Dose escalation PET imaging for safety and effective therapy dose optimization of a bispecific antibody
Selecting the dose for efficacy and first-in-human studies of bispecific antibodies (BsAbs) is a challenging process. Herein, positron emission tomography (PET) imaging with 89Zr-labeled IBI322, an anti-CD47/PD-L1 BsAb, was used to optimize the safety and effective therapy dose. By labeling with 89Z...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2020-01-01
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| Series: | mAbs |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/19420862.2020.1748322 |
| _version_ | 1818023771547631616 |
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| author | Yan Wang Donghui Pan Chenrong Huang Bingliang Chen Mingzhu Li Shuaixiang Zhou Lizhen Wang Min Wu Xinyu Wang Yicong Bian Junjie Yan Junjian Liu Min Yang Liyan Miao |
| author_facet | Yan Wang Donghui Pan Chenrong Huang Bingliang Chen Mingzhu Li Shuaixiang Zhou Lizhen Wang Min Wu Xinyu Wang Yicong Bian Junjie Yan Junjian Liu Min Yang Liyan Miao |
| author_sort | Yan Wang |
| collection | DOAJ |
| description | Selecting the dose for efficacy and first-in-human studies of bispecific antibodies (BsAbs) is a challenging process. Herein, positron emission tomography (PET) imaging with 89Zr-labeled IBI322, an anti-CD47/PD-L1 BsAb, was used to optimize the safety and effective therapy dose. By labeling with 89Zr, we aimed to assess the pharmacokinetics (PK), safety, and target engagement of IBI322 with dose escalation dynamic PET imaging in humanized transgenic animal models bearing MC38 tumors (knock-in of hCD47 and hPDL1). 89Zr-labeled IBI322 specifically accumulated in tumors with a tumor-to-muscle ratio of 12.37 ± 1.42 at 168 h (0.22 mg/kg) and the biodistribution of normal tissues from PET imaging could be used for preliminary safety prediction. According to the Pearson correlation analysis between the ELISA-quantified serum concentration and heart uptake (%ID/g) (r = 0.980), a modified Patlak model was proposed. The exploratory target-mediated 50% (0.38 mg/kg) and 90% (0.63 mg/kg) inhibitory mass doses were calculated with the current modified Patlak model. The preliminary pharmacodynamics (PD) study with 0.34 mg/kg revealed that the dose prediction was rational. In conclusion, dose escalation PET imaging with 89Zr-labeled antibodies is promising for PK/PD modeling and safety prediction, and helpful for determining rational dosing for preclinical and clinical trials of BsAbs. |
| first_indexed | 2024-12-10T03:49:37Z |
| format | Article |
| id | doaj.art-f20e199e2cd74d2bb487593d53b9eae9 |
| institution | Directory Open Access Journal |
| issn | 1942-0862 1942-0870 |
| language | English |
| last_indexed | 2024-12-10T03:49:37Z |
| publishDate | 2020-01-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | mAbs |
| spelling | doaj.art-f20e199e2cd74d2bb487593d53b9eae92022-12-22T02:03:19ZengTaylor & Francis GroupmAbs1942-08621942-08702020-01-0112110.1080/19420862.2020.1748322Dose escalation PET imaging for safety and effective therapy dose optimization of a bispecific antibodyYan Wang0Donghui Pan1Chenrong Huang2Bingliang Chen3Mingzhu Li4Shuaixiang Zhou5Lizhen Wang6Min Wu7Xinyu Wang8Yicong Bian9Junjie Yan10Junjian Liu11Min Yang12Liyan Miao13Department of Clinical Pharmacology, The First Affiliated Hospital of Soochow University, Suzhou, ChinaNHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, Jiangsu, ChinaDepartment of Clinical Pharmacology, The First Affiliated Hospital of Soochow University, Suzhou, ChinaDrug Discovery Department, Innovent Biopharmaceutical (Suzhou) Co., Ltd, Suzhou, ChinaNHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, Jiangsu, ChinaDrug Discovery Department, Innovent Biopharmaceutical (Suzhou) Co., Ltd, Suzhou, ChinaNHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, Jiangsu, ChinaDrug Discovery Department, Innovent Biopharmaceutical (Suzhou) Co., Ltd, Suzhou, ChinaNHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, Jiangsu, ChinaDepartment of Clinical Pharmacology, The First Affiliated Hospital of Soochow University, Suzhou, ChinaNHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, Jiangsu, ChinaDrug Discovery Department, Innovent Biopharmaceutical (Suzhou) Co., Ltd, Suzhou, ChinaNHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, Jiangsu, ChinaDepartment of Clinical Pharmacology, The First Affiliated Hospital of Soochow University, Suzhou, ChinaSelecting the dose for efficacy and first-in-human studies of bispecific antibodies (BsAbs) is a challenging process. Herein, positron emission tomography (PET) imaging with 89Zr-labeled IBI322, an anti-CD47/PD-L1 BsAb, was used to optimize the safety and effective therapy dose. By labeling with 89Zr, we aimed to assess the pharmacokinetics (PK), safety, and target engagement of IBI322 with dose escalation dynamic PET imaging in humanized transgenic animal models bearing MC38 tumors (knock-in of hCD47 and hPDL1). 89Zr-labeled IBI322 specifically accumulated in tumors with a tumor-to-muscle ratio of 12.37 ± 1.42 at 168 h (0.22 mg/kg) and the biodistribution of normal tissues from PET imaging could be used for preliminary safety prediction. According to the Pearson correlation analysis between the ELISA-quantified serum concentration and heart uptake (%ID/g) (r = 0.980), a modified Patlak model was proposed. The exploratory target-mediated 50% (0.38 mg/kg) and 90% (0.63 mg/kg) inhibitory mass doses were calculated with the current modified Patlak model. The preliminary pharmacodynamics (PD) study with 0.34 mg/kg revealed that the dose prediction was rational. In conclusion, dose escalation PET imaging with 89Zr-labeled antibodies is promising for PK/PD modeling and safety prediction, and helpful for determining rational dosing for preclinical and clinical trials of BsAbs.https://www.tandfonline.com/doi/10.1080/19420862.2020.174832289zr-immunoPETbispecific antibodiestarget engagementdose selection |
| spellingShingle | Yan Wang Donghui Pan Chenrong Huang Bingliang Chen Mingzhu Li Shuaixiang Zhou Lizhen Wang Min Wu Xinyu Wang Yicong Bian Junjie Yan Junjian Liu Min Yang Liyan Miao Dose escalation PET imaging for safety and effective therapy dose optimization of a bispecific antibody mAbs 89zr-immunoPET bispecific antibodies target engagement dose selection |
| title | Dose escalation PET imaging for safety and effective therapy dose optimization of a bispecific antibody |
| title_full | Dose escalation PET imaging for safety and effective therapy dose optimization of a bispecific antibody |
| title_fullStr | Dose escalation PET imaging for safety and effective therapy dose optimization of a bispecific antibody |
| title_full_unstemmed | Dose escalation PET imaging for safety and effective therapy dose optimization of a bispecific antibody |
| title_short | Dose escalation PET imaging for safety and effective therapy dose optimization of a bispecific antibody |
| title_sort | dose escalation pet imaging for safety and effective therapy dose optimization of a bispecific antibody |
| topic | 89zr-immunoPET bispecific antibodies target engagement dose selection |
| url | https://www.tandfonline.com/doi/10.1080/19420862.2020.1748322 |
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