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Comparison of approaches for increasing affinity of affibody molecules for imaging of B7-H3 : dimerization and affinity maturation

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  • معلومة اضافية
    • Publisher Information:
      Uppsala universitet, Cancerprecisionsmedicin Uppsala universitet, Theranostics Affibody AB, S-17165 Solna, Sweden Affibody AB, S-17165 Solna, Sweden. Affibody AB, S-17165 Solna, Sweden. Affibody AB, S-17165 Solna, Sweden 2024
    • نبذة مختصرة :
      Background 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. Results Two dimeric variants of anti-B7-H3 Affibody molecules were produced (designated ZAC12*-ZAC12*-GGGC and ZAC12*-ZTaq_3-GGGC). Both variants were labelled with Tc-99m (99mTc) and demonstrated specific binding to B7-H3-expressing cells in vitro. [99mTc]Tc-ZAC12*-ZAC12*-GGGC showed subnanomolar affinity (KD1=0.28 ± 0.10 nM, weight = 68%), which was 7.6-fold higher than for [99mTc]Tc-ZAC12*-ZTaq_3-GGGC (KD=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 99mTc) 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. Conclusion The improved functional affinity by dimerization does not compensate the disadvantage of increased molecular size for imaging purposes.
    • الموضوع:
      B7-H3; Affibody molecule; Dimerization; Affinity maturation; Technetium-99m (99mTc); SKOV-3 xenograft; SPECT/CT imaging; Biochemistry and Molecular Biology; Biokemi och molekylärbiologi; Radiology, Nuclear Medicine and Medical Imaging; Radiologi och bildbehandling; Article in journal; info:eu-repo/semantics/article; text
    • الرقم المعرف:
      10.1186.s41181-024-00261-3
    • Availability:
      Open access content. Open access content
      info:eu-repo/semantics/openAccess
    • Note:
      application/pdf
      English
    • Other Numbers:
      UPE oai:DiVA.org:uu-527240
      0000-0003-2660-9837
      0000-0001-6120-2683
      0000-0002-6122-1734
      0000-0002-6421-4142
      doi:10.1186/s41181-024-00261-3
      PMID 38625607
      ISI:001204536900001
      1457586533
    • Contributing Source:
      UPPSALA UNIV LIBR
      From OAIster®, provided by the OCLC Cooperative.
    • الرقم المعرف:
      edsoai.on1457586533
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