Generation and in vivo characterization of a novel high-affinity human antibody targeting carcinoembryonic antigen
There are no effective treatment options for most patients with metastatic colorectal cancer (mCRC). mCRC remains a leading cause of tumor-related death, with a five-year survival rate of only 15%, highlighting the urgent need for novel pharmacological products. Current standard drugs are based on c...
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Taylor & Francis Group
2023-12-01
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| Series: | mAbs |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/19420862.2023.2217964 |
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| author | Louis Plüss Frederik Peissert Abdullah Elsayed Giulia Rotta Jonas Römer Sheila Dakhel Plaza Alessandra Villa Emanuele Puca Roberto De Luca Annette Oxenius Dario Neri |
| author_facet | Louis Plüss Frederik Peissert Abdullah Elsayed Giulia Rotta Jonas Römer Sheila Dakhel Plaza Alessandra Villa Emanuele Puca Roberto De Luca Annette Oxenius Dario Neri |
| author_sort | Louis Plüss |
| collection | DOAJ |
| description | There are no effective treatment options for most patients with metastatic colorectal cancer (mCRC). mCRC remains a leading cause of tumor-related death, with a five-year survival rate of only 15%, highlighting the urgent need for novel pharmacological products. Current standard drugs are based on cytotoxic chemotherapy, VEGF inhibitors, EGFR antibodies, and multikinase inhibitors. The antibody-based delivery of pro-inflammatory cytokines provides a promising and differentiated strategy to improve the treatment outcome for mCRC patients. Here, we describe the generation of a novel fully human monoclonal antibody (termed F4) targeting the carcinoembryonic antigen (CEA), a tumor-associated antigen overexpressed in colorectal cancer and other malignancies. The F4 antibody was selected by antibody phage display technology after two rounds of affinity maturation. F4 in single-chain variable fragment format bound to CEA in surface plasmon resonance with an affinity of 7.7 nM. Flow cytometry and immunofluorescence on human cancer specimens confirmed binding to CEA-expressing cells. F4 selectively accumulated in CEA-positive tumors, as evidenced by two orthogonal in vivo biodistribution studies. Encouraged by these results, we genetically fused murine interleukin (IL) 12 to F4 in the single-chain diabody format. F4-IL12 exhibited potent antitumor activity in two murine models of colon cancer. Treatment with F4-IL12 led to an increased density of tumor-infiltrating lymphocytes and an upregulation of interferon γ expression by tumor-homing lymphocytes. These data suggest that the F4 antibody is an attractive delivery vehicle for targeted cancer therapy. |
| format | Article |
| id | doaj-art-b2b1ebf228944e2ba4c6dcab246edd47 |
| institution | Kabale University |
| issn | 1942-0862 1942-0870 |
| language | English |
| publishDate | 2023-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | mAbs |
| spelling | doaj-art-b2b1ebf228944e2ba4c6dcab246edd472025-08-20T03:51:53ZengTaylor & Francis GroupmAbs1942-08621942-08702023-12-0115110.1080/19420862.2023.2217964Generation and in vivo characterization of a novel high-affinity human antibody targeting carcinoembryonic antigenLouis Plüss0Frederik Peissert1Abdullah Elsayed2Giulia Rotta3Jonas Römer4Sheila Dakhel Plaza5Alessandra Villa6Emanuele Puca7Roberto De Luca8Annette Oxenius9Dario Neri10Philochem AG, Libernstrasse 3, Otelfingen, SwitzerlandPhilochem AG, Libernstrasse 3, Otelfingen, SwitzerlandPhilochem AG, Libernstrasse 3, Otelfingen, SwitzerlandPhilochem AG, Libernstrasse 3, Otelfingen, SwitzerlandDepartment of Biology, Swiss Federal Institute of Technology (ETH Zürich), Zurich, SwitzerlandPhilochem AG, Libernstrasse 3, Otelfingen, SwitzerlandPhilochem AG, Libernstrasse 3, Otelfingen, SwitzerlandPhilochem AG, Libernstrasse 3, Otelfingen, SwitzerlandPhilochem AG, Libernstrasse 3, Otelfingen, SwitzerlandDepartment of Biology, Swiss Federal Institute of Technology (ETH Zürich), Zurich, SwitzerlandPhilochem AG, Libernstrasse 3, Otelfingen, SwitzerlandThere are no effective treatment options for most patients with metastatic colorectal cancer (mCRC). mCRC remains a leading cause of tumor-related death, with a five-year survival rate of only 15%, highlighting the urgent need for novel pharmacological products. Current standard drugs are based on cytotoxic chemotherapy, VEGF inhibitors, EGFR antibodies, and multikinase inhibitors. The antibody-based delivery of pro-inflammatory cytokines provides a promising and differentiated strategy to improve the treatment outcome for mCRC patients. Here, we describe the generation of a novel fully human monoclonal antibody (termed F4) targeting the carcinoembryonic antigen (CEA), a tumor-associated antigen overexpressed in colorectal cancer and other malignancies. The F4 antibody was selected by antibody phage display technology after two rounds of affinity maturation. F4 in single-chain variable fragment format bound to CEA in surface plasmon resonance with an affinity of 7.7 nM. Flow cytometry and immunofluorescence on human cancer specimens confirmed binding to CEA-expressing cells. F4 selectively accumulated in CEA-positive tumors, as evidenced by two orthogonal in vivo biodistribution studies. Encouraged by these results, we genetically fused murine interleukin (IL) 12 to F4 in the single-chain diabody format. F4-IL12 exhibited potent antitumor activity in two murine models of colon cancer. Treatment with F4-IL12 led to an increased density of tumor-infiltrating lymphocytes and an upregulation of interferon γ expression by tumor-homing lymphocytes. These data suggest that the F4 antibody is an attractive delivery vehicle for targeted cancer therapy.https://www.tandfonline.com/doi/10.1080/19420862.2023.2217964CEAcolorectal cancerimmunocytokineinterleukin-12monoclonal antibodiesphage display technology |
| spellingShingle | Louis Plüss Frederik Peissert Abdullah Elsayed Giulia Rotta Jonas Römer Sheila Dakhel Plaza Alessandra Villa Emanuele Puca Roberto De Luca Annette Oxenius Dario Neri Generation and in vivo characterization of a novel high-affinity human antibody targeting carcinoembryonic antigen mAbs CEA colorectal cancer immunocytokine interleukin-12 monoclonal antibodies phage display technology |
| title | Generation and in vivo characterization of a novel high-affinity human antibody targeting carcinoembryonic antigen |
| title_full | Generation and in vivo characterization of a novel high-affinity human antibody targeting carcinoembryonic antigen |
| title_fullStr | Generation and in vivo characterization of a novel high-affinity human antibody targeting carcinoembryonic antigen |
| title_full_unstemmed | Generation and in vivo characterization of a novel high-affinity human antibody targeting carcinoembryonic antigen |
| title_short | Generation and in vivo characterization of a novel high-affinity human antibody targeting carcinoembryonic antigen |
| title_sort | generation and in vivo characterization of a novel high affinity human antibody targeting carcinoembryonic antigen |
| topic | CEA colorectal cancer immunocytokine interleukin-12 monoclonal antibodies phage display technology |
| url | https://www.tandfonline.com/doi/10.1080/19420862.2023.2217964 |
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