Pre-clinical study of IRDye800CW-nimotuzumab formulation, stability, pharmacokinetics, and safety

BMC Cancer - 2021
Wendy Bernhard1, Kris Barreto1, Ayman El-Sayed1, Carolina González1, Raja Solomon Viswas2, Darién Toledo3, Á. Casacó3, John F. DeCoteau1, Humphrey Fonge2, C. Ronald Geyer1
1Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada
2Department of Medical Imaging, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada
3Center of Molecular Immunology, Havana, Cuba

Tóm tắt

Abstract Background Epidermal growth factor receptor (EGFR) is a target for cancer therapy as it is overexpressed in a wide variety of cancers. Therapeutic antibodies that bind EGFR are being evaluated in clinical trials as imaging agents for positron emission tomography and image-guided surgery. However, some of these antibodies have safety concerns such as infusion reactions, limiting their use in imaging applications. Nimotuzumab is a therapeutic monoclonal antibody that is specific for EGFR and has been used as a therapy in a number of countries. Methods Formulation of IRDye800CW-nimotuzumab for a clinical trial application was prepared. The physical, chemical, and pharmaceutical properties were tested to develop the specifications to determine stability of the product. The acute and delayed toxicities were tested and IRDye800CW-nimotuzumab was determined to be non-toxic. Non-compartmental pharmacokinetics analysis was used to determine the half-life of IRDye800CW-nimotuzumab. Results IRDye800CW-nimotuzumab was determined to be non-toxic from the acute and delayed toxicity study. The half-life of IRDye800CW-nimotuzumab was determined to be 38 ± 1.5 h. A bi-exponential analysis was also used which gave a t1/2 alpha of 1.5 h and t1/2 beta of 40.8 h. Conclusions Here, we show preclinical studies demonstrating that nimotuzumab conjugated to IRDye800CW is safe and does not exhibit toxicities commonly associated with EGFR targeting antibodies.

Từ khóa


Tài liệu tham khảo

Yewale C, Baradia D, Vhora I, Patil S, Misra A. Epidermal growth factor receptor targeting in cancer: a review of trends and strategies. Biomaterials. 2013;34:8690–707.

Yarden Y, Sliwkowski MX. Untangling the erbb signalling network. Nat Rev Mol Cell Biol. 2001;2:127–37.

Tipirneni KE, Warram JM, Moore LS, Prince AC, de Boer E, Jani AH, et al. Oncologic procedures amenable to fluorescence-guided surgery. Ann Surg. 2017;266:36–47.

Pleijhuis RG, Graafland M, de Vries J, Bart J, de Jong JS, van Dam GM. Obtaining adequate surgical margins in breast-conserving therapy for patients with early-stage breast cancer: current modalities and future directions. Ann Surg Oncol. 2009;16:2717–30.

Rosenthal EL, Moore LS, Tipineni K, de Boer E, Stevens TM, et al. Sensitivity and specificity of Cetuximab-IRDye800CW to identify regional metastatic disease in head and neck cancer. Clin Cancer Res. 2017;23:4744–52.

Heath CH, Deep NL, Sweeny L, Zinn KR, Rosenthal EL. Use of panitumumab-IRDye800 to image microscopic head and neck cancer in an orthotopic surgical model. Ann Surg Oncol. 2012;19:3879–87.

Gao RW, Teraphongphom N, de Boer E, van den Berg NS, Divi V, Kaplan MJ, et al. Safety of panitumumab-IRDye800CW and cetuximab-IRDye800CW for fluorescence-guided surgical navigation in head and neck cancers. Theranostics. 2018;9:2488–95.

Saurez-Martinez G, Bencomo-Yane A. Nimotuzumab, effective immunotherapy for the treatment of malignant epithelial tumors. Biotecnol Apl. 2014;2:159–67.

Zhu Z. Targeted cancer therapies based on antibodies directed against epidermal growth factor receptor: status and perspectives. Acta Pharmacol Sin. 2007;28:1476–93.

