Bispecific antibodies tethering innate receptors induce human tolerant-dendritic cells and regulatory T cells

Front Immunol. 2024 Mar 26:15:1369117. doi: 10.3389/fimmu.2024.1369117. eCollection 2024.

Abstract

There is an urgent need for alternative therapies targeting human dendritic cells (DCs) that could reverse inflammatory syndromes in many autoimmune and inflammatory diseases and organ transplantations. Here, we describe a bispecific antibody (bsAb) strategy tethering two pathogen-recognition receptors at the surface of human DCs. This cross-linking switches DCs into a tolerant profile able to induce regulatory T-cell differentiation. The bsAbs, not parental Abs, induced interleukin 10 and transforming growth factor β1 secretion in monocyte-derived DCs and human peripheral blood mononuclear cells. In addition, they induced interleukin 10 secretion by synovial fluid cells in rheumatoid arthritis and gout patients. This concept of bsAb-induced tethering of surface pathogen-recognition receptors switching cell properties opens a new therapeutic avenue for controlling inflammation and restoring immune tolerance.

Keywords: TGF-β1; TLR2; bispecific antibody; human dendritic cell; innate receptors; interleukine-10; tolerant dendritic cell; type C lectin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Bispecific* / metabolism
  • Antibodies, Bispecific* / pharmacology
  • Dendritic Cells
  • Humans
  • Interleukin-10 / metabolism
  • Leukocytes, Mononuclear
  • T-Lymphocytes, Regulatory*

Substances

  • Interleukin-10
  • Antibodies, Bispecific

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This research was funded by the French Higher Education and Research Ministry under the “Investissements d’Avenir” grant program (LabEx MAbImprove ANR-10-LABX-53-01), a regional grant from “Centre val de Loire” APR-IA-2013 “Tol-DC&AcTh”, and the program ARD2020 “Biomédicaments” (Project BIO-S). LL was a PhD fellow (2014–2018) supported by the Centre-Val de Loire regional authorities and the Labex MabImprove. ND-K was recruited under the Centre-Val de Loire ANRT CIFRE by the EFS-CA program for her PhD (2015–2019). FV-R was supported by grants from the EU COST BM1406 program between 2015 and 2019.