RT Journal Article
SR Electronic
T1 The Impact of FcγRI Binding on ImmunoPET
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP jnumed.118.223636
DO 10.2967/jnumed.118.223636
A1 Delphine Vivier
A1 Sai Kiran Sharma
A1 Pierre Adumeau
A1 Cindy Rodriguez
A1 Kimberly Fung
A1 Brian Zeglis
YR 2019
UL http://jnm.snmjournals.org/content/early/2019/01/31/jnumed.118.223636.abstract
AB Antibodies are promising vectors for positron-emission tomography (PET) imaging. However, the high uptake of radioimmunoconjugates in non-target 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 (FcγR) that bind to the Fc regions of antibodies. Methods: Since the heavy chain glycans influence the affinity of FcγR for the Fc domain, we set out to investigate whether radioimmunoconjugates with truncated glycans would exhibit altered binding to FcγRI and, in turn, improved in vivo performance. Using the HER2-targeting antibody trastuzumab, we synthesized a series of desferrioxamine (DFO)-bearing immunoconjugates with differing glycosylation states and interrogated their FcγRI binding via surface plasmon resonance (SPR), ELISA, and flow cytometry. Furthermore, we labeled these immunoconjugates with 89Zr and explored their biodistribution in athymic nude, NSG, and humanized NSG mice bearing HER2-expressing human breast cancer xenografts. Results: We observed a strong correlation between the impaired in vitro FcγRI binding of deglycosylated immunoconjugates and significant decreases in the in vivo off-target uptake of the corresponding 89Zr-labeled radioimmunoconjugates (i.e. liver activity concentrations are reduced by ~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 immunoPET in animal models as well as in certain patient populations.