Abstract
4058
Introduction: Carbonic Anhydrase IX (CAIX) is a transmembrane metalloprotease highly expressed in many hypoxic tumor types, thus representing an attractive diagnostic and therapeutic target. DPI-4452 and DPI-4501 are novel CAIX-targeting peptides that can be labelled with different radionuclides, such as 111In and 177Lu. In vitro, DPI-4452 and DPI-4501 bind human and dog CAIX but not mouse CAIX. In vivo, radioactivity uptake in CAIX-positive tumor can be investigated in tumor-xenografted mice, whereas radioactivity uptake in non-tumor organs where CAIX is naturally expressed can only be studied in dogs. Here we report the first biodistribution and dosimetry of 111In-DPI-4452 and 111In-DPI-4501 in the SK-RC-52 and HT-29 mouse tumor models and in healthy dog, using in vivo SPECT-CT imaging.
Methods: Female NMRI nude mice were subcutaneously implanted with CAIX-positive human cancer cell line, either HT-29 or SK-RC-52. Every mouse received a single IV dose of either 111In-DPI-4452 or 111In-DPI-4501. Whole-body SPECT-CT scanning was performed at selected timepoints up to 48h post injection (p.i.), and radioactivity uptake was quantified in the tumor, kidneys, liver, and heart (estimate of blood).
Male and female healthy Beagle dogs received a single dose of either 111In-DPI-4452 or 111In-DPI-4501. Biodistribution was evaluated on a selection of organs using whole-body SPECT-CT imaging. Dosimetry was conducted based on radioactivity uptake data in dog organs after administration of 111In-labelled compounds and extrapolation to 177Lu radionuclide, followed by extrapolation to humans.
Results: In the mouse, for both tumor models, and for both test compounds, peak tumor uptake was observed at the first time point. The mean peak tumor uptake was high: up to between 7 and 10 %ID/g for 111In-DPI-4452 and 111In-DPI-4501, in the SK-RC-52 tumor model. Tumor-to-kidney ratios showed preferential uptake in the tumor. Uptake at 4h p.i. in the liver and blood had decreased to background levels for both tested compounds and both tumor models.
In the dog, significant radioactivity accumulation was observed at 1h p.i. in the bladder, in the small intestine and in the stomach. At the last time point (48h), for both test compounds, observed radioactivity was located essentially in the stomach and in the small intestine. The high level of radioactivity in the bladder early after injection likely resulted from extensive excretion in urine. The high levels of radioactivity in the small intestine and stomach likely resulted from the presence of naturally expressed CAIX.
Dosimetry with adaptation to the 177Lu radiation and extrapolation to humans showed that the dose-limiting organ would be the small intestine and/or the stomach wall for both test compounds. The maximum allowed radioactivity dose would be in the range of 21 to 30 GBq for both test compounds.
Conclusions: These nonclinical biodistribution results show that 111In-labelled DPI-4452 or DPI-4501 deliver radioactivity to CAIX-expressing solid tumors in vivo. The currently estimated maximum allowed dose of 177Lu-labelled DPI-4452 or DPI-4501 is compatible with therapeutic dose in human patients.
