Simultaneous Imaging and Therapy Using Epitope-Specific Anti-Epidermal Growth Factor Receptor (EGFR) Antibody Conjugates
Matuzumab and nimotuzumab are anti-EGFR monoclonal antibodies that bind to different epitopes of domain III of EGFR. We developed <sup>89</sup>Zr-matuzumab as a PET probe for diagnosis/monitoring of response to treatment of a noncompeting anti-EGFR nimotuzumab antibody drug conjugate (AD...
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MDPI AG
2022-09-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/14/9/1917 |
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| author | Anjong Florence Tikum Anand Krishnan Nambisan Jessica Pougoue Ketchemen Hanan Babeker Musharraf N. Khan Emina E. Torlakovic Humphrey Fonge |
| author_facet | Anjong Florence Tikum Anand Krishnan Nambisan Jessica Pougoue Ketchemen Hanan Babeker Musharraf N. Khan Emina E. Torlakovic Humphrey Fonge |
| author_sort | Anjong Florence Tikum |
| collection | DOAJ |
| description | Matuzumab and nimotuzumab are anti-EGFR monoclonal antibodies that bind to different epitopes of domain III of EGFR. We developed <sup>89</sup>Zr-matuzumab as a PET probe for diagnosis/monitoring of response to treatment of a noncompeting anti-EGFR nimotuzumab antibody drug conjugate (ADC) using mouse colorectal cancer (CRC) xenografts. We developed <sup>89</sup>Zr-matuzumab and performed quality control in EGFR-positive DLD-1 cells. The K<sub>D</sub> of matuzumab, DFO-matuzumab and <sup>89</sup>Zr-matuzumab in DLD-1 cells was 5.9, 6.2 and 3 nM, respectively. A competitive radioligand binding assay showed that <sup>89</sup>Zr-matuzumab and nimotuzumab bound to noncompeting epitopes of EGFR. MicroPET/CT imaging and biodistribution of <sup>89</sup>Zr-matuzumab in mice bearing EGFR-positive xenografts (HT29, DLD-1 and MDA-MB-231) showed high uptake that was blocked with pre-dosing with matuzumab but not with the noncompeting binder nimotuzumab. We evaluated nimotuzumab-PEG<sub>6</sub>-DM1 ADC in CRC cells. IC<sub>50</sub> of nimotuzumab-PEG<sub>6</sub>-DM1 in SNU-C2B, DLD-1 and SW620 cells was dependent on EGFR density and was up to five-fold lower than that of naked nimotuzumab. Mice bearing the SNU-C2B xenograft were treated using three 15 mg/kg doses of nimotuzumab-PEG<sub>6</sub>-DM1, and <sup>89</sup>Zr-matuzumab microPET/CT was used to monitor the response to treatment. Treatment resulted in complete remission of the SNU-C2B tumor in 2/3 mice. Matuzumab and nimotuzumab are noncompeting and can be used simultaneously. |
| first_indexed | 2024-03-09T22:49:42Z |
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| id | doaj.art-b869aea12e3240479a417d80d6f263b2 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-09T22:49:42Z |
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| spelling | doaj.art-b869aea12e3240479a417d80d6f263b22023-11-23T18:22:55ZengMDPI AGPharmaceutics1999-49232022-09-01149191710.3390/pharmaceutics14091917Simultaneous Imaging and Therapy Using Epitope-Specific Anti-Epidermal Growth Factor Receptor (EGFR) Antibody ConjugatesAnjong Florence Tikum0Anand Krishnan Nambisan1Jessica Pougoue Ketchemen2Hanan Babeker3Musharraf N. Khan4Emina E. Torlakovic5Humphrey Fonge6Department of Medical Imaging, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 0W8, CanadaDepartment of Medical Imaging, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 0W8, CanadaDepartment of Medical Imaging, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 0W8, CanadaDepartment of Medical Imaging, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 