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Radioisotopes in diagnostics and therapy (pre-)clinical view

Radioisotopes in diagnostics and therapy (pre-)clinical view. Otto C. Boerman. Radboud University Nijmegen Medical Center, The Netherlands. Radioisotopes in diagnostics and therapy. Radioimmunotherapy of cancer Radioimmunoscintigraphy Pretargeted imaging of cancer

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Radioisotopes in diagnostics and therapy (pre-)clinical view

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  1. Radioisotopes in diagnostics and therapy (pre-)clinical view Otto C. Boerman Radboud University Nijmegen Medical Center, The Netherlands

  2. Radioisotopes in diagnostics and therapy • Radioimmunotherapy of cancer • Radioimmunoscintigraphy • Pretargeted imaging of cancer • Peptide receptor radionuclide imaging • Peptide receptor radionuclide therapy Radboud University Nijmegen Medical Center, The Netherlands

  3. Radiolabeled antibody Antibody targeting of tumors Radboud University Nijmegen Medical Center, The Netherlands

  4. Radioimmunotargeting of renalcellcarcinoma G250 Antigen • Identified as Carbonic Anhydrase IX • Expressed on > 95% of clear cell RCC • No expression in normal kidney • Expression in normal tissues restricted to: • larger bile ducts • Mucosa of the upper gastrointestinal tract • not detected in serum Carbonic anhydrase IX • cG250 Antibody • Chimeric IgG1 • Ka = 4 x 10-9 l/mol Chimeric G250 IgG1 Radboud University Nijmegen Medical Center, The Netherlands

  5. Radioimmunotargeting of renal cell carcinoma • Protein dose escalation in RCC patients • 5 dose levels: 2 - 5 - 10 - 25 - 50 mg • 3 patients per dose level • 6 mCi 131I-cG250 i.v. • Surgery 7 days p.i. 2 mg ³ 5 mg Liver uptake (%ID/kg) 3.4 ± 0.2 0.9 ± 0.3 t½ (h) 40 ± 10 69 ± 13 2 mg 5 mg J Clin Oncol 15: 1529-1537, 1997 Radboud University Nijmegen Medical Center, The Netherlands

  6. ProteinDoseEscalationStudy 2 mg 5 mg 10 mg 25 mg 50 mg Anterior posterior J Clin Oncol 15: 1529-1537, 1997 Radboud University Nijmegen Medical Center, The Netherlands

  7. Heterogeneity of MAb uptake in Renal Cell Carcinoma Anterior posterior Radboud University Nijmegen Medical Center, The Netherlands

  8. Heterogeneity of MAb uptake in Renal Cell Carcinoma Radboud University Nijmegen Medical Center, The Netherlands

  9. Heterogeneity of MAb uptake in Renal Cell Carcinoma Radboud University Nijmegen Medical Center, The Netherlands

  10. Heterogeneity of MAb uptake in Renal Cell Carcinoma Radboud University Nijmegen Medical Center, The Netherlands

  11. 125I-cG250 131I-cG250 Surgical resection Day 9 Day 4 Day 0 Heterogeneity of MAbuptake in RenalCellCarcinoma • Analysis of the intratumoral distribution of cG250 of 2 successiveinjections Radboud University Nijmegen Medical Center, The Netherlands

  12. Heterogeneity of MAbuptake in RenalCellCarcinoma remaining normal tissue (kidney and fat) average uptake: 125I-cG250: 0.0007 131I-cG250: 0.0012 Radboud University Nijmegen Medical Center, The Netherlands

  13. Heterogeneity of MAbuptake in RenalCellCarcinoma 131I-cG250 125I-cG250 Twosuccessive cG250 injections • High intratumoralMAbuptakevariations • Minimal variationsbetween125I and 131I uptake • Mean 131I/125I uptake ratio: 1.72 ± 0.45 • Intratumoral distribution of 131I and 125I was highlysimilar 9 days p.i. 5 days p.i. Cancer Res 59:1615-1619, 1999 Radboud University Nijmegen Medical Center, The Netherlands

