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

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.

IL‐6 upregulates the expression of IL‐6R through the JAK2/STAT3 signalling pathway to promote progression of hepatocellular carcinoma

“…And new therapeutic targets for HCC are urgently needed. IL‐6R is highly expressed in colorectal cancer, gastric cancer, multiple myeloma, prostate cancer and breast cancer, and it is closely associated with the development of these tumours 28–33 . IL‐6R promotes epithelial‐mesenchymal transition and stem transformation of tumour cells, and it promotes invasion and metastasis, thus enhancing the viability of tumour cells 34 .…”

IL-6 up-regulates the expression of IL-6R through JAK2/STAT3 signaling pathway to promote HCC progression

“…Therefore, new therapeutic targets for HCC are urgently needed. It has been reported that IL-6R is highly expressed in colorectal cancer, gastric cancer, multiple myeloma, prostate cancer and breast cancer and is closely associated with the development of these tumors [18][19][20][21][22][23]. IL-6R can promote EMT and stem transformation of tumor cells, and promote invasion and metastasis, thus enhancing the viability of tumor cells [24].…”

IL-6 up-regulates the expression of IL-6R through JAK2/STAT3 signaling pathway to promote HCC progression

“…Therefore, new therapeutic targets for HCC are urgently needed. It has been reported that IL-6R is highly expressed in colorectal cancer, gastric cancer, multiple myeloma, prostate cancer and breast cancer and is closely associated with the development of these tumors [18][19][20][21][22][23]. IL-6R can promote EMT and stem transformation of tumor cells, and promote invasion and metastasis, thus enhancing the viability of tumor cells [24].…”