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

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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 t _1/2 alpha of 1.5 h and t _1/2 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.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12885-021-08003-3.

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Most cited references 24

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Chetan Yewale, Dipesh Baradia, Imran Vhora … (2013)

The epidermal growth factor receptor (EGFR) is a cell-surface receptor belonging to ErbB family of tyrosine kinase and it plays a vital role in the regulation of cell proliferation, survival and differentiation. However; EGFR is aberrantly activated by various mechanisms like receptor overexpression, mutation, ligand-dependent receptor dimerization, ligand-independent activation and is associated with development of variety of tumors. Therefore, specific EGFR inhibition is one of the key targets for cancer therapy. Two major approaches have been developed and demonstrated benefits in clinical trials for targeting EGFR; monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs). EGFR inhibitors like, cetuximab, panitumumab, etc. (mAbs) and gefitinib, erlotinib, lapatinib, etc. (TKIs) are now commercially available for treatment of variety of cancers. Recently, many other agents like peptides, nanobodies, affibodies and antisense oligonucleotide have also shown better efficacy in targeting and inhibiting EGFR. Now a days, efforts are being focused to identify molecular markers that can predict patients more likely to respond to anti-EGFR therapy; to find out combinatorial approaches with EGFR inhibitors and to bring new therapeutic agents with clinical efficacy. In this review we have outlined the role of EGFR in cancer, different types of EGFR inhibitors, preclinical and clinical status of EGFR inhibitors as well as summarized the recent efforts made in the field of molecular EGFR targeting. © 2013 Elsevier Ltd. All rights reserved.

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Obtaining Adequate Surgical Margins in Breast-Conserving Therapy for Patients with Early-Stage Breast Cancer: Current Modalities and Future Directions

Rick Pleijhuis, Maurits Graafland, Jakob de Vries … (2009)

Inadequate surgical margins represent a high risk for adverse clinical outcome in breast-conserving therapy (BCT) for early-stage breast cancer. The majority of studies report positive resection margins in 20% to 40% of the patients who underwent BCT. This may result in an increased local recurrence (LR) rate or additional surgery and, consequently, adverse affects on cosmesis, psychological distress, and health costs. In the literature, various risk factors are reported to be associated with positive margin status after lumpectomy, which may allow the surgeon to distinguish those patients with a higher a priori risk for re-excision. However, most risk factors are related to tumor biology and patient characteristics, which cannot be modified as such. Therefore, efforts to reduce the number of positive margins should focus on optimizing the surgical procedure itself, because the surgeon lacks real-time intraoperative information on the presence of positive resection margins during breast-conserving surgery. This review presents the status of pre- and intraoperative modalities currently used in BCT. Furthermore, innovative intraoperative approaches, such as positron emission tomography, radioguided occult lesion localization, and near-infrared fluorescence optical imaging, are addressed, which have to prove their potential value in improving surgical outcome and reducing the need for re-excision in BCT.

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Author and article information

Contributors

Humphrey Fonge: humphrey.fonge@usask.ca

Clarence Ronald Geyer:

ORCID: http://orcid.org/0000-0003-1628-9665

ron.geyer@usask.ca

Journal

Journal ID (nlm-ta): BMC Cancer

Journal ID (iso-abbrev): BMC Cancer

Title: BMC Cancer

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2407

Publication date (Electronic): 12 March 2021

Publication date PMC-release: 12 March 2021

Publication date Collection: 2021

Volume: 21

Electronic Location Identifier: 270

Affiliations

[1 ]GRID grid.25152.31, ISNI 0000 0001 2154 235X, Department of Pathology and Laboratory Medicine, College of Medicine, , University of Saskatchewan, ; Saskatoon, SK Canada

[2 ]GRID grid.25152.31, ISNI 0000 0001 2154 235X, Department of Medical Imaging, College of Medicine, , University of Saskatchewan, ; Saskatoon, SK Canada

[3 ]GRID grid.417645.5, ISNI 0000 0004 0444 3191, Center of Molecular Immunology, ; Havana, Cuba

[4 ]GRID grid.412271.3, ISNI 0000 0004 0462 8356, Department of Medical Imaging, , Royal University Hospital, ; Saskatoon, SK Canada

Author information

Clarence Ronald Geyer http://orcid.org/0000-0003-1628-9665

Article

Publisher ID: 8003

DOI: 10.1186/s12885-021-08003-3

PMC ID: 7953729

PubMed ID: 33711962

SO-VID: 2e06f135-ede0-4568-8f92-94415fa0fc87

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 29 September 2020

Date accepted : 2 March 2021

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100000045, Western Economic Diversification Canada;

Award ID: #12939

Award Recipient : Clarence Ronald Geyer

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: nimotuzumab,egfr,near-infrared fluorescence imaging,irdye800cw,image-guided surgery,investigator’s brochure

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: nimotuzumab, egfr, near-infrared fluorescence imaging, irdye800cw, image-guided surgery, investigator’s brochure

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

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Abstract

Background

Methods

Results

Conclusions

Supplementary Information

Related collections

Karger: Oncology

Most cited references 24

Untangling the ErbB signalling network.

Epidermal growth factor receptor targeting in cancer: a review of trends and strategies.

Obtaining Adequate Surgical Margins in Breast-Conserving Therapy for Patients with Early-Stage Breast Cancer: Current Modalities and Future Directions

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Contributors

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