0W8, CanadaDepartment of Medical Imaging, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 0W8, CanadaDepartment of Pathology and Lab. Medicine, College of Medicine, University of Saskatchewan, 107 Wiggins Rd, Saskatoon, SK S7N 5A2, CanadaDepartment of Medical Imaging, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 0W8, CanadaMatuzumab and nimotuzumab are anti-EGFR monoclonal antibodies that bind to different epitopes of domain III of EGFR. We developed <sup>89</sup>Zr-matuzumab as a PET probe for diagnosis/monitoring of response to treatment of a noncompeting anti-EGFR nimotuzumab antibody drug conjugate (ADC) using mouse colorectal cancer (CRC) xenografts. We developed <sup>89</sup>Zr-matuzumab and performed quality control in EGFR-positive DLD-1 cells. The K<sub>D</sub> of matuzumab, DFO-matuzumab and <sup>89</sup>Zr-matuzumab in DLD-1 cells was 5.9, 6.2 and 3 nM, respectively. A competitive radioligand binding assay showed that <sup>89</sup>Zr-matuzumab and nimotuzumab bound to noncompeting epitopes of EGFR. MicroPET/CT imaging and biodistribution of <sup>89</sup>Zr-matuzumab in mice bearing EGFR-positive xenografts (HT29, DLD-1 and MDA-MB-231) showed high uptake that was blocked with pre-dosing with matuzumab but not with the noncompeting binder nimotuzumab. We evaluated nimotuzumab-PEG<sub>6</sub>-DM1 ADC in CRC cells. IC<sub>50</sub> of nimotuzumab-PEG<sub>6</sub>-DM1 in SNU-C2B, DLD-1 and SW620 cells was dependent on EGFR density and was up to five-fold lower than that of naked nimotuzumab. Mice bearing the SNU-C2B xenograft were treated using three 15 mg/kg doses of nimotuzumab-PEG<sub>6</sub>-DM1, and <sup>89</sup>Zr-matuzumab microPET/CT was used to monitor the response to treatment. Treatment resulted in complete remission of the SNU-C2B tumor in 2/3 mice. Matuzumab and nimotuzumab are noncompeting and can be used simultaneously.https://www.mdpi.com/1999-4923/14/9/1917<sup>89</sup>Zr-matuzumabepitope-specific immunoconjugatesnimotuzumab antibody drug conjugatePET/CT imagingcolorectal cancer EGFR |
| spellingShingle | Anjong Florence Tikum Anand Krishnan Nambisan Jessica Pougoue Ketchemen Hanan Babeker Musharraf N. Khan Emina E. Torlakovic Humphrey Fonge Simultaneous Imaging and Therapy Using Epitope-Specific Anti-Epidermal Growth Factor Receptor (EGFR) Antibody Conjugates Pharmaceutics <sup>89</sup>Zr-matuzumab epitope-specific immunoconjugates nimotuzumab antibody drug conjugate PET/CT imaging colorectal cancer EGFR |
| title | Simultaneous Imaging and Therapy Using Epitope-Specific Anti-Epidermal Growth Factor Receptor (EGFR) Antibody Conjugates |
| title_full | Simultaneous Imaging and Therapy Using Epitope-Specific Anti-Epidermal Growth Factor Receptor (EGFR) Antibody Conjugates |
| title_fullStr | Simultaneous Imaging and Therapy Using Epitope-Specific Anti-Epidermal Growth Factor Receptor (EGFR) Antibody Conjugates |
| title_full_unstemmed | Simultaneous Imaging and Therapy Using Epitope-Specific Anti-Epidermal Growth Factor Receptor (EGFR) Antibody Conjugates |
| title_short | Simultaneous Imaging and Therapy Using Epitope-Specific Anti-Epidermal Growth Factor Receptor (EGFR) Antibody Conjugates |
| title_sort | simultaneous imaging and therapy using epitope specific anti epidermal growth factor receptor egfr antibody conjugates |
| topic | <sup>89</sup>Zr-matuzumab epitope-specific immunoconjugates nimotuzumab antibody drug conjugate PET/CT imaging colorectal cancer EGFR |
| url | https://www.mdpi.com/1999-4923/14/9/1917 |
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