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9. Effectiveness of [67Cu]Cu-trastuzumab as a theranostic against HER2-positive breast cancer.

Author

Pougoue Ketchemen, Jessica, Njotu, Fabrice Ngoh, Babeker, Hanan, Ahenkorah, Stephen, Tikum, Anjong Florence, Nwangele, Emmanuel, Henning, Nikita, Cleeren, Frederik, and Fonge, Humphrey

Subjects
HER2 positive breast cancer, EPIDERMAL growth factor receptors, FC receptors, BREAST, RADIOLIGAND assay
Abstract

Purpose: To evaluate the imaging and therapeutic properties (theranostic) of 67Cu-labeled anti-human epidermal growth factor receptor II (HER2) monoclonal antibody trastuzumab against HER2-positive breast cancer (BC). Methods: We conjugated trastuzumab with p-SCN-Bn-NOTA, 3p-C-NETA-NCS, or p-SCN-Bn-DOTA, and radiolabeled with [67Cu]CuCl2. Immunoconjugate internalization was evaluated in BT-474, JIMT-1 and MCF-7 BC cells. In vitro stability was studied in human serum (HS) and Phosphate Buffered Saline (PBS). Flow cytometry, radioligand binding and immunoreactive fraction assays were carried out. ImmunoSPECT imaging of [67Cu]Cu-NOTA-trastuzumab was done in mice bearing BT-474, JIMT-1 and MCF-7 xenografts. Pharmacokinetic was studied in healthy Balb/c mice while dosimetry was done in both healthy Balb/c and in athymic nude mice bearing JIMT-1 xenograft. The therapeutic effectiveness of [67Cu]Cu-NOTA-trastuzumab was evaluated in mice bearing BT-474 and JIMT-1 xenografts after a single intravenous (i.v.) injection of ~ 16.8 MBq. Results: Pure immunoconjugates and radioimmunoconjugates (> 95%) were obtained. Internalization was HER2 density-dependent with highest internalization observed with NOTA-trastuzumab. After 5 days, in vitro stabilities were 97 ± 1.7%, 31 ± 6.2%, and 28 ± 4% in HS, and 79 ± 3.5%, 94 ± 1.2%, and 86 ± 2.3% in PBS for [67Cu]Cu-NOTA-trastuzumab, [67Cu]Cu-3p-C-NETA-trastuzumab and [67Cu]Cu-DOTA-trastuzumab, respectively. [67Cu]Cu-NOTA-trastuzumab was chosen for further evaluation. BT-474 flow cytometry showed low KD, 8.2 ± 0.2 nM for trastuzumab vs 26.5 ± 1.6 nM for NOTA-trastuzumab. There were 2.9 NOTA molecules per trastuzumab molecule. Radioligand binding assay showed a low KD of 2.1 ± 0.4 nM and immunoreactive fraction of 69.3 ± 0.9. Highest uptake of [67Cu]Cu-NOTA-trastuzumab was observed in JIMT-1 (33.9 ± 5.5% IA/g) and BT-474 (33.1 ± 10.6% IA/g) xenograft at 120 h post injection (p.i.). Effectiveness of the radioimmunoconjugate was also expressed as percent tumor growth inhibition (%TGI). [67Cu]Cu-NOTA-trastuzumab was more effective than trastuzumab against BT-474 xenografts (78% vs 54% TGI after 28 days), and JIMT-1 xenografts (90% vs 23% TGI after 19 days). Mean survival of [67Cu]Cu-NOTA-trastuzumab, trastuzumab and saline treated groups were > 90, 77 and 72 days for BT-474 xenografts, while that of JIMT-1 were 78, 24, and 20 days, respectively. Conclusion: [67Cu]Cu-NOTA-trastuzumab is a promising theranostic agent against HER2-positive BC. [ABSTRACT FROM AUTHOR]

Published
2024
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13. Figure S4 from A Multipronged Unbiased Strategy Guides the Development of an Anti-EGFR/EPHA2–Bispecific Antibody for Combination Cancer Therapy

