Anti-HER2 biparatopic antibody KJ015 has near-native structure, functional balanced high affinity, and synergistic efficacy with anti-PD-1 treatment in vivo
Currently approved human epidermal growth factor receptor 2 (HER2)-targeted antibody therapies are largely derived from trastuzumab, including trastuzumab-chemotherapy combinations, fixed-dose trastuzumab-pertuzumab combinations, and trastuzumab antibody-drug conjugates. To expand the options, bispe...
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| Language: | English |
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Taylor & Francis Group
2024-12-01
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| Series: | mAbs |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/19420862.2024.2412881 |
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| author | Zheng Wang Yu Liu Yunxia Xu Lin Lu Zhen Zhu Baojie Lv Xin Fang Yao Tang Jinhua Wang Yu Cheng Ying Hu Junwen Lou Peican Wu Chendan Liu Yanjun Liu Xin Zeng Qing Xu |
| author_facet | Zheng Wang Yu Liu Yunxia Xu Lin Lu Zhen Zhu Baojie Lv Xin Fang Yao Tang Jinhua Wang Yu Cheng Ying Hu Junwen Lou Peican Wu Chendan Liu Yanjun Liu Xin Zeng Qing Xu |
| author_sort | Zheng Wang |
| collection | DOAJ |
| description | Currently approved human epidermal growth factor receptor 2 (HER2)-targeted antibody therapies are largely derived from trastuzumab, including trastuzumab-chemotherapy combinations, fixed-dose trastuzumab-pertuzumab combinations, and trastuzumab antibody-drug conjugates. To expand the options, bispecific antibodies, which may better utilize the benefits of combination therapy, are being developed. Among them, biparatopic antibodies (bpAbs) have shown improved efficacy compared to monoclonal antibody (mAb) combinations in HER2-positive patients. BpAbs bind two independent epitopes on the same antigen, which allows fine-tuning of mechanisms of action, including enhancement of on-target specificity and induction of strong antigen clustering due to the unique binding mode. To fully utilize the potential of bpAbs for anti-HER2 drug development, it is crucial to consider formats that offer stability and high-yield production, along with a functional balance between the two epitopes. In this study, we rationally designed a bpAb, KJ015, that shares a common light chain with two Fab arms and exhibits functionally balanced high affinity for two HER2 non-overlapping epitopes. KJ015 demonstrated high-expression titers over 7 g/L and stable physicochemical properties at elevated concentrations, facilitating subcutaneous administration with hyaluronidase. Moreover, KJ015 maintained comparable antibody-dependent cytotoxicity, phagocytosis, and complement-dependent cytotoxicity with trastuzumab plus pertuzumab. It exhibited enhanced synergy when administered subcutaneously with hyaluronidase and anti-PD-1 mAb in a mouse tumor model, suggesting promising clinical prospects for this combination. |
| format | Article |
| id | doaj-art-7d08bc471b9245bea159a6d008edd6d0 |
| institution | Kabale University |
| issn | 1942-0862 1942-0870 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | mAbs |
| spelling | doaj-art-7d08bc471b9245bea159a6d008edd6d02025-01-31T04:19:37ZengTaylor & Francis GroupmAbs1942-08621942-08702024-12-0116110.1080/19420862.2024.2412881Anti-HER2 biparatopic antibody KJ015 has near-native structure, functional balanced high affinity, and synergistic efficacy with anti-PD-1 treatment in vivoZheng Wang0Yu Liu1Yunxia Xu2Lin Lu3Zhen Zhu4Baojie Lv5Xin Fang6Yao Tang7Jinhua Wang8Yu Cheng9Ying Hu10Junwen Lou11Peican Wu12Chendan Liu13Yanjun Liu14Xin Zeng15Qing Xu16Shanghai Bao Pharmaceuticals Co.Ltd, Baoshan, Shanghai, ChinaDepartment of Oncology, Shanghai Tenth People’s Hospital, Tongji University Cancer Center, Shanghai, ChinaShanghai Bao Pharmaceuticals Co.Ltd, Baoshan, Shanghai, ChinaShanghai Bao Pharmaceuticals Co.Ltd, Baoshan, Shanghai, ChinaShanghai Bao Pharmaceuticals Co.Ltd, Baoshan, Shanghai, ChinaShanghai Bao Pharmaceuticals Co.Ltd, Baoshan, Shanghai, ChinaShanghai Bao Pharmaceuticals Co.Ltd, Baoshan, Shanghai, ChinaShanghai Bao Pharmaceuticals Co.Ltd, Baoshan, Shanghai, ChinaShanghai Bao