%0 Journal Article %A Frank G. van Schaijk %A Matthias Broekema %A Egbert Oosterwijk %A Juliette E.M. van Eerd %A Bill J. McBride %A David M. Goldenberg %A Frans H.M. Corstens %A Otto C. Boerman %T Residualizing Iodine Markedly Improved Tumor Targeting Using Bispecific Antibody-Based Pretargeting %D 2005 %J Journal of Nuclear Medicine %P 1016-1022 %V 46 %N 6 %X Previous studies have shown that pretargeting allows rapid visualization of renal cell carcinomas (RCC) with an 111In-labeled bivalent peptide. For radioimmunotherapy, a β-emitting radionuclide labeled to a bivalent peptide is required. Therapeutic efficacy of these radionuclides depends on the Emax, physical half-life, and residence time of the radiolabel in the tumor. The 131I radiolabel generally clears rapidly from the tumor after internalization and subsequent degradation of the bivalent l-amino acid peptide (l-a.a. peptide) in the tumor cells. To improve the residence time of the iodine label in the tumor, a new bivalent peptide was synthesized that is peptidase resistant and consists of 4 d-amino acids (d-a.a. peptide). Here we investigated the characteristics of the residualizing iodine label in SK-RC-52 RCC tumors. Methods: The d-a.a. peptide was manually synthesized according to standard solid-phase Fmoc/HBTU (2-[1H-benzotriazole-1-yl]-1,1,3,3-tetramethyluronium hexafluorophosphate) chemistry. The uptake and retention in the tumor of 111In-/125I-labeled bivalent peptides (l-a.a. peptide and d-a.a. peptide) were studied in female BALB/c athymic mice with subcutaneous SK-RC-52 RCC tumors. Tumors were pretargeted with the bispecific monoclonal antibody (bs-mAb) G250xDTIn-1 and, 72 h later, mice were injected intravenously with one of both radiolabeled peptides. The effect of bs-mAb—diDTPA—bs-mAb (DTPA is diethylenetriaminepentaacetic acid) bridging at the tumor cell surface on the internalization of the bs-mAb—diDTPA complex was investigated in SK-RC-52 tumor-bearing mice. Results: The maximum uptake and retention of 125I-labeled l-a.a. peptide in the tumor were significantly lower compared with that of the 111In-labeled l-a.a. peptide. In contrast, the tumor uptake and retention of the 125I-labeled d-a.a. peptide) were similar to that of the 111In-labeled l-a.a. peptide but were superior at later time points. The biodistribution of the radioiodinated d-a.a. peptide was highly similar to that of the 111In-labeled d-a.a. peptide, and both radiolabeled peptides were retained significantly better in the tumor than the 111In-labeled l-a.a. peptide. bs-mAb—diDTPA—bs-mAb bridge formation did not affect internalization of the bs-mAb—diDTPA complex. Conclusion: Uptake and retention in the tumor of the iodinated peptide after pretargeting with a bs-mAb can be significantly improved using d-a.a. peptides. Accordingly, the radiation dose to the tumor, correlating with the therapeutic efficacy of pretargeted RCC, can be enhanced substantially. %U https://jnm.snmjournals.org/content/jnumed/46/6/1016.full.pdf