Author

El Zawily, Amr, primary, Vizeacoumar, Frederick S., primary, Dahiya, Renuka, primary, Banerjee, Sara L., primary, Bhanumathy, Kalpana K., primary, Elhasasna, Hussain, primary, Hanover, Glinton, primary, Sharpe, Jessica C., primary, Sanchez, Malkon G., primary, Greidanus, Paul, primary, Stacey, R. Greg, primary, Moon, Kyung-Mee, primary, Alexandrov, Ilya, primary, Himanen, Juha P., primary, Nikolov, Dimitar B., primary, Fonge, Humphrey, primary, White, Aaron P., primary, Foster, Leonard J., primary, Wang, Bingcheng, primary, Toosi, Behzad M., primary, Bisson, Nicolas, primary, Mirzabekov, Tajib A., primary, Vizeacoumar, Franco J., primary, and Freywald, Andrew, primary

Published
2023
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14. Supplementary Table S7 from A Multipronged Unbiased Strategy Guides the Development of an Anti-EGFR/EPHA2–Bispecific Antibody for Combination Cancer Therapy

Author

El Zawily, Amr, primary, Vizeacoumar, Frederick S., primary, Dahiya, Renuka, primary, Banerjee, Sara L., primary, Bhanumathy, Kalpana K., primary, Elhasasna, Hussain, primary, Hanover, Glinton, primary, Sharpe, Jessica C., primary, Sanchez, Malkon G., primary, Greidanus, Paul, primary, Stacey, R. Greg, primary, Moon, Kyung-Mee, primary, Alexandrov, Ilya, primary, Himanen, Juha P., primary, Nikolov, Dimitar B., primary, Fonge, Humphrey, primary, White, Aaron P., primary, Foster, Leonard J., primary, Wang, Bingcheng, primary, Toosi, Behzad M., primary, Bisson, Nicolas, primary, Mirzabekov, Tajib A., primary, Vizeacoumar, Franco J., primary, and Freywald, Andrew, primary

Published
2023
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15. Data from A Multipronged Unbiased Strategy Guides the Development of an Anti-EGFR/EPHA2–Bispecific Antibody for Combination Cancer Therapy

Author

El Zawily, Amr, primary, Vizeacoumar, Frederick S., primary, Dahiya, Renuka, primary, Banerjee, Sara L., primary, Bhanumathy, Kalpana K., primary, Elhasasna, Hussain, primary, Hanover, Glinton, primary, Sharpe, Jessica C., primary, Sanchez, Malkon G., primary, Greidanus, Paul, primary, Stacey, R. Greg, primary, Moon, Kyung-Mee, primary, Alexandrov, Ilya, primary, Himanen, Juha P., primary, Nikolov, Dimitar B., primary, Fonge, Humphrey, primary, White, Aaron P., primary, Foster, Leonard J., primary, Wang, Bingcheng, primary, Toosi, Behzad M., primary, Bisson, Nicolas, primary, Mirzabekov, Tajib A., primary, Vizeacoumar, Franco J., primary, and Freywald, Andrew, primary

Published
2023
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16. Supplementary Materials and Methods1 from A Multipronged Unbiased Strategy Guides the Development of an Anti-EGFR/EPHA2–Bispecific Antibody for Combination Cancer Therapy

Author

El Zawily, Amr, primary, Vizeacoumar, Frederick S., primary, Dahiya, Renuka, primary, Banerjee, Sara L., primary, Bhanumathy, Kalpana K., primary, Elhasasna, Hussain, primary, Hanover, Glinton, primary, Sharpe, Jessica C., primary, Sanchez, Malkon G., primary, Greidanus, Paul, primary, Stacey, R. Greg, primary, Moon, Kyung-Mee, primary, Alexandrov, Ilya, primary, Himanen, Juha P., primary, Nikolov, Dimitar B., primary, Fonge, Humphrey, primary, White, Aaron P., primary, Foster, Leonard J., primary, Wang, Bingcheng, primary, Toosi, Behzad M., primary, Bisson, Nicolas, primary, Mirzabekov, Tajib A., primary, Vizeacoumar, Franco J., primary, and Freywald, Andrew, primary

Published
2023
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21. A Multipronged Unbiased Strategy Guides the Development of an Anti-EGFR/EPHA2–Bispecific Antibody for Combination Cancer Therapy

