography, X-Ray Computed; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D007140:Immunoglobulin Fab Fragments; D017526:Receptor, IGF Type 1; C551399:teprotumumab
keywords: Ewing sarcoma; F(ab′)(2); IGF-1R; Immuno-SPECT; R1507