Fc engineering of anti-Nectin-2 antibody improved thrombocytopenic adverse event in monkey.
Nectin-2 is a transmembrane glycoprotein which is involved in the process of Ca2+-independent cell-cell adhesion. In our previous study, we have demonstrated that Nectin-2 is over-expressed in breast and ovarian cancer tissues by using gene expression analysis and immunohistochemistry. Furthermore,...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2018-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC5933732?pdf=render |
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| author | Tsutomu Oshima Hideaki Miyashita Yoshimasa Ishimura Yuki Ito Yoko Tanaka Akira Hori Toshio Kokubo Tomofumi Kurokawa |
| author_facet | Tsutomu Oshima Hideaki Miyashita Yoshimasa Ishimura Yuki Ito Yoko Tanaka Akira Hori Toshio Kokubo Tomofumi Kurokawa |
| author_sort | Tsutomu Oshima |
| collection | DOAJ |
| description | Nectin-2 is a transmembrane glycoprotein which is involved in the process of Ca2+-independent cell-cell adhesion. In our previous study, we have demonstrated that Nectin-2 is over-expressed in breast and ovarian cancer tissues by using gene expression analysis and immunohistochemistry. Furthermore, we discovered multiple anti-Nectin-2 fully human monoclonal antibodies which inhibited tumor growth in in vivo subcutaneous xenograft models with antibody-dependent cellular cytotoxicity (ADCC) as the principal mechanism of action. In this report, we assessed the toxicity of Y-443, a fully human IgG1/kappa anti-Nectin-2 monoclonal antibody exhibiting strong in vitro ADCC and in vivo anti-tumor activity in cynomolgus monkeys (Macaca fascicularis (Cynos)). Unexpectedly, upon administration, Y-443 induced strong thrombocytopenia through Nectin-2 expressed on Cyno platelets, presumably followed by phagocytosis in the mononuclear phagocytic system. To mitigate the adverse safety profile, we mutated the Fc region of Y-443 to reduce the Fc binding activity to Fcγ receptor I, which is the primary receptor for phagocytosis on macrophages. Moreover, we further engineered the Fc through defucosylation to maintain ADCC activity. The resultant Fc engineered antibody, termed Y-634, demonstrated diminished thrombocytopenia in Cyno toxicological studies and maintained anti-tumor activity in a mouse xenograft model. These findings suggest that Y-634 may have a therapeutic potential for the treatment of Nectin-2 positive cancers, and moreover, Fc engineering is a potential mitigation strategy to ameliorate safety liabilities in antibody induced thrombocytopenia while maintaining antibody potency. |
| first_indexed | 2024-12-21T15:45:28Z |
| format | Article |
| id | doaj.art-040b68ce303e4f72b53513848a3e1d77 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-21T15:45:28Z |
| publishDate | 2018-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-040b68ce303e4f72b53513848a3e1d772022-12-21T18:58:22ZengPublic Library of Science (PLoS)PLoS ONE1932-62032018-01-01135e019642210.1371/journal.pone.0196422Fc engineering of anti-Nectin-2 antibody improved thrombocytopenic adverse event in monkey.Tsutomu OshimaHideaki MiyashitaYoshimasa IshimuraYuki ItoYoko TanakaAkira HoriToshio KokuboTomofumi KurokawaNectin-2 is a transmembrane glycoprotein which is involved in the process of Ca2+-independent cell-cell adhesion. In our previous study, we have demonstrated that Nectin-2 is over-expressed in breast and ovarian cancer tissues by using gene expression analysis and immunohistochemistry. Furthermore, we discovered multiple anti-Nectin-2 fully human monoclonal antibodies which inhibited tumor growth in in vivo subcutaneous xenograft models with antibody-dependent cellular cytotoxicity (ADCC) as the principal mechanism of action. In this report, we assessed the toxicity of Y-443, a fully human IgG1/kappa anti-Nectin-2 monoclonal antibody exhibiting strong in vitro ADCC and in vivo anti-tumor activity in cynomolgus monkeys (Macaca fascicularis (Cynos)). Unexpectedly, upon administration, Y-443 induced strong thrombocytopenia through Nectin-2 expressed on Cyno platelets, presumably followed by phagocytosis in the mononuclear phagocytic system. To mitigate the adverse safety profile, we mutated the Fc region of Y-443 to reduce the Fc binding activity to Fcγ receptor I, which is the primary receptor for phagocytosis on macrophages. Moreover, we further engineered the Fc through defucosylation to maintain ADCC activity. The resultant Fc engineered antibody, termed Y-634, demonstrated diminished thrombocytopenia in Cyno toxicological studies and maintained anti-tumor activity in a mouse xenograft model. These findings suggest that Y-634 may have a therapeutic potential for the treatment of Nectin-2 positive cancers, and moreover, Fc engineering is a potential mitigation strategy to ameliorate safety liabilities in antibody induced thrombocytopenia while maintaining antibody potency.http://europepmc.org/articles/PMC5933732?pdf=render |
| spellingShingle | Tsutomu Oshima Hideaki Miyashita Yoshimasa Ishimura Yuki Ito Yoko Tanaka Akira Hori Toshio Kokubo Tomofumi Kurokawa Fc engineering of anti-Nectin-2 antibody improved thrombocytopenic adverse event in monkey. PLoS ONE |
| title | Fc engineering of anti-Nectin-2 antibody improved thrombocytopenic adverse event in monkey. |
| title_full | Fc engineering of anti-Nectin-2 antibody improved thrombocytopenic adverse event in monkey. |
| title_fullStr | Fc engineering of anti-Nectin-2 antibody improved thrombocytopenic adverse event in monkey. |
| title_full_unstemmed | Fc engineering of anti-Nectin-2 antibody improved thrombocytopenic adverse event in monkey. |
| title_short | Fc engineering of anti-Nectin-2 antibody improved thrombocytopenic adverse event in monkey. |
| title_sort | fc engineering of anti nectin 2 antibody improved thrombocytopenic adverse event in monkey |
| url | http://europepmc.org/articles/PMC5933732?pdf=render |
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