Author

El Zawily, Amr, primary, Vizeacoumar, Frederick S., additional, Dahiya, Renuka, additional, Banerjee, Sara L., additional, Bhanumathy, Kalpana K., additional, Elhasasna, Hussain, additional, Hanover, Glinton, additional, Sharpe, Jessica C., additional, Sanchez, Malkon G., additional, Greidanus, Paul, additional, Stacey, R. Greg, additional, Moon, Kyung-Mee, additional, Alexandrov, Ilya, additional, Himanen, Juha P., additional, Nikolov, Dimitar B., additional, Fonge, Humphrey, additional, White, Aaron P., additional, Foster, Leonard J., additional, Wang, Bingcheng, additional, Toosi, Behzad M., additional, Bisson, Nicolas, additional, Mirzabekov, Tajib A., additional, Vizeacoumar, Franco J., additional, and Freywald, Andrew, additional

Published
2023
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24. Evaluation of nimotuzumab Fab2 as an optical imaging agent in EGFR positive cancers.

Author

Bernhard, Wendy, Barreto, Kris, Toledo, Darien, El-Sayed, Ayman, Jett, Kimberly A., Casaco, Angel, Fonge, Humphrey, and Geyer, C. Ronald

Subjects
OPTICAL images, EPIDERMAL growth factor receptors, POSITRON emission tomography, PEPSIN, COMPUTER-assisted surgery, FLUORESCENT antibody technique, OPTICAL properties
Abstract

Molecular-targeted imaging probes can be used with a variety of imaging modalities to detect diseased tissues and guide their removal. EGFR is a useful biomarker for a variety of cancers, because it is expressed at high levels relative to normal tissues. Previously, we showed the anti-EGFR antibody nimotuzumab can be used as a positron emission tomography and fluorescent imaging probe for EGFR positive cancers in mice. These imaging probes are currently in clinical trials for PET imaging and image-guided surgery, respectively. One issue with using antibody probes for imaging is their long circulation time and slow tissue penetration, which requires patients to wait a few days after injection before imaging or surgery, multiple visits and longer radiation exposure. Here, we generated a Fab2 fragment of nimotuzumab, by pepsin digestion and labeled it with IRDye800CW to evaluate its optical imaging properties. The Fab2 had faster tumor accumulation and clearance in mice relative to the nimotuzumab IgG. The fluorescent signal peaked at 2 h post injection and remained high until 6 h post injection. The properties of the Fab2 allow a higher signal to background to be obtained in a shorter time frame, reducing the wait time for imaging after probe infusion. [ABSTRACT FROM AUTHOR]

Published
2023
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27. 3p-C-NETA-TATE: a versatile somatostatin analogue for Al18F-labeled and therapeutic SSTR2 targeting radiopharmaceuticals

Author

Ahenkorah, Stephen, primary, Murce, Erika, additional, Ketchemen, Jessica, additional, Cawthorne, Christopher, additional, Seimbille, Yann, additional, Cardinaels, Thomas, additional, Deroose, Christophe, additional, Bormans, Guy, additional, Fonge, Humphrey, additional, Ooms, Maarten, additional, and Cleeren, Frederik, additional

Published
2022
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30. 3p-C-NETA: A versatile and effective chelator for development of Al18F-labeled and therapeutic radiopharmaceuticals

Author

Ahenkorah, Stephen, primary, Murce, Erika, additional, Cawthorne, Christopher, additional, Ketchemen, Jessica Pougoue, additional, Deroose, Christophe M., additional, Cardinaels, Thomas, additional, Seimbille, Yann, additional, Fonge, Humphrey, additional, Gsell, Willy, additional, Bormans, Guy, additional, Ooms, Maarten, additional, and Cleeren, Frederik, additional

Published
2022
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34. A 89Zr-labeled lipoplex nanosystem for image-guided gene delivery: design, evaluation of stability and in vivo behavior

Author

Hajdu, Istvan, Makhlouf, Amal, Solomon, Viswas Raja, Michel, Deborah, Al-Dulaymi, Mays, Wasan, Kishor M, Fonge, Humphrey, and Badea, Ildiko