  14. Post. Ant. 131I-cG250 activity dose escalation • Patients with progressive metastatic RCC • Diagnostic dose: 6 mCi 131I-cG250 (5 mg) • Therapeutic dose: 45 mCi/m2 (5 mg) • Dose escalation with 15 mCi/m2 • 3 patients per dose level Clin Cancer Res5; 3268-3274, 1999 Radboud University Nijmegen Medical Center, The Netherlands

  15. 131I-cG250 Activitydoseescalation Results of activity dose escalation study: • Dose limiting toxicity: myelotoxicity • MTD 131I-cG250: 60 mCi/m2 • 1 PR, 1 SD, 6 PD Clin Cancer Res5; 3268-3274, 1999 Radboud University Nijmegen Medical Center, The Netherlands

  16. 6 mCi 131I-cG250 6 mCi 131I-cG250 60 mCi/m2 30/45/60 mCi/m2 WB 4x WB 2x WB 4x WB 2x 1 Week 12 Weeks 1 Week 12 Weeks CT-scans CT-scans CT-scans Phase II Study: Radioimmunotherapy withtwodoses 131I-cG250 Radboud University Nijmegen Medical Center, The Netherlands

  17. Ant. Post. 1 week p.i. 109 mCi Phase II Study: Radioimmunotherapy with 131I-cG250 • MTD 2nd treatment was 75% of MTD of 1st treatment • 16 Patients completed two courses of 131I-cG250 RITs at 60 and 45 mCi/m2. • 4/16 SD, 12/16 PD • Highest radiation doses to smaller lesions Ant. Post. 2 weeks p.i. 112 mCi J Clin Oncol 23; 6540-8: 2005 Radboud University Nijmegen Medical Center, The Netherlands

  18. The Quest for the optimal radionuclide for RIT Radboud University Nijmegen Medical Center, The Netherlands

  19. Radionuclides for radioimmunotherapy

  20. 131I-cG250 90Y-cG250 177Lu-cG250 186Re-cG250 The Quest for the optimal radionuclide for RIT J Nucl Med. 2004;45:327-337 Radboud University Nijmegen Medical Center, The Netherlands

  21. 131I-cG250 90Y-cG250 177Lu-cG250 186Re-cG250 The Quest for the optimal radionuclide for RIT J Nucl Med. 2004;45:327-337 Radboud University Nijmegen Medical Center, The Netherlands

  22. 131I-cG250 90Y-cG250 177Lu-cG250 186Re-cG250 The Quest for the optimal radionuclide for RIT J Nucl Med. 2004;45:327-337 Radboud University Nijmegen Medical Center, The Netherlands

  23. 111In-cG250 131I-cG250 Day 8 Day 0 Day 4 WB WB WB WB The Quest for the optimal radionuclide for RIT 131I-cG250 vs. 111In-cG250: an intra-patient comparison Radboud University Nijmegen Medical Center, The Netherlands

  24. I-131 In-111 131I-cG250 111In-cG250 The Quest for the optimal radionuclide for RIT n = 25 4 days p.i. Clin Cancer Res 9: 3953-3960, 2003 Radboud University Nijmegen Medical Center, The Netherlands

  25. 5 mCi 111In-cG250 5 mCi 111In-cG250 a.10 mCi/m2177Lu-cG250 WB 4x WB 2x WB 4x WB 4x 1 Week 12 Weeks 1 Week 12 Weeks CT-scans CT-scans CT-scans Radioimmunotherapy of RCC with 177Lu-cG250 0.75(a.10 mCi/m2) 177Lu-cG250 Radboud University Nijmegen Medical Center, The Netherlands

  26. 177Lu-cG250, 6 days p.i. Radioimmunotherapy of RCC with 177Lu-cG250 111In-cG250, 6 days p.i. Radboud University Nijmegen Medical Center, The Netherlands

  27. Radioimmunotherapy of RCC with 177Lu-cG250 Radboud University Nijmegen Medical Center, The Netherlands

  28. Radioimmunotherapy of RCC with 177Lu-cG250 Radboud University Nijmegen Medical Center, The Netherlands

  29. Radioimmunotherapy with 177Lu-cG250 stabilized growth of RCC Radboud University Nijmegen Medical Center, The Netherlands

