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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 (89)Zr-labeled IBI322, an anti-CD47/PD-L1 BsAb, was used to optimize the safety and effective therapy dose. By labeling with (...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Taylor & Francis
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7153848/ https://www.ncbi.nlm.nih.gov/pubmed/32275842 http://dx.doi.org/10.1080/19420862.2020.1748322 |
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author | Wang, Yan Pan, Donghui Huang, Chenrong Chen, Bingliang Li, Mingzhu Zhou, Shuaixiang Wang, Lizhen Wu, Min Wang, Xinyu Bian, Yicong Yan, Junjie Liu, Junjian Yang, Min Miao, Liyan |
author_facet | Wang, Yan Pan, Donghui Huang, Chenrong Chen, Bingliang Li, Mingzhu Zhou, Shuaixiang Wang, Lizhen Wu, Min Wang, Xinyu Bian, Yicong Yan, Junjie Liu, Junjian Yang, Min Miao, Liyan |
author_sort | Wang, Yan |
collection | PubMed |
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 (89)Zr-labeled IBI322, an anti-CD47/PD-L1 BsAb, was used to optimize the safety and effective therapy dose. By labeling with (89)Zr, 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). (89)Zr-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 (89)Zr-labeled antibodies is promising for PK/PD modeling and safety prediction, and helpful for determining rational dosing for preclinical and clinical trials of BsAbs. |
format | Online Article Text |
id | pubmed-7153848 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Taylor & Francis |
record_format | MEDLINE/PubMed |
spelling | pubmed-71538482020-04-20 Dose escalation PET imaging for safety and effective therapy dose optimization of a bispecific antibody Wang, Yan Pan, Donghui Huang, Chenrong Chen, Bingliang Li, Mingzhu Zhou, Shuaixiang Wang, Lizhen Wu, Min Wang, Xinyu Bian, Yicong Yan, Junjie Liu, Junjian Yang, Min Miao, Liyan MAbs Report 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 (89)Zr-labeled IBI322, an anti-CD47/PD-L1 BsAb, was used to optimize the safety and effective therapy dose. By labeling with (89)Zr, 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). (89)Zr-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 (89)Zr-labeled antibodies is promising for PK/PD modeling and safety prediction, and helpful for determining rational dosing for preclinical and clinical trials of BsAbs. Taylor & Francis 2020-04-10 /pmc/articles/PMC7153848/ /pubmed/32275842 http://dx.doi.org/10.1080/19420862.2020.1748322 Text en © 2020 The Author(s). Published with license by Taylor & Francis Group, LLC. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) ), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Report Wang, Yan Pan, Donghui Huang, Chenrong Chen, Bingliang Li, Mingzhu Zhou, Shuaixiang Wang, Lizhen Wu, Min Wang, Xinyu Bian, Yicong Yan, Junjie Liu, Junjian Yang, Min Miao, Liyan Dose escalation PET imaging for safety and effective therapy dose optimization of a bispecific antibody |
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 | Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7153848/ https://www.ncbi.nlm.nih.gov/pubmed/32275842 http://dx.doi.org/10.1080/19420862.2020.1748322 |
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