99mTc-HYNIC-Fab(Bevacizumab): potential imaging agent for diagnosis of Non-Hodgkin's Lymphoma
DOI:
https://doi.org/10.35954/SM2017.36.2.2Keywords:
Lymphoma, Non-Hodgkin, VEGF, Fab 99m (Bevacizumab), Tc, HYNIC, Tumor AngiogenesisAbstract
Vascular endothelial growth factor (VEGF) is a key factor in tumor angiogenesis in many types of tumors, including non-Hodgkin's lymphoma (NHL). The aim of the present work is the radiolabeling of antigen binding fragments (Fab) of the 99m monoclonal antibody Bevacizumab with Tc and its evaluation as a potential imaging agent for NHL. To achieve this, VEGF expression was analyzed by flow cytometry in a NHL cell line (Toledo). Fragmentation was performed using papain and the Fab obtained were conjugated with NHS-HYNIC-Tfa and 99m radiolabeled with Tc. Radiochemical purity and stability were assayed. Biodistribution studies were performed in both healthy and NHL-bearing mice. Toledo cells were found to have elevated VEGF expression. Radiolabeling was performed in a rapid, simple, reproducible and stable manner, with radiochemical purities >90%. Biodistribution studies revealed significant renal and tumor uptake, indicating that the main route of elimination is renal. From the 99m results obtained we conclude that Tc-HYNIC-Fab (Bevacizumab) represents a potential imaging agent for VEGF expression associated with NHL.
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(1) Swerdlow AJ. Epidemiology of Hodgkin's disease and nonHodgkin's lymphoma. Eur J Nucl Med Mol Imaging 2003; 30 Suppl 1:S3-12.
(2) Ferrara N, Alitalo K. Clinical applications of angiogenic growth factors and their inhibitors. Nat Med 1999; 15(12):1359-64.
(3) Rosen LS. VEGF-Targeted Therapy: Therapeutic Potential and Recent Advances. The Oncologist 2005; 10(6):382-91.
(4) Koster A, Raemaekers JM. Angiogenesis in malignant lymphoma. Curr Opin Oncol 2005; 17(6):611-6.
(5) Foss HD, Araujo I, Demel G, Klotzbach H, Hummel M, Stein H. Expression of vascular endotelial growth factor
in lymphomas and Castelman disease. J Pathol 1997; 183(1):44-50.
(6) Vacca A, Ribatti D, Ruco L, Giacchetta F, Nico B, Quondamtteo F,et al. Angiogenesis extent and macrophage density increase simultaneously with pathological progression in B-cell non-Hodgkin´s lymphomas. Br J Cancer 1999; 79(5-6):965-70.
(7) Riley LB, Desai DC. The Molecular Basis of Cancer Development of Targeted Therapy. Surg Clin N Am 2009; 89(1):1-15.vii.
(8) Jain RK, Duda DG, Clark JW, Loeffler JS. Lessons from phase III clinical trials on anti-VEGF therapy for cancer. Nat Clin Oncol 2006; 3(1):24-40.
(9) Nagengast WB, de Vries EG, Hospers GA, Mulder NH, de Jong JR, Hollema H, et al. In vivo VEGF imaging with radiolabeled Bevacizumab in a human ovarian tumor xenograft. J Nucl Med 2007; 48(8):1313-1319.
(10) Stollman TH, Scheer MG, Leenders WP, Verrijp KN, Soede AC, Oyen Wj, et al. Specific imaging of VEGF-A expression with radiolabelled anti-VEGF monoclonal antibody. Int J Cancer 2008; 122(10):2310-4.
(11) Stollman TH, Scheer MG, Franssen GM, Verrijp KN, Oyen Wj, Ruers TJ, et al. Tumor accumulation of radiolabelled bevacizumab due to targeting of cell- and matrix-associated VEGF-Aisoforms. Cancer Biother Radiopharm 2009; 24(2):195-200.
(12) Chang SK, Rizvi I, Solban N, Hasan T. In vivo optical molecular imaging of vascular endothelial growth factor for monitoring cancer treatment. Clin Cancer Res 2008; 14(13):4146-53.
(13) Scheer MG, Stollman TH, Boerman OC, Verrijp KN, Sweep FC, Leenders PJ, et al. Imaging liver metastases of colorectal cancer patients with radiolabelled bevacizumab: lack of correlation with VEGF-A expression. Eur J Cancer 2008; 44(13):1835-40.
(14) Camacho X, Calzada V, Fernández M, Alonso O, Chammas R, Riva E, et al. “177Lu-DOTA-Bevacizumab: Radioimmunotherapy Agent for Melanoma”. Curr Radiopharm 2017; 10(1):21-8.
(15) Camacho X, García MF, Calzada V, Fernández M, 99 Alonso O, Gambini JP, et al. “ mTc-labeled Bevacizumab vía HYNIC for Imaging of Melanoma”. J Anal Oncol 2014; 3(1):53-64.
(16) Camacho X, García MF, Calzada V, Fernández M, 99 Chabalgoity JA, Moreno M, et al. “[ mTc(CO3)]-Radiolabeled Bevacizumab: In vitro and in vivo Evaluation in a Melanoma Model”. Oncology 2013: 84(4):200-9.
(17) Camacho X, García MF, Calzada V, Fernández M, Porcal W, Alonso O, et al. “Synthesis and Evaluation of 99mTc Chelate-conjugated Bevacizumab”. Curr Radiopharm 2013; 6(1):12-9.
(18) Hurwitz H, Fehrenbacher L, Novotny W, Crtwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastic colorectal cancer. N Engl J Med 2004; 350(23):2335-42.
(19) Presta LG, Chen H, O'Connor SJ, Chisholm V, Meng YG, Krummen L, et al. Humanization of an anti- vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res 1997; 57(20):4593-9.
(20) Jurisson S, Berning D, Jia W, Ma D. Coordination Compounds in Nuclear Medicine. Chem Rev 1993; 93(3):1137-56.
(21) Dilworth JR.; Parrottb JS. The biomedical chemistry of technetium and rhenium. Chem Soc Rev 1998; 27(1):43-55.
(22) Wu AM.; Olafsen T. Antibodies for molecular imaging in cancer. Cancer J 2008; 14(3):191-7.
(23) Calzada V, García MF, Alonso-Martínez LM, Camacho X, Goicochea E, Fernández M, et al. “Fab (nimotuzumab)-HYNIC-99mTc: Antibody fragmentation for molecular imaging agents”. Anticancer Agents Med Chem 2016; 16(9):1184-9.
(24) Hantowich DJ, Virzi F, Fogarasi M, Rusckowski M, Winnard P Jr. Can a Cysteine Challenge Assay Predict the In vivo Behavior of 99mTc-labeled Antibodies? Nuc Med Biol 1994; 21(8):1035-1044.
(25) Abrams MJ, Juweid M, tenKate CI, Schwartz DA, Hauser MM, Gaul FE, et al. Technetium-99m-Human Polyclonal IgG Radiolabeled via the Hydrazino Nicotinamide Derivatives for Imaging Focal Sites of Infection in Rats. J Nuc Med 1990; 31(12):2022-2018.
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