The Impact of Fc gamma RI binding on immuno-PET Journal Article
| Authors: | Vivier, D.; Sharma, S. K.; Adumeau, P.; Rodriguez, C.; Fung, K.; Zeglis, B. M. |
| Article Title: | The Impact of Fc gamma RI binding on immuno-PET |
| Abstract: | Antibodies are promising vectors for PET imaging. However, the high uptake of radioimmunoconjugates in nontarget tissues such as the liver and spleen hampers their performance as radiotracers. This off-target uptake can lead to suboptimal tumor-to-background activity concentration ratios, decreasing the contrast of images and reducing their diagnostic utility. A possible cause of this uptake is the sequestration of radioimmunoconjugates by immune cells bearing Fc-gamma-receptors (Fc gamma R) that bind to the Fc regions of antibodies. Methods: Since the heavy chain glycans influence the affinity of Fc gamma R for the Fc domain, we set out to investigate whether radio-immunoconjugates with truncated glycans would exhibit altered binding to Fc gamma RI and, in turn, improved in vivo performance. Using the HER2-targeting antibody trastuzumab, we synthesized a series of desferrioxamine-bearing immunoconjugates with differing glycosylation states and interrogated their Fc gamma RI binding via surface plasmon resonance, enzyme-linked immunosorbent assay, and flow cytometry. Furthermore, we labeled these immunoconjugates with Zr-89 and explored their biodistribution in athymic nude, NSG, and humanized NSG mice bearing human epidermal growth factor receptor 2-expressing human breast cancer xenografts. Results: We observed a strong correlation between the impaired in vitro Fc gamma RI binding of deglycosylated immunoconjugates and significant decreases in the in vivo off-target uptake of the corresponding Zr-89-labeled radioimmunoconjugates (i.e., liver activity concentrations are reduced by similar to 3.5-fold in humanized NSG mice). These reductions in off-target uptake were accompanied by concomitant increases in the tumoral activity concentrations of the glycoengineered radioimmunoconjugates, ultimately yielding improved tumor-to-healthy organ contrast and higher quality PET images. Conclusion: Our findings suggest that the deglycosylation of antibodies represents a facile strategy for improving the quality of immuno-PET in animal models as well as in certain patient populations. |
| Keywords: | mouse; tissue distribution; glycosylation; fc receptor; receptor; pet; glycans; monoclonal-antibodies; function; strategy; effector; radioimmunoconjugate; affinity; humanized mice; fc region; fc gamma ri; human-igg |
| Journal Title: | Journal of Nuclear Medicine |
| Volume: | 60 |
| Issue: | 8 |
| ISSN: | 0161-5505 |
| Publisher: | Society of Nuclear Medicine |
| Date Published: | 2019-08-01 |
| Start Page: | 1174 |
| End Page: | 1182 |
| Language: | English |
| ACCESSION: | WOS:000478077500023 |
| DOI: | 10.2967/jnumed.118.223636 |
| PROVIDER: | wos |
| PMCID: | PMC6681692 |
| PUBMED: | 30733320 |
| Notes: | Article -- Source: Wos |
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