Selective Elimination of Autoreactive B Cells Using Multivalent Polyisocyanopeptide-Based Antigen-Toxin Conjugates.

Authors

K R Venrooij, M J van Weijsten, S Kroos, R Hammink, F Turlings, C G Figdor, M Verdoes, R E M Toes, K M Bonger

Published in

Biomacromolecules. Jun 22, 2026. Epub Jun 22, 2026.

Abstract

Rheumatoid arthritis (RA) is a debilitating autoimmune disease characterized by chronic inflammation and joint damage. Current treatments rely on systemic immune suppressors, which increases infection risk. Autoreactive B cells directed against citrullinated antigens and producing anticitrullinated protein antibodies (ACPAs) are thought to play a key role in RA pathogenesis, making their selective elimination a promising therapeutic strategy. Previous research demonstrated that a synthetic multivalent citrullinated antigen, cyclic citrullinated peptide 4 (CCP4), is efficiently internalized by these autoreactive B cells through an antigen-specific B cell receptor (BCR), positioning it as a potential delivery vehicle for targeted therapy. Here, we explored the elimination of autoreactive B cells using multivalent antigen-cleavable linker-toxin conjugates. Initial evaluation of diCCP4-VCP-MMAE revealed that it lacked sufficient toxicity toward ACPA BCR-expressing Ramos cells despite cathepsin-mediated linker cleavage and the absence of steric hindrance from diCCP4 or the BCR. Therefore, we investigated polyisocyano peptide (PIC) polymers, which allow for a higher CCP4 and toxin density. PIC 13 (containing 13 CCP4 units), functionalized with 0.5 equiv of MMAE per CCP4, selectively eliminated Ramos 3F3 cells with a midnanomolar IC₅₀. Increasing MMAE to 1, 2, or 5 equiv further reduced the IC₅₀ to low nanomolar. PIC 13 + 5 equiv MMAE demonstrated selective toxicity in Ramos cells expressing various ACPA BCRs, as well as patient-derived, immortalized ACPA-expressing B cells. These findings underscore the importance of optimizing delivery modules and toxin ratios and highlight PIC-based antigen-toxin conjugates as a promising strategy for selectively eliminating autoreactive B cells in RA.

PMID:
42329059
Bibliographic data and abstract were imported from PubMed on 22 Jun 2026.

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