Objectives Small cell lung cancer (SCLC) is an exceptionally radiosensitive tumor, with selective cell surface expression of the inhibitory Notch ligand Delta-like ligand 3 (DLL3). The selective expression of surface DLL3 on cancer cells presents a target for a variety of diagnostic and therapeutic strategies, including radioimmunoconjugates. The goal of this project is to develop a next-generation DLL3-targeting radioimmunoconjugate for both imaging and therapy. Methods In collaboration with the Tri-Institutional Therapeutics Discovery Institute, we screened and assessed &gt;100 antibodies for their binding affinities and internalization rates. Due to pending intellectual property, the specific clones cannot be disclosed. Herein, we present the top-performing clone (mAb1) for imaging purposes of DLL3 expressing SCLC tumors. The mAb1 was conjugated with the bifunctional chelate p-isothiocyanatobenzyl-desferrioxamine (DFO-Bz-NCS) in a 10-fold molar excess. The conjugated antibody, DFO-mAb1, was then radiolabeled with Zirconium-89 (89Zr), and iTLCs were performed on the final solution to ensure high radiochemical purity. The in vitro and in vivo studies were performed on the NCI-H82 cell line that was selected as a DLL3-medium positive cell line and was derived from the pleural fluid of a SCLC patient. Single tumor subcutaneous xenografts were performed in nude mice. Tumor-bearing animals were injected with [89Zr]Zr -DFO-mAb1 (~ 30 µg and 120 µCi / mouse) via tail vein. Immuno-positron emission tomography (immunoPET) was acquired during 24 h-120 h post-injection. A terminal biodistribution study was also performed. Results The cell binding assay showed good binding affinity of the [89Zr]Zr -DFO-mAb1 to H82 tumor cells (&gt;20%). In vitro serum stability assays presented no issues with the radioimmunoconjugate. Furthermore, the pilot imaging study showed high tumor uptake of the radioimmunoconjugate (~ 20 % ID/g). Most importantly, the [89Zr]Zr -DFO-mAb1 showed low uptake in non-tumor organs, with a good delineation of the tumor to background. The in vivo biodistribution study, performed 120 h post-injection, confirmed high tumor uptake (~ 20 % ID/g). The uptake of the radioimmunoconjugate in all non-tumor organs was less than 5 % ID/g. Conclusions This study shows the potential of utilizing a novel radioimmunoconjugate as a diagnostic tracer, prognostic biomarker, and a predictive biomarker in conjunction with DLL3-targeted therapies.

Novel radioimmunoconjugate targeting delta-like ligand 3 for small-cell lung cancer imaging in vivo.

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