Multifunctional, Multivalent PIC Polymer Scaffolds for Targeting Antigen-Specific, Autoreactive B Cells

ACS Biomaterials Science & Engineering, vol. 8, pp. 1486–1493

Abstract

Multivalent scaffolds that carry multiple molecules with immunophenotyping or immunomodulatory properties are invaluable tools for studying and modulating specific functions of human immune responses. So far, streptavidin-biotin-based tetramers have been widely used for B-cell immunophenotyping purposes. However, the utility of these tetramers is limited by their tetravalency, the inherent immunogenicity of streptavidin (a bacterial protein that can potentially be recognized by B cells), and the limited feasibility to functionalize these reagents. This has rendered tetramers suboptimal for studying rare, in particular, antigen-specific B-cell populations in the context of clinical applications. Here, we used polyisocyanopeptides (PICs), multivalent polymeric scaffolds functionalized with around 50 peptide antigens, to detect autoreactive B cells in the peripheral blood of patients with rheumatoid arthritis. To explore the potential immunomodulatory functionalities, we functionalized PICs with autoantigenic peptides and a trisaccharide CD22 ligand to inhibit autoreactive B-cell activation through interference with the B-cell receptor activation pathway, as evidenced by reduced phospho-Syk expression upon PIC binding. Given the possibilities to functionalize PICs, our data demonstrate that the modular and versatile character of PIC scaffolds makes them promising candidates for future clinical applications in B-cell-mediated diseases.

Authors 9

1. Hendy Kristyanto Aachen Department of Rheumatology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Rheumatology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands

2. Miles D. Holborough-Kerkvliet Aachen Department of Rheumatology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Rheumatology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands

3. Lianne P. W. M. Lelieveldt

   Radboud University Nijmegen

   Affiliation as printed

   Department of Synthetic Organic Chemistry, Radboud University, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands

4. Yvonne L Bartels

   Radboud University Nijmegen

   Affiliation as printed

   Department of Synthetic Organic Chemistry, Radboud University, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands

5. Roel Hammink

   Radboud University Nijmegen · Radboud University Medical Center · Radboud Institute for Molecular Life Sciences

   Affiliation as printed

   Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Division of Immunotherapy, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands

   Oncode Institute, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands

6. Karin Anna van Schie Aachen Department of Rheumatology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Rheumatology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands

7. René E. M. Toes Aachen Department of Rheumatology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Rheumatology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands

8. Kimberly M. Bonger corresponding

   Radboud University Nijmegen

   Affiliation as printed

   Department of Synthetic Organic Chemistry, Radboud University, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands

9. Hans Ulrich Scherer corresponding Aachen Department of Rheumatology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Rheumatology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands