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Selective Elimination of Autoreactive B Cells Using Multivalent Polyisocyanopeptide-Based Antigen-Toxin Conjugates
K R Venrooij1, M J van Weijsten1, S Kroos2
1Institute for Molecules and Materials, Radboud University, Nijmegen, 6525 AJ, The Netherlands.
Biomacromolecules
|June 22, 2026
Summary
New polymer-drug conjugates selectively target and eliminate autoreactive B cells in rheumatoid arthritis (RA). This targeted approach offers a promising alternative to systemic immune suppressors, reducing infection risks for RA patients.
Area of Science:
- Immunology
- Rheumatology
- Drug Delivery
Background:
- Rheumatoid arthritis (RA) is an autoimmune disease causing chronic inflammation and joint damage.
- Current RA treatments using systemic immune suppressors carry a high risk of infection.
- Autoreactive B cells producing anticitrullinated protein antibodies (ACPAs) are key drivers of RA pathogenesis.
Purpose of the Study:
- To explore the targeted elimination of autoreactive B cells in RA using novel antigen-toxin conjugates.
- To investigate the efficacy of polyisocyano peptide (PIC) polymers as delivery vehicles for targeted RA therapy.
Main Methods:
- Development of multivalent citrullinated antigen (CCP4) conjugates with cleavable linkers and toxins.
- Evaluation of conjugate toxicity against ACPA B cell receptor (BCR)-expressing cell lines.
- Optimization of CCP4 density and toxin ratios on PIC polymer scaffolds.
Main Results:
- Initial conjugates (diCCP4-VCP-MMAE) showed insufficient toxicity.
- Polyisocyano peptide (PIC) 13-based conjugates demonstrated potent and selective toxicity against ACPA BCR-expressing cells.
- Optimized PIC 13 conjugates achieved low nanomolar IC50 values and showed efficacy in patient-derived B cells.
Conclusions:
- Polyisocyano peptide (PIC)-based antigen-toxin conjugates are a promising strategy for selectively eliminating autoreactive B cells in RA.
- Optimizing delivery modules and toxin ratios is crucial for developing effective targeted therapies.
- This approach offers a potential alternative to systemic immunosuppression for RA treatment.
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