Marshall MV, Draney D, Sevick-Muraca EM, Olive DM. Single-dose intravenous toxicity study of IRDye 800CW in Sprague-Dawley rats. Mol Imaging Biol. 2010;12:583–94.

Bernhard W, El-Sayed A, Barreto K, Gonzalez C, Hill W, Parada AC, et al. Near infrared fluorescence imaging of EGFR expression in vivo using IRDye800CW-nimotuzumab. Oncotarget. 2018;9:6213–27.

ICH. https://www.ich.org/home.html Accessed 24 May 2019.

R Core Team. R: a language and environment for statistical computing. Vienna: R Foundation for Statistical Computing; 2017.

Jaki T, Wolfsegger MJ. Estimation of pharmacokinetic parameters with the R package PK. Pharm Stat. 2011;10(3):294–88.

Gao RW, Teraphongphom NT, van den Berg NS, Martin BA, Oberhelman NJ, et al. Determination of tumor margins with surgical specimen mapping using near-infrared fluorescence. Cancer Res. 2018;78:5144–454.

Rosenthal EL, Warram JM, de Boer E, Chung TK, Korb ML, et al. Safety and tumor specificity of cetuximab-IRDye800 for surgical navigation in head and neck cancer. Clin Cancer Res. 2015;21:3658–66.

Miller SE, Tummers WS, Teraphongphom N, van den Berg NS, Hasan A, et al. First-in-human intraoperative near-infrared fluorescence imaging of glioblastoma using cetuximab-IRDye800. J Neurooncol. 2018;139:135–43.

Hekman MC, Rijpkema M, Muselaers CH, Oosterwijk E, Hulsbergen-Van de Kaa CA, et al. Tumor-targeted dual-modality imaging to improve intraoperative visulaizaiton of clear cell renal cell carcinoma: a first in man study. Theranostics. 2018;8:2161–70.

Tummers WS, Miller SE, Teraphongphom NT, Gomez A, Steinberg I, et al. Intraoperative pancreatic cancer detection using tumor-specific multimodality molecular imaging. Ann Surg Oncol. 2018;25:1880–8.

Lamberts LE, Koch M, de Jong JS, ALL A, Glatz J, et al. Tumor-specific uptake of fluorescent bevacizumab-IRDye800CW microdosing in patients with primary breast cancer: A phase I feasibility study. Clin Cancer Res. 2017;23:2730–41.

Harlaar NJ, Koller M, de Jongh SJ, van Leeuwen BL, Hemmer PH. Molecular fluorescence-guided surgery of peritoneal carcinomatosis of colorectal origin: a single-centre feasibility study. Lancet Gastroenterol Hepatol. 2016;1:283–90.

Hartmans E, JJJ T, Linssen MD, PBG A, Koller M, et al. Potential red-flag identification of colorectal adenomas with wide-field fluorescence molecular endoscopy. Theranostics. 2018;8:1458–67.

Okamoto W, Yoshino T, Takahashi T, Okamoto I, Ueda S, Tsuya A, et al. A phase I, pharmacokinetic and pharmacodynamic study of nimotuzumab in japanese patients with advanced solid tumors. Cancer Chemother Pharmacol. 2013;72:1063–71.

Strumberg D, Schultheis B, Scheulen ME, Hilger RA, Krauss J, Marschner N, et al. Safety, efficacy and pharmacokinetics of nimotuzumab, a humanized monoclonal anti-epidermal growth factor receptor (EGFR) antibody, in patients with locally advanced or metastatic pancreatic cancer. Int J Clin Pharmacol Ther. 2010;48:473–5.

Kato K, Ura T, Koizumi W, Iwasa S, Katada C, Azuma M, et al. Nimotuzumab combined with concurrent chemoradiotherapy in japanese patients with esophageal cancer: a phase I study. Cancer Sci. 2018;109:785–93.

Thông tin
Thông tin xuất bản

BMC Cancer

Thông tin tác giả