The strength of small: Improved targeting of Insulin-like Growth Factor-1 Receptor (IGF-1R) with F(ab′)2-R1507 fragments in Ewing sarcomas

PurposeTo 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).Materials and methodsBALB/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 (111In-R1507), respectively. Mice were injected with 111In-F(ab′)2-R1507 or 111In-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 111In-F(ab′)2-R1507 and 24 h p.i. for 111In-R1507.ResultsBiodistribution studies showed specific accumulation of 111In-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 111In-F(ab′)2-R1507 immuno-SPECT showed almost homogeneous intratumoural distribution at t = 24 h p.i. Tumour-to-blood ratios of 111In-F(ab′)2-R1507 were significantly higher than those of 111In-R1507 at t = 24 h p.i. (2.4 ± 0.4 versus 0.5 ± 0.1, respectively; p < 0.05). More importantly, 111In-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 111In-F(ab′)2-R1507 tumour distribution.Conclusion111In-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 111In-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.