Thomas E Wuensche, Natascha Stergiou, Iris Mes, Mariska Verlaan, Esther J M Kooijman, Albert D Windhorst, Allan Jensen, Ayodeji A Asuni, Benny Bang-Andersen, Guus A M S van Dongen, Danielle J Vugts, Wissam Beaino
{"title":"Investigation of the Impact of the H310A FcRn Region Mutation on <sup>89</sup>Zr-Immuno-PET Brain Imaging with a BBB-Shuttle Anti‑Amyloid Beta Antibody.","authors":"Thomas E Wuensche, Natascha Stergiou, Iris Mes, Mariska Verlaan, Esther J M Kooijman, Albert D Windhorst, Allan Jensen, Ayodeji A Asuni, Benny Bang-Andersen, Guus A M S van Dongen, Danielle J Vugts, Wissam Beaino","doi":"10.1007/s11307-024-01931-z","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>In the emerging field of antibody treatments for neurodegenerative diseases, reliable tools are needed to evaluate new therapeutics, diagnose and select patients, monitor disease progression, and assess therapy response. Immuno-PET combines the high affinity and exceptional specificity of monoclonal antibodies with the non-invasive imaging technique positron emission tomography (PET). Its application in neurodegenerative disease brain imaging has been limited due to the marginal uptake across the blood-brain barrier (BBB). The emergence of BBB-shuttle antibodies with enhanced uptake across the BBB extended immuno-PET to brain imaging. We recently reported about specific brain uptake of a bispecific aducanumab mTfR antibody in APP/PS1 TG mice using <sup>89</sup>Zr-immuno-PET. However, a sufficient target-to-background ratio was reached at a relatively late scanning time point of 7 days post-injection. To investigate if a better target-to-background ratio could be achieved earlier, an aducanumab BBB-shuttle with a mutated Fc region for reduced FcRn affinity was evaluated.</p><p><strong>Procedures: </strong>Adu<sup>H310A</sup>-8D3 and Adu-8D3 were modified with DFO*-NCS and subsequently radiolabeled with <sup>89</sup>Zr. The potential influence of the H310A mutation, modification with DFO*-NCS, and subsequent radiolabeling on the in vitro binding to amyloid-beta and mTfR1 was investigated via amyloid-beta peptide ELISA and FACS analysis using mTfR1 transfected CHO-S cells. Blood kinetics, brain uptake, in vivo PET imaging and target engagement of radiolabeled Adu<sup>H310A</sup>-8D3 were evaluated and compared to non-mutated Adu-8D3 in APP/PS1 TG mice and wild-type animals as controls.</p><p><strong>Results: </strong>Radiolabeling was performed with sufficient radiochemical yields and radiochemical purity. In vitro binding to amyloid-beta and mTfR1 showed no impairment. [<sup>89</sup>Zr]Zr-Adu<sup>H310A</sup>-8D3 showed faster blood clearance and earlier differentiation of amyloid-beta-related brain uptake compared to [<sup>89</sup>Zr]Zr-Adu-8D3. However, only half of the brain uptake was observed for [<sup>89</sup>Zr]Zr-Adu<sup>H310A</sup>-8D3.</p><p><strong>Conclusions: </strong>Although a faster blood clearance of Adu<sup>H310A</sup>-8D3 was observed, it was concluded that no beneficial effects for <sup>89</sup>Zr-immuno-PET imaging of brain uptake were obtained.</p>","PeriodicalId":18760,"journal":{"name":"Molecular Imaging and Biology","volume":" ","pages":"823-834"},"PeriodicalIF":3.0000,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11436416/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Imaging and Biology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s11307-024-01931-z","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/8/2 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING","Score":null,"Total":0}
引用次数: 0
Abstract
Purpose: In the emerging field of antibody treatments for neurodegenerative diseases, reliable tools are needed to evaluate new therapeutics, diagnose and select patients, monitor disease progression, and assess therapy response. Immuno-PET combines the high affinity and exceptional specificity of monoclonal antibodies with the non-invasive imaging technique positron emission tomography (PET). Its application in neurodegenerative disease brain imaging has been limited due to the marginal uptake across the blood-brain barrier (BBB). The emergence of BBB-shuttle antibodies with enhanced uptake across the BBB extended immuno-PET to brain imaging. We recently reported about specific brain uptake of a bispecific aducanumab mTfR antibody in APP/PS1 TG mice using 89Zr-immuno-PET. However, a sufficient target-to-background ratio was reached at a relatively late scanning time point of 7 days post-injection. To investigate if a better target-to-background ratio could be achieved earlier, an aducanumab BBB-shuttle with a mutated Fc region for reduced FcRn affinity was evaluated.
Procedures: AduH310A-8D3 and Adu-8D3 were modified with DFO*-NCS and subsequently radiolabeled with 89Zr. The potential influence of the H310A mutation, modification with DFO*-NCS, and subsequent radiolabeling on the in vitro binding to amyloid-beta and mTfR1 was investigated via amyloid-beta peptide ELISA and FACS analysis using mTfR1 transfected CHO-S cells. Blood kinetics, brain uptake, in vivo PET imaging and target engagement of radiolabeled AduH310A-8D3 were evaluated and compared to non-mutated Adu-8D3 in APP/PS1 TG mice and wild-type animals as controls.
Results: Radiolabeling was performed with sufficient radiochemical yields and radiochemical purity. In vitro binding to amyloid-beta and mTfR1 showed no impairment. [89Zr]Zr-AduH310A-8D3 showed faster blood clearance and earlier differentiation of amyloid-beta-related brain uptake compared to [89Zr]Zr-Adu-8D3. However, only half of the brain uptake was observed for [89Zr]Zr-AduH310A-8D3.
Conclusions: Although a faster blood clearance of AduH310A-8D3 was observed, it was concluded that no beneficial effects for 89Zr-immuno-PET imaging of brain uptake were obtained.
期刊介绍：
Molecular Imaging and Biology (MIB) invites original contributions (research articles, review articles, commentaries, etc.) on the utilization of molecular imaging (i.e., nuclear imaging, optical imaging, autoradiography and pathology, MRI, MPI, ultrasound imaging, radiomics/genomics etc.) to investigate questions related to biology and health. The objective of MIB is to provide a forum to the discovery of molecular mechanisms of disease through the use of imaging techniques. We aim to investigate the biological nature of disease in patients and establish new molecular imaging diagnostic and therapy procedures.
Some areas that are covered are:
Preclinical and clinical imaging of macromolecular targets (e.g., genes, receptors, enzymes) involved in significant biological processes.
The design, characterization, and study of new molecular imaging probes and contrast agents for the functional interrogation of macromolecular targets.
Development and evaluation of imaging systems including instrumentation, image reconstruction algorithms, image analysis, and display.
Development of molecular assay approaches leading to quantification of the biological information obtained in molecular imaging.
Study of in vivo animal models of disease for the development of new molecular diagnostics and therapeutics.
Extension of in vitro and in vivo discoveries using disease models, into well designed clinical research investigations.
Clinical molecular imaging involving clinical investigations, clinical trials and medical management or cost-effectiveness studies.
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
