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Residualizing Iodine Markedly Improved Tumor Targeting Using Bispecific Antibody-Based Pretargeting

¹ Department of Nuclear Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
² Department of Urology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
³ Ludwig Institute for Cancer Research, New York, New York
⁴ Immunomedics, Inc., Morris Plains, New Jersey
⁵ Center for Molecular Medicine and Immunology, Garden State Cancer Center, Belleville, New Jersey

Previous studies have shown that pretargeting allows rapid visualization of renal cell carcinomas (RCC) with an ¹¹¹In-labeled bivalent peptide. For radioimmunotherapy, a ß-emitting radionuclide labeled to a bivalent peptide is required. Therapeutic efficacy of these radionuclides depends on the E_max, 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.

Key Words: pretargeting strategy • residualizing iodine • internalization • bs-mAb G250xDTIn-1

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