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99mTechnetium- or Cy7-Labeled Fab(Tocilizumab) as Potential Multiple Myeloma Imaging Agents

[ Vol. 21 , Issue. 14 ]

Author(s):

Ximena Camacho*, Carolina Perroni, Camila L. Machado, Camila de Godoi Carneiro, Mara de Souza Junqueira, Daniele Faria, María F. García, Marcelo Fernández, Natalia Oddone, Juan Benech, Carlos A. Buchpiguel, Hugo Cerecetto, Roger Chammas, Eloisa Riva, Pablo Cabral and Juan P. Gambini   Pages 1883 - 1893 ( 11 )

Abstract:


Background: Multiple myeloma (MM) is malignant hematologic disorder and the second most common blood cancer. Interleukin-6 (IL-6) has been identified as a crucial factor for proliferation and survival of MM cells and the overexpression of IL-6 receptor is being studied as a molecular target for therapeutic and diagnostic use in myelomas and other comorbidities. Tocilizumab is a humanized monoclonal antibody that binds IL-6R.

Objective: We aim to label and evaluate Fab(Tocilizumab) with 99mTechnetium or Cy7 as potential MM imaging agents.

Methods: IL-6R distribution was analyzed by laser confocal microscopy (LCM) in MM cell lines. Fab(Tocilizumab) were produced by digestion of Tocilizumab with papain for 24 h at 37 °C, derivatized with NHS-HYNIC-Tfa and radiolabeled with 99mTc. Radiochemical stability and in vitro cell assays were evaluated. Biodistribution and SPECT/CT were performed. Also, Fab(Tocilizumab) was labeled with Cy7 for in vivo fluorescence imaging up to 72 h.

Results: LCM analysis demonstrates IL-6R distribution on MM cell lines. Incubation with papain resulted in complete digestion of Tocilizumab and exhibited a good purity and homogeneity. Radiolabeling with 99mTc via NHS-HYNIC-Tfa was found to be fast, easy, reproducible and stable, revealing high radiochemical purity and without interfering with IL-6R recognition. Biodistribution and SPECT/CT studies showed a quick blood clearance and significant kidney and MM engrafted tumor uptake. Cy7-Fab(Tocilizumab) fluorescent imaging allowed MM1S tumor identification up to 72 h p.i.

Conclusion: These new molecular imaging agents could potentially be used in the clinical setting for staging and follow up of MM through radioactive whole-body IL-6R expression visualization in vivo. The fluorescent version could be used for tissue sample evaluation and to guide the surgical excision if necessary.

Keywords:

Fab(Tocilizumab), molecular imaging, IL-6R, multiple myeloma, 99mTechnetium- or Cy7-lableled Fab(Tocilizumab).

Affiliation:

Departamento de Radiofarmacia, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Montevideo, Departamento de Radiofarmacia, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Montevideo, Nuclear Medicine Medical Investigation Laboratory LIM43-Hospital das Clínicas da Faculdade de Medicina da Universidade de Sao Paulo - HCFMUSP, Sao Paulo, Nuclear Medicine Medical Investigation Laboratory LIM43-Hospital das Clínicas da Faculdade de Medicina da Universidade de Sao Paulo - HCFMUSP, Sao Paulo, Laboratório de Oncologia Experimental, Faculdade de Medicina, Universidade de São Paulo, Av. Dr. Arnaldo Nº 455- Cerqueira César - CEP: 01246903, São Paulo, Nuclear Medicine Medical Investigation Laboratory LIM43-Hospital das Clínicas da Faculdade de Medicina da Universidade de Sao Paulo - HCFMUSP, Sao Paulo, Departamento de Radiofarmacia, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Montevideo, Departamento de Radiofarmacia, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Montevideo, Laboratorio de Señalización Celular y Nanobiología, Instituto de Investigaciones Biológicas Clemente Estable, Montevideo, Laboratorio de Señalización Celular y Nanobiología, Instituto de Investigaciones Biológicas Clemente Estable, Montevideo, Nuclear Medicine Medical Investigation Laboratory LIM43-Hospital das Clínicas da Faculdade de Medicina da Universidade de Sao Paulo - HCFMUSP, Sao Paulo, Departamento de Radiofarmacia, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Montevideo, Laboratório de Oncologia Experimental, Faculdade de Medicina, Universidade de São Paulo, Av. Dr. Arnaldo Nº 455- Cerqueira César - CEP: 01246903, São Paulo, Clínica Hematológica. Hospital de Clínicas. Facultad de Medicina. Universidad de la República, Montevideo, Departamento de Radiofarmacia, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Montevideo, Centro de Medicina Nuclear e Imagenología Molecular, Hospital de Clínicas, Facultad de Medicina, Universidad de la República, Montevideo



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