  30. Imagingwith radiolabeled antibodies ImagingAngiogenesis in tumors bevacizumab binding with VEGF bevacizumab Radboud University Nijmegen Medical Center, The Netherlands

  31. Radiolabeled anti-VEGF antibodyin nudemicewith LS174T tumors I-125 bevacizumab In-111 bevacizumab bevacizumab (3 µg) bevacizumab (300 µg) Radboud University Nijmegen Medical Center, The Netherlands

  32. In-111-bevacizumab at 1, 3 and 7 daysp.i. Radboud University Nijmegen Medical Center, The Netherlands

  33. Scintigraphicimaging of VEGF-A expression day 0 day 1 day 3 day 7 Radboud University Nijmegen Medical Center, The Netherlands

  34. Scintigraphicimaging of VEGF-A expression day 0 day 1 day 3 day 7 Radboud University Nijmegen Medical Center, The Netherlands

  35. Scintigraphicimaging of VEGF-A expression day 0 day 1 day 3 day 7 Radboud University Nijmegen Medical Center, The Netherlands

  36. Scintigraphicimaging of VEGF-A expression day 0 day 1 day 3 day 7 Radboud University Nijmegen Medical Center, The Netherlands

  37. microPETimaging of VEGF-A expressionwith 89Zr-bevacizumab day 0 day 1 day 4 day 7 Radboud University Nijmegen Medical Center, The Netherlands

  38. microPET/CT imaging of VEGF-A expressionwith 89Zr-bevacizumab 89Zr-bevacizumab, 7 days p.i. 89Zr-bevacizumab + 300 μg cold 38

  39. Scintigraphic imaging of VEGF expression Radboud University Nijmegen Medical Center, The Netherlands

  40. The antibody targeting dilemma Radboud University Nijmegen Medical Center, The Netherlands

  41. Radionuclides for PET imaging

  42. 68Ga 18F Pretargeted immunoPET imaging IMP288 TF2 TF2 CEA CEA CEA CEA CEA LS174THuman Colon Cancer cell CEA CEA Radboud University Nijmegen Medical Center, The Netherlands

  43. Pretargeted immunoPETusing a Ga-68-labeled peptide t = 0, trivalent bsAb anti-CEA x anti-HSG bsAb t = 16 h, Ga-68-IMP-288 Ga-68-di-HSG-peptide 68Ga

  44. Biodistribution Ga-68-diHSG peptide t = 0 : 400 μg TF2 (2.5 nmol) t = 16 h : 150 ng Ga-68-IMP-288 (0.1 nmol ) t = 17 h : imaging and dissection

  45. Pretargeted immunoPET imaging Nude mouse with LS174T tumor Inflammation Tumor t= 0 : anti-CEA x anti-HSG bsAb t= 16 h : 68Ga-IMP288 t=17 : microPET imaging Schoffelen et al. Mol Cancer Ther 2009; in press Radboud University Nijmegen Medical Center, The Netherlands

  46. Pretargeted immunoPET imaging of cancer [18F]FDG 68Ga-immunoPET Inflammation Tumor Schoffelen et al. Mol Cancer Ther 2009; in press Radboud University Nijmegen Medical Center, The Netherlands

  47. Pretargeted immunoPETimaging of i.p. tumors Diaphragm Liver hilus Omentum Mesenterium Subcutaneous tumor at place of injection Fatpad testes Radboud University Nijmegen Medical Centre, The Netherlands

  48. Pretargeted ImmunoPET imaging of i.p. LS174T tumors with 68Ga-diHSG Radboud University Nijmegen Medical Centre, The Netherlands

  49. Pretargeted ImmunoPET imaging of i.p. LS174T tumors with 68Ga-diHSG Radboud University Nijmegen Medical Centre, The Netherlands

  50. Pretargeted immunoPETimaging In-111, Ga-68, Y-90, Lu-177 F-18 Radboud University Nijmegen Medical Center, The Netherlands

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