New imaging technique targets hidden cancer marker, offering path to personalized treatment
Researchers developed a dual-protein imaging tool that better detects B7-H3, a marker overexpressed in multiple cancer types. The advance could help oncologists identify which patients benefit most from newer immunotherapies, potentially improving outcomes while reducing unnecessary treatment.
Originaltitel: Comparison of approaches for increasing affinity of affibody molecules for imaging of B7-H3: dimerization and affinity maturation
<p>Background</p><p>Radionuclide molecular imaging can be used to visualize the expression levels of molecular targets. Affibody molecules, small and high affinity non-immunoglobulin scaffold-based proteins, have demonstrated promising properties as targeting vectors for radionuclide tumour imaging of different molecular targets. B7-H3 (CD276), an immune checkpoint protein belonging to the B7 family, is overexpressed in different types of human malignancies. Visualization of overexpression of B7-H3 in malignancies enables stratification of patients for personalized therapies. Affinity maturation of anti-B7-H3 Affibody molecules as an approach to improve the binding affinity and targeting properties was recently investigated. In this study, we tested the hypothesis that a dimeric format may be an alternative option to increase the apparent affinity of Affibody molecules to B7-H3 and accordingly improve imaging contrast.</p><p>Results</p><p>Two dimeric variants of anti-B7-H3 Affibody molecules were produced (designated Z<sub>AC12*</sub>-Z<sub>AC12*</sub>-GGGC and Z<sub>AC12*</sub>-Z<sub>Taq_3</sub>-GGGC). Both variants were labelled with Tc-99m (<sup>99m</sup>Tc) and demonstrated specific binding to B7-H3-expressing cells in vitro. [<sup>99m</sup>Tc]Tc-Z<sub>AC12*</sub>-Z<sub>AC12*</sub>-GGGC showed subnanomolar affinity (K<sub>D1</sub>=0.28 ± 0.10 nM, weight = 68%), which was 7.6-fold higher than for [<sup>99m</sup>Tc]Tc-Z<sub>AC12*</sub>-Z<sub>Taq_3</sub>-GGGC (K<sub>D</sub>=2.1 ± 0.9 nM). Head-to-head biodistribution of both dimeric variants of Affibody molecules compared with monomeric affinity matured SYNT-179 (all labelled with <sup>99m</sup>Tc) in mice bearing B7-H3-expressing SKOV-3 xenografts demonstrates that both dimers have lower tumour uptake and lower tumour-to-organ ratios compared to the SYNT-179 Affibody molecule.</p><p>Conclusion</p><p>The improved functional affinity by dimerization does not compensate the disadvantage of increased molecular size for imaging purposes.</p>