Predicting IGF-1R Therapy Response in Bone Sarcomas: Immuno-SPECT Imaging with Radiolabeled R1507

Abstract

Purpose To investigate whether 111In-R1507 immuno-SPECT, a novel non-invasive, in vivo screening method to visualize membranous Insulin-like Growth Factor 1 Receptor (IGF-1R) expression and accessibility, can be used to predict IGF-1R treatment (R1507) responsein bone sarcomas. Experimental design BALB/c nude mice were subcutaneously implanted with IGF-1R-expressing human bone sarcoma xenografts (OS-1, EW-5 and EW-8) which demonstrated high, modest or no response, respectively, to R1507, a monoclonal antibody targeting the extracellular domain of IGF-1R. An IGF-1R-negative tumor (OS-33), unresponsive to IGF-1R inhibitors, was examined as well. Mice were injected with indium-111 labeled R1507 (111In-R1507). Biodistribution and immuno-SPECT/CT imaging studies were performed 1, 3 and 7 days p.i. in mice with OS-1 and EW-5 xenografts and 3 days p.i. in mice with EW-8 and OS-33 xenografts. Results Biodistribution studies showed specific accumulation of 111In-R1507 in OS-1 and EW-5 xenografts (27.5±6.5%ID/g and 14.0±2.8%ID/g, 3 days p.i., respectively). Most importantly, 111In-R1507 uptake in IGF-1R-positive, but unresponsive, EW-8 xenografts (6.5±1.5%ID/g, 3 days p.i.) was similar to that of the IGF-1R-negative OS-33 tumor (5.5±0.6%ID/g, 3 days p.i.). Uptake in normal tissues was low and non-specific. Corresponding immuno-SPECT images clearly discriminated between high, modest and non-responding tumors by demonstrating a homogeneous (OS-1), heterogeneous (EW-5) or non-specific (EW-8 and OS-33)tumor uptake of 111In-R1507. Conclusions 111In-R1507 immuno-SPECT is an excellent method to visualize membranous IGF-1R expression and target accessibility in vivo in human bone sarcoma xenografts and may serve as an independent marker to predict IGF-1R therapy (R1507) responsein bone sarcoma patients.

[99mTc(CO)3]+-(HE)3-ZIGF1R:4551, a new Affibody conjugate for visualization of insulin-like growth factor-1 receptor expression in malignant tumours

“…In this way, not only the level of a molecular target in the tumour, but also its accessibility to proposed therapy might be evaluated [16,30,31]. However, slow clearance from blood and organs in equilibrium with blood requires several (three-to-seven) days between injection of the probe and measurement, to obtain a reasonably high tumour-to-blood ratio.…”

“…This creates a rationale for radionuclide molecular imaging of extracellular domain of IGF-1R for patient stratification for therapy using blocking antibodies. Indeed, pre-clinical studies have demonstrated that imaging of IGF-1R can be used to predict the response to anti-IGF-1R antibody therapy of bone sarcoma [16] and IFG-1R-mediated resistance to trastuzumab therapy in breast cancer [17].…”

Antibody biodistribution coefficients

“…Twenty-one different mouse tissue distribution studies from published references other than the ones used to develop the mouse training data set, with various kinds of mAbs and ADC, in various animal models and with diverse radiolabels, were used to build the mouse validation data set. [13][14][15][20][21][22][23][24][25][26][27][28] Details about the individual biodistribution studies are provided in Table S2. Based on Equation 1, using the plasma mAb concentration and ABC values, expected tissue concentrations were calculated for each tissue.…”

Phosphoproteomic Profiling Reveals ALK and MET as Novel Actionable Targets across Synovial Sarcoma Subtypes

“…Therefore, mutation screening to select non-GIST sarcoma patients for targeted therapy has not led to clinical benefit so far (1,10,11). Regarding protein biomarkers, most studies to date have focused on total protein expression levels, while specific screening for phosphorylation status or other read-outs of activation state may provide more accurate information regarding the pathway dependency of tumor cells and likely therapeutic benefit (2,(12)(13)(14). To this end, we characterized tyrosine kinase signaling networks in a large panel of sarcoma cell lines (n ¼ 20).…”