Abstract
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Objectives: Insulin-like growth factor-1 receptor (IGF-1R) is an oncogenic protein associated with multiple cancer types. FPX-01 is a novel IGF-1R directed radioimmunoconjugate containing the targeting antibody FPI-1175 (formerly AVE1642). Potential imaging (In-111) and therapeutic (Ac-225) forms of FPX-01 were subjected to biological evaluation in pre-clinical cancer models.
Methods: The antibody was conjugated with a lysine directed bifunctional chelate containing a DOTA and radiolabeled with Ac-225, In-111, or Lu-177. In vitro binding and residualization studies (with [177Lu]-FPX-01) were conducted using a panel of cancer cell lines that express different levels of IGF-1R and was validated by immunoblotting. Comparative biodistribution studies were carried out using Colo-205 (colorectal cancer) xenograft bearing athymic nude mice.
Results: Binding studies demonstrated high affinity (Kd of 0.7 - 3.0 nM) of [177Lu]-FPX-01 across 8 different IGF-1R expressing cell lines (from lung, pancreatic, prostate cancers) and the Bmax values correlated with IGF-1R expression levels determined by immunoblotting. Residualization assays revealed strong retention of internalized [177Lu]-FPX-01. [225Ac]-FPX-01 biodistribution data demonstrated high levels of uptake in Colo-205 xenografts (35.5 ± 4.2 %ID/g @ 168 h) and biphasic blood clearance with low radioimmunoconjugate uptake in normal organs (less than 5.2 %ID/g @ 168 h). Further studies showed that [111In] and [177Lu]-FPX-01 had equivalent biodistribution to [225Ac]-FPX-01 demonstrating comparability across multiple isotopes. Tumor uptake at 168 h for [111In] and [177Lu]-FPX-01 was 50.7 ± 8.7 and 45.3 ± 6.7 %ID/g respectively. Tumor uptake of [177Lu]-FPX-01 was blocked by excess native FPI-1175 mAb demonstrating the specificity of FPX-01 for its biological target. Conclusion: The utility of FPX-01 as a radiopharmaceutical with application for oncologic imaging and radiotherapy was demonstrated in a series of preclinical studies. [111In]-FPX-01 had equivalent biodistribution to [225Ac]-FPX-01 and is suitable for use as an imaging surrogate.