Subjects
gemini surfactant, Radioisotopes, Cell Survival, Gene Transfer Techniques, Mice, Nude, Genetic Therapy, Deferoxamine, Lipids, Surface-Active Agents, Imaging, Three-Dimensional, Gene Expression Regulation, microPET imaging, Neoplasms, Positron-Emission Tomography, melanoma, Animals, Nanoparticles, Tissue Distribution, Zirconium, pharmacokinetic, Radiopharmaceuticals, biodistribution, Original Research
Abstract

Background With the advances in radiopharmaceutical research, the development of image-guided therapy has become a major interest. While the development of theranostic nanotherapeutics is frequently associated with cancer chemotherapy, phototherapy and radiotherapy, there is little information available on the in vivo monitoring of gene delivery systems and the application of image-guided approach in gene therapy. The goal of this work was to determine the in vivo behavior of DNA delivery nanosystems - based on cationic gemini surfactants – designed for image-guided gene therapy. We tested the feasibility of monitoring tumor accumulation of gene delivery nanoparticles by positron emission tomography. Methods To be able to conjugate radiotracers to the nanoparticles, a deferoxamine-modified gemini surfactant was synthesized, DNA-containing lipoplex nanoparticles were formulated, and radiolabeled with Zirconium-89 (89Zr). The pharmacokinetics and biodistribution of 89Zr labeled surfactant and 89Zr labeled nanoparticles were monitored in mice by microPET/CT imaging and ex vivo gamma counting. Results Modification of the nanoparticles with deferoxamine did not alter their physicochemical properties. The radiolabeled nanoparticles (labeling efficiency of 95±3%) were stable in PBS and serum. The biological half-life of the 89Zr labeled nanoparticles was significantly higher compared to 89Zr labeled surfactant. As expected, the nanoparticles had significantly higher liver accumulation than the radiolabeled surfactant alone and lower kidney accumulation. Tumor uptake was detected at 2 hours post injection and decreased throughout the 3-day monitoring. Conclusion We propose that radiolabeling DNA delivery lipoplex nanosystems is a promising approach for the design and optimization of image-guided nanomedicines, especially in the context of cancer gene therapy.

Published
2018

35. Additional file 6 of Pre-clinical study of IRDye800CW-nimotuzumab formulation, stability, pharmacokinetics, and safety

Author

Bernhard, Wendy, Barreto, Kris, El-Sayed, Ayman, Gonzalez, Carolina, Viswas, Raja Solomon, Toledo, Darien, Casaco, Angel, DeCoteau, John, Fonge, Humphrey, and Geyer, Clarence Ronald

Subjects
congenital, hereditary, and neonatal diseases and abnormalities, hemic and lymphatic diseases, circulatory and respiratory physiology
Abstract

Additional file 6. Hematology results from toxicity study. White blood cells (WBC), lymphocytes (LY), monocytes (MO), granulocytes (GR), red blood cells (RBC) and red blood cell distribution width (RDW), hematocrits (Hct), platelets (Plt), haemoglobin (Hgb), mean corpuscular haemoglobin (MCH), mean corpuscular haemoglobin count (MCHC) and mean corpuscular volume (MCV) measurements from the IRDye800CW-nimotuzumab (800CW-Nz) toxicity studies.

Published
2021
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36. Additional file 1 of Pre-clinical study of IRDye800CW-nimotuzumab formulation, stability, pharmacokinetics, and safety

Author

Bernhard, Wendy, Barreto, Kris, El-Sayed, Ayman, Gonzalez, Carolina, Viswas, Raja Solomon, Toledo, Darien, Casaco, Angel, DeCoteau, John, Fonge, Humphrey, and Geyer, Clarence Ronald

Abstract

Additional file 1. Clinical trials by probe. A table listing the clinical trials by probe with IRDye800CW and the number (n) of clinical trials.

Published
2021
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37. Additional file 9 of Pre-clinical study of IRDye800CW-nimotuzumab formulation, stability, pharmacokinetics, and safety

Author

Bernhard, Wendy, Barreto, Kris, El-Sayed, Ayman, Gonzalez, Carolina, Viswas, Raja Solomon, Toledo, Darien, Casaco, Angel, DeCoteau, John, Fonge, Humphrey, and Geyer, Clarence Ronald

Abstract

Additional file 9. Clinical trials by probe and trial status. A table listing clinical trials by probe of probes similar to IRDye800CW-nimotuzumab showing trials ‘completed’, ‘in progress’ and ‘terminated’ or ‘withdrawn’.

