Development of a variant of dinutuximab with enhanced antitumor efficacy and reduced induction of neuropathic pain
Dinutuximab (ch14.18) was the first approved monoclonal antibody against the tumor‐associated antigen disialoganglioside GD2. Despite its success in treating neuroblastoma (NB), it triggers a significant amount of neuropathic pain in patients, possibly through complement‐dependent cytotoxicity (CDC)...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2022-09-01
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| Series: | FEBS Open Bio |
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| Online Access: | https://doi.org/10.1002/2211-5463.13464 |
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| author | Xin‐Yuan Liu Yi‐Li Chen Guo‐Jian Liu Xiang‐Nan Deng Yue Cui Jie Tan Xing‐Chen Dong Hua‐Ying Li Gan‐Jun Chen Zhi‐Min Ou Chun‐He Wang |
| author_facet | Xin‐Yuan Liu Yi‐Li Chen Guo‐Jian Liu Xiang‐Nan Deng Yue Cui Jie Tan Xing‐Chen Dong Hua‐Ying Li Gan‐Jun Chen Zhi‐Min Ou Chun‐He Wang |
| author_sort | Xin‐Yuan Liu |
| collection | DOAJ |
| description | Dinutuximab (ch14.18) was the first approved monoclonal antibody against the tumor‐associated antigen disialoganglioside GD2. Despite its success in treating neuroblastoma (NB), it triggers a significant amount of neuropathic pain in patients, possibly through complement‐dependent cytotoxicity (CDC). We hypothesized that modifying ch14.18 using antibody engineering techniques, such as humanization, affinity maturation, and Fc engineering, may enable the development of next‐generation GD2‐specific antibodies with reduced neuropathic pain and enhanced antitumor activity. In this study we developed the H3‐16 IgG1m4 antibody from ch14.18 IgG1. H3‐16 IgG1m4 exhibited enhanced binding activity to GD2 molecules and GD2‐positive cell lines as revealed by ELISA, and its cross‐binding activity to other gangliosides was not altered. The CDC activity of H3‐16 IgG1m4 was decreased, and the antibody‐dependent cellular cytotoxicity (ADCC) activity was enhanced. The pain response after H3‐16 IgG1m4 antibody administration was also reduced, as demonstrated using the von Frey test in Sprague–Dawley (SD) rats. In summary, H3‐16 IgG1m4 may have potential as a monoclonal antibody with reduced side effects. |
| first_indexed | 2024-04-14T02:18:41Z |
| format | Article |
| id | doaj.art-81bf6d4c32d14a42b60844d317b002a4 |
| institution | Directory Open Access Journal |
| issn | 2211-5463 |
| language | English |
| last_indexed | 2024-04-14T02:18:41Z |
| publishDate | 2022-09-01 |
| publisher | Wiley |
| record_format | Article |
| series | FEBS Open Bio |
| spelling | doaj.art-81bf6d4c32d14a42b60844d317b002a42022-12-22T02:18:06ZengWileyFEBS Open Bio2211-54632022-09-011291644165610.1002/2211-5463.13464Development of a variant of dinutuximab with enhanced antitumor efficacy and reduced induction of neuropathic painXin‐Yuan Liu0Yi‐Li Chen1Guo‐Jian Liu2Xiang‐Nan Deng3Yue Cui4Jie Tan5Xing‐Chen Dong6Hua‐Ying Li7Gan‐Jun Chen8Zhi‐Min Ou9Chun‐He Wang10College of Pharmaceutical Science Zhejiang University of Technology Hangzhou ChinaDepartment of Antibody Discovery Shanghai Mabstone Biotechonology, Ltd. ChinaDepartment of Reasearch and Development Center Dartsbio Pharmaceuticals Ltd. Zhongshan ChinaDepartment of Antibody Discovery Shanghai Mabstone Biotechonology, Ltd. ChinaDepartment of Antibody Discovery Shanghai Mabstone Biotechonology, Ltd. ChinaDepartment of Antibody Discovery Shanghai Mabstone Biotechonology, Ltd. ChinaDepartment of Antibody Discovery Shanghai Mabstone Biotechonology, Ltd. ChinaDepartment of Antibody Discovery Shanghai Mabstone Biotechonology, Ltd. ChinaDepartment of Reasearch and Development Center Dartsbio Pharmaceuticals Ltd. Zhongshan ChinaCollege of Pharmaceutical Science Zhejiang University of Technology Hangzhou ChinaDepartment of Antibody Discovery Shanghai Mabstone Biotechonology, Ltd. ChinaDinutuximab (ch14.18) was the first approved monoclonal antibody against the tumor‐associated antigen disialoganglioside GD2. Despite its success in treating neuroblastoma (NB), it triggers a significant amount of neuropathic pain in patients, possibly through complement‐dependent cytotoxicity (CDC). We hypothesized that modifying ch14.18 using antibody engineering techniques, such as humanization, affinity maturation, and Fc engineering, may enable the development of next‐generation GD2‐specific antibodies with reduced neuropathic pain and enhanced antitumor activity. In this study we developed the H3‐16 IgG1m4 antibody from ch14.18 IgG1. H3‐16 IgG1m4 exhibited enhanced binding activity to GD2 molecules and GD2‐positive cell lines as revealed by ELISA, and its cross‐binding activity to other gangliosides was not altered. The CDC activity of H3‐16 IgG1m4 was decreased, and the antibody‐dependent cellular cytotoxicity (ADCC) activity was enhanced. The pain response after H3‐16 IgG1m4 antibody administration was also reduced, as demonstrated using the von Frey test in Sprague–Dawley (SD) rats. In summary, H3‐16 IgG1m4 may have potential as a monoclonal antibody with reduced side effects.https://doi.org/10.1002/2211-5463.13464ADCCaffinity maturationantibody engineeringanti‐GD2 antibodiesengineered Fc domainhumanized |
| spellingShingle | Xin‐Yuan Liu Yi‐Li Chen Guo‐Jian Liu Xiang‐Nan Deng Yue Cui Jie Tan Xing‐Chen Dong Hua‐Ying Li Gan‐Jun Chen Zhi‐Min Ou Chun‐He Wang Development of a variant of dinutuximab with enhanced antitumor efficacy and reduced induction of neuropathic pain FEBS Open Bio ADCC affinity maturation antibody engineering anti‐GD2 antibodies engineered Fc domain humanized |
| title | Development of a variant of dinutuximab with enhanced antitumor efficacy and reduced induction of neuropathic pain |
| title_full | Development of a variant of dinutuximab with enhanced antitumor efficacy and reduced induction of neuropathic pain |
| title_fullStr | Development of a variant of dinutuximab with enhanced antitumor efficacy and reduced induction of neuropathic pain |
| title_full_unstemmed | Development of a variant of dinutuximab with enhanced antitumor efficacy and reduced induction of neuropathic pain |
| title_short | Development of a variant of dinutuximab with enhanced antitumor efficacy and reduced induction of neuropathic pain |
| title_sort | development of a variant of dinutuximab with enhanced antitumor efficacy and reduced induction of neuropathic pain |
| topic | ADCC affinity maturation antibody engineering anti‐GD2 antibodies engineered Fc domain humanized |
| url | https://doi.org/10.1002/2211-5463.13464 |
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