ImmunoPET imaging of insulin-like growth factor 1 receptor (IGF-1R) in pancreatic cancer

Objectives The role of insulin-like growth factor-1 receptor (IGF-1R) in cancer tumorigenesis and growth was established decades ago, yet there are limited studies evaluating the imaging and therapeutic properties of anti-IGF-1R antibodies. Currently, immunohistochemistry is the primary means of assessing IGF-1R expression in human tumors, yet this procedure is limited by the invasiveness and heterogeneous expression of IGF-1R found in many solid tumors. As a means to overcome these limitations, researchers have adapted molecular imaging techniques for the non-invasive assessment of IGF-1R expression in tumor models, including pancreatic cancer. Non-invasive imaging of IGF-1R may allow for optimized patient stratification and monitoring of therapeutic response in patients.

Methods An IGF-1R antibody (1A2G11) was radiolabeled with the long-lived isotope Zirconium-89 (⁸⁹Zr) for molecular imaging of pancreatic cancer with positron emission tomography (PET). Three pancreatic cancer cell lines expressing varying levels of IGF-1R expression (MiaPaCa-2, BxPC-3, and AsPC-1), as determined by flow cytometry and Western blot studies, were subcutaneously implanted into athymic mice. ImmunoPET imaging was performed to monitor the biodistribution of ⁸⁹Zr-Df-1A2G11 for five days post-injection, followed by ex vivo biodistribution and immunohistochemistry studies.

Results The three pancreatic cancer cell lines showed differing levels of IGF-1R expression through flow cytometry analysis with MiaPaCa-2 cells displaying the most significant shift and highest expression of IGF-1R. The BxPC-3 cells showed moderate levels of IGF-1R cell binding while AsPC-1 cells displayed minimal levels of binding. These results were confirmed through quantitative Western blot analysis, with both MiaPaCa-2 and BxPC-3 showing higher IGF-1R expression levels than AsPC-1. Successful chelation and radiolabeling of the antibody yielded a highly stable construct with a long circulation half-life in vivo. The tumor accumulation of ⁸⁹Zr-Df-1A2G11 varied in each model, with MiaPaCa-2 displaying the highest accumulation of 9.7 ± 1.0 percentage of injected dose (%ID/g) at 120 h post-injection. Accumulation was lower in BxPC-3 and AsPC-1 xenograft tumors with values of 6.7 ± 0.7 and 3.5 ± 0.3 %ID/g at 120 h post-injection, respectively (n = 3). PET data were supported by ex vivo biodistribution studies and immunohistochemistry.

Conclusions In conclusion, this study provides the initial evidence that our IGF-1R-targeted antibody may be successfully radiolabeled ⁸⁹Zr and employed for imaging of IGF-1R-expressing xenograft tumors in vivo. To date, this is the first study that employs a long-lived isotope (⁸⁹Zr) for molecular imaging of IGF-1R expression, allowing for longer blood circulation and providing a more clinically accessible construct for further preclinical or clinical studies. $$graphic_5BEB1F15-EF59-4285-B16E-6E7DB2AAD292$$