Published
2021
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38. Additional file 8 of Pre-clinical study of IRDye800CW-nimotuzumab formulation, stability, pharmacokinetics, and safety

Author

Bernhard, Wendy, Barreto, Kris, El-Sayed, Ayman, Gonzalez, Carolina, Viswas, Raja Solomon, Toledo, Darien, Casaco, Angel, DeCoteau, John, Fonge, Humphrey, and Geyer, Clarence Ronald

Abstract

Additional file 8. Indications of clinical trials with IRDye800CW. A table listing the clinical trials, indications and the number of indications (n).

Published
2021
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39. Additional file 4 of Pre-clinical study of IRDye800CW-nimotuzumab formulation, stability, pharmacokinetics, and safety

Author

Bernhard, Wendy, Barreto, Kris, El-Sayed, Ayman, Gonzalez, Carolina, Viswas, Raja Solomon, Toledo, Darien, Casaco, Angel, DeCoteau, John, Fonge, Humphrey, and Geyer, Clarence Ronald

Subjects
urogenital system
Abstract

Additional file 4. Weight of mouse liver, kidney, and spleen from toxicity studies. Graphs showing the weights of the liver, spleen and kidney of the mice used for the toxicity experiments.

Published
2021
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40. Additional file 5 of Pre-clinical study of IRDye800CW-nimotuzumab formulation, stability, pharmacokinetics, and safety

Author

Bernhard, Wendy, Barreto, Kris, El-Sayed, Ayman, Gonzalez, Carolina, Viswas, Raja Solomon, Toledo, Darien, Casaco, Angel, DeCoteau, John, Fonge, Humphrey, and Geyer, Clarence Ronald

Abstract

Additional file 5. Clinical chemistry results from the toxicity study. Sodium, potassium, sodium: potassium (Na:K) ratio, chloride, calcium, phosphorus magnesium, urea, creatinine, amylase, lipase, glucose, cholesterol, bilirubin, alkaline phosphatase (Alk Phos), alanine aminotransferase (ALT), glutamate dehydrogenase (GLDH), CK (creatine kinase), protein, albumin, globulin and albumin:globulin (A:G) ratio measurements from the IRDye800CW-nimotuzumab (800CW-Nz) toxicity studies.

Published
2021
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42. Additional file 3 of Pre-clinical study of IRDye800CW-nimotuzumab formulation, stability, pharmacokinetics, and safety

Author

Bernhard, Wendy, Barreto, Kris, El-Sayed, Ayman, Gonzalez, Carolina, Viswas, Raja Solomon, Toledo, Darien, Casaco, Angel, DeCoteau, John, Fonge, Humphrey, and Geyer, Clarence Ronald

Abstract

Additional file 3. Mouse weights from toxicity studies. Graphs showing the weights of the mice used for the toxicity experiments prior to and during the experiments.

Published
2021
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43. Additional file 2 of Pre-clinical study of IRDye800CW-nimotuzumab formulation, stability, pharmacokinetics, and safety

Author

Bernhard, Wendy, Barreto, Kris, El-Sayed, Ayman, Gonzalez, Carolina, Viswas, Raja Solomon, Toledo, Darien, Casaco, Angel, DeCoteau, John, Fonge, Humphrey, and Geyer, Clarence Ronald

Abstract

Additional file 2. Schematic of how the meta-analysis on clinical trials with IRDye800CW was done and tables showing the clinical trials with IRD800CW with results published on pubmed.

Published
2021
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49. Nimotuzumab Site-Specifically Labeled with 89Zr and 225Ac Using SpyTag/SpyCatcher for PET Imaging and Alpha Particle Radioimmunotherapy of Epidermal Growth Factor Receptor Positive Cancers

Author

Solomon, Viswas Raja, primary, Barreto, Kris, additional, Bernhard, Wendy, additional, Alizadeh, Elahe, additional, Causey, Patrick, additional, Perron, Randy, additional, Gendron, Denise, additional, Alam, Md. Kausar, additional, Carr, Adriana, additional, Geyer, C. Ronald, additional, and Fonge, Humphrey, additional

Published
2020
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