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

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.

Glycobiology of rheumatic diseases

“…The functionality of this system was demonstrated by specifically targeting and inhibiting immortalized ACPA-expressing B cell lines using multivalent scaffolds that carried citrullinated antigens and ligands for the immunomodulatory receptor CD22 (ref. 164 ). In addition to STALs, other glycosylation-based protein-degradation platforms could be harnessed to modulate the pathogenic effects of immunoglobulins.…”

Biomaterial engineering strategies for B cell immunity modulations

“… 250 In vitro treatment with the obtained polymers on B cells induced CD22 phosphorylation and attenuated tyrosine phosphorylation, resulting in B cell inhibition. Kristyanto et al delivered the same CD22 ligands with CCP antigens in polyisocyanopeptides (PICs) that form stable helical filaments 251 ( Fig. 6B ).…”

“…(A) Siglec-engaging tolerance-inducing antigenic liposomes (STAL) display antigens and synthetic siglec CD22L suppresses antigen-specific B cells by engaging inhibitory CD22 receptor and B cell receptor (BCR). (B) Helical polyisocyanopeptide (PIC) 251 and PEGylated cationic liposome (PCL) 252 display both antigens and glycan or peptide CD22L respectively to inhibit B cell functions. (C) Soluble antigen array (SAgA) is designed based on hyaluronic acid (HA) polymers or 4-arm PEG polymers to deliver antigens, myelin sheath peptide antigen (PLP) or insulin, with inhibitory peptide (LABL) for intercellular adhesion molecule-1 (ICAM-1) to inhibit B cell activation.…”

Convergent Synthesis of a Hexadecavalent Heterobifunctional ABO Blood Group Glycoconjugate

“…[24][25][26] Linear polymers generated by stoichiometric control with two epitopes have been used to investigate BCR and CD22 coclustering. [22,23,27,28] Larger IgM, liposome, and nanoparticle complexes have been used to target BCR and CD22, [20,21,[29][30][31][32][33] and CD22 ligands displayed on N-glycan structures have been used for targeted delivery of toxins to cells. [34] A heterobifunctional display of https://doi.org/10.26434/chemrxiv-2023-8ct0c ORCID: https://orcid.org/0000-0003-3363-8708 Content not peer-reviewed by ChemRxiv.…”