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| Content Provider | Springer Nature : BioMed Central |
|---|---|
| Author | Hagemans, Iris M. Wierstra, Peter J. Steuten, Kas Molkenboer-Kuenen, Janneke D. M. van Dalen, Duco ter Beest, Martin van der Schoot, Johan M. S. Ilina, Olga Gotthardt, Martin Figdor, Carl G. Scheeren, Ferenc A. Heskamp, Sandra Verdoes, Martijn |
| Abstract | Background While immune checkpoint inhibitors such as anti-PD-L1 antibodies have revolutionized cancer treatment, only subgroups of patients show durable responses. Insight in the relation between clinical response, PD-L1 expression and intratumoral localization of PD-L1 therapeutics could improve patient stratification. Therefore, we present the modular synthesis of multimodal antibody-based imaging tools for multiscale imaging of PD-L1 to study intratumoral distribution of PD-L1 therapeutics. Results To introduce imaging modalities, a peptide containing a near-infrared dye (sulfo-Cy5), a chelator (DTPA), an azide, and a sortase-recognition motif was synthesized. This peptide and a non-fluorescent intermediate were used for site-specific functionalization of c-terminally sortaggable mouse IgG1 (mIgG1) and Fab anti-PD-L1. To increase the half-life of the Fab fragment, a 20 kDa PEG chain was attached via strain-promoted azide-alkyne cycloaddition (SPAAC). Biodistribution and imaging studies were performed with 111In-labeled constructs in 4T1 tumor-bearing mice. Comparing our site-specific antibody-conjugates with randomly conjugated antibodies, we found that antibody clone, isotype and method of DTPA conjugation did not change tumor uptake. Furthermore, addition of sulfo-Cy5 did not affect the biodistribution. PEGylated Fab fragment displayed a significantly longer half-life compared to unPEGylated Fab and demonstrated the highest overall tumor uptake of all constructs. PD-L1 in tumors was clearly visualized by SPECT/CT, as well as whole body fluorescence imaging. Immunohistochemistry staining of tumor sections demonstrated that PD-L1 co-localized with the fluorescent and autoradiographic signal. Intratumoral localization of the imaging agent could be determined with cellular resolution using fluorescent microscopy. Conclusions A set of molecularly defined multimodal antibody-based PD-L1 imaging agents were synthesized and validated for multiscale monitoring of PD-L1 expression and localization. Our modular approach for site-specific functionalization could easily be adapted to other targets. Graphical Abstract |
| Related Links | https://jnanobiotechnology.biomedcentral.com/counter/pdf/10.1186/s12951-022-01272-5.pdf |
| Ending Page | 15 |
| Page Count | 15 |
| Starting Page | 1 |
| File Format | HTM / HTML |
| ISSN | 14773155 |
| DOI | 10.1186/s12951-022-01272-5 |
| Journal | Journal of Nanobiotechnology |
| Issue Number | 1 |
| Volume Number | 20 |
| Language | English |
| Publisher | BioMed Central |
| Publisher Date | 2022-02-02 |
| Access Restriction | Open |
| Subject Keyword | Biotechnology Nanotechnology Molecular Medicine Fluorescence imaging Nuclear imaging Immune checkpoints Antibody Cancer |
| Content Type | Text |
| Resource Type | Article |
| Subject | Bioengineering Pharmaceutical Science Medicine Applied Microbiology and Biotechnology Biomedical Engineering Molecular Medicine Nanoscience and Nanotechnology |
| Journal Impact Factor | 10.6/2023 |
| 5-Year Journal Impact Factor | 11.4/2023 |
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