Pharmaceuticals Co.Ltd, Baoshan, Shanghai, ChinaShanghai Bao Pharmaceuticals Co.Ltd, Baoshan, Shanghai, ChinaShanghai Bao Pharmaceuticals Co.Ltd, Baoshan, Shanghai, ChinaShanghai Bao Pharmaceuticals Co.Ltd, Baoshan, Shanghai, ChinaShanghai Bao Pharmaceuticals Co.Ltd, Baoshan, Shanghai, ChinaShanghai Bao Pharmaceuticals Co.Ltd, Baoshan, Shanghai, ChinaShanghai Bao Pharmaceuticals Co.Ltd, Baoshan, Shanghai, ChinaShanghai Bao Pharmaceuticals Co.Ltd, Baoshan, Shanghai, ChinaDepartment of Oncology, Shanghai Tenth People’s Hospital, Tongji University Cancer Center, Shanghai, ChinaCurrently approved human epidermal growth factor receptor 2 (HER2)-targeted antibody therapies are largely derived from trastuzumab, including trastuzumab-chemotherapy combinations, fixed-dose trastuzumab-pertuzumab combinations, and trastuzumab antibody-drug conjugates. To expand the options, bispecific antibodies, which may better utilize the benefits of combination therapy, are being developed. Among them, biparatopic antibodies (bpAbs) have shown improved efficacy compared to monoclonal antibody (mAb) combinations in HER2-positive patients. BpAbs bind two independent epitopes on the same antigen, which allows fine-tuning of mechanisms of action, including enhancement of on-target specificity and induction of strong antigen clustering due to the unique binding mode. To fully utilize the potential of bpAbs for anti-HER2 drug development, it is crucial to consider formats that offer stability and high-yield production, along with a functional balance between the two epitopes. In this study, we rationally designed a bpAb, KJ015, that shares a common light chain with two Fab arms and exhibits functionally balanced high affinity for two HER2 non-overlapping epitopes. KJ015 demonstrated high-expression titers over 7 g/L and stable physicochemical properties at elevated concentrations, facilitating subcutaneous administration with hyaluronidase. Moreover, KJ015 maintained comparable antibody-dependent cytotoxicity, phagocytosis, and complement-dependent cytotoxicity with trastuzumab plus pertuzumab. It exhibited enhanced synergy when administered subcutaneously with hyaluronidase and anti-PD-1 mAb in a mouse tumor model, suggesting promising clinical prospects for this combination.https://www.tandfonline.com/doi/10.1080/19420862.2024.2412881Bispecific antibodycombination therapy with immune checkpoint inhibitors (ICIs)HER2pertuzumabtrastuzumab |
| spellingShingle | Zheng Wang Yu Liu Yunxia Xu Lin Lu Zhen Zhu Baojie Lv Xin Fang Yao Tang Jinhua Wang Yu Cheng Ying Hu Junwen Lou Peican Wu Chendan Liu Yanjun Liu Xin Zeng Qing Xu Anti-HER2 biparatopic antibody KJ015 has near-native structure, functional balanced high affinity, and synergistic efficacy with anti-PD-1 treatment in vivo mAbs Bispecific antibody combination therapy with immune checkpoint inhibitors (ICIs) HER2 pertuzumab trastuzumab |
| title | Anti-HER2 biparatopic antibody KJ015 has near-native structure, functional balanced high affinity, and synergistic efficacy with anti-PD-1 treatment in vivo |
| title_full | Anti-HER2 biparatopic antibody KJ015 has near-native structure, functional balanced high affinity, and synergistic efficacy with anti-PD-1 treatment in vivo |
| title_fullStr | Anti-HER2 biparatopic antibody KJ015 has near-native structure, functional balanced high affinity, and synergistic efficacy with anti-PD-1 treatment in vivo |
| title_full_unstemmed | Anti-HER2 biparatopic antibody KJ015 has near-native structure, functional balanced high affinity, and synergistic efficacy with anti-PD-1 treatment in vivo |
| title_short | Anti-HER2 biparatopic antibody KJ015 has near-native structure, functional balanced high affinity, and synergistic efficacy with anti-PD-1 treatment in vivo |
| title_sort | anti her2 biparatopic antibody kj015 has near native structure functional balanced high affinity and synergistic efficacy with anti pd 1 treatment in vivo |
| topic | Bispecific antibody combination therapy with immune checkpoint inhibitors (ICIs) HER2 pertuzumab trastuzumab |
| url | https://www.tandfonline.com/doi/10.1080/19420862.2024.2412881 |
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