Anti-CD40L prevents meningeal B cell aggregates and mitigates progressive autoimmune encephalomyelitis

Product:

Mouse Panel 120

Topic:

Neurology

Disease Area:

Multiple Sclerosis (MS), Progressive Autoimmune Encephalomyelitis

Sample Type:

Mouse CSF, Serum-Mouse

Abstract

Compartmentalized inflammation within the CNS is considered to drive progressive immunopathology in multiple sclerosis (MS) independently of relapses. Meningeal tertiary lymphoid structures (TLS) represent an immune niche associated with histological signs of immunopathology, including demyelination in the adjacent CNS parenchyma.

Here, we show that the opticospinal encephalomyelitis (OSE) mouse model, in which meningeal TLS develop spontaneously based on the interaction of myelin oligodendrocyte glycoprotein (MOG)-specific T cell receptor (TCR) transgenic T cells with MOG B cell receptor (BCR) transgenic B cells, recapitulates the dynamics and the histological features of meningeal TLS observed in human MS. Based on scRNAseq datasets of meningeal TLS from OSE mice, the CD40L-CD40 pathway is highly active in the T cell-B cell interaction in this niche. Accordingly, a monoclonal antibody to CD40L, applied systemically, abrogates the T-B interaction in the systemic compartment and even more so in the meningeal compartment. This leads to near-complete clearance of meningeal TLS, concomitant with clinical improvement of the progressive disease phase of OSE mice. In contrast, systemic B cell depletion with a monoclonal antibody to CD20 does not improve signs of progressive disease in the OSE model. Treatment with anti-CD40L is more effective in disrupting T-B interaction, the more the T-B interaction relies on the CD40L-CD40 pathway, and thus leads to a “semi-selective” targeting of meningeal TLS. In addition, not only B cells but the entire antigen-presenting compartment in the CNS is remodeled in the absence of CD40 engagement. Since these effects persist even after withdrawal of anti-CD40L treatment, no rebound episodes or resumption of progression are observed.In conclusion, anti-CD40L treatment may be an effective intervention to mitigate progressive immunopathology associated with meningeal TLS. Beyond B cells, anti-CD40L treatment also modulates and likely silences other CD40-dependent antigen-presenting cells in the CNS, including myeloid cells and astrocyte subsets.

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Authors and Affiliations

Sofia Tyystjärvi¹, Diego E. Ruiz Navarro¹, Leni-Mihaela Kulisch¹, Annika H. Hartmann¹, Christopher Sie¹, Monika Schmidt¹, Hsin-Hsiang Chen¹, Andreas Muschaweckh¹, Sylvia Heink¹, Lisa C. Richter¹, Lea Seeholzer¹, Katja Steiger², Sudhakar Reddy Kalluri³, Sean K. Ryan⁴, Gregory S. Wirak⁴, Dimitry Ofengeim⁴, Ali Maisam Afzali¹,³, and Thomas Korn¹,³,⁵

¹ Institute for Experimental Neuroimmunology, Technical University of Munich School of Medicine and Health, 81675 Munich, Germany
² Institute of Pathology, Technical University of Munich, 81675 Munich, Germany
³ Department of Neurology, Technical University of Munich School of Medicine and Health, 81675 Munich, Germany
⁴ Sanofi, Cambridge, MA 02141, USA
⁵ Munich Cluster for Systems Neurology, 81377 Munich, Germany

Steve Williams, MD, PhD

CSO

Dr. Willams serves as the company’s Chief Scientific Officer. He was previously Chief Medical Officer at Standard Biotools and at SomaLogic where he pioneered the discipline for discovery and validation of predictive, diagnostic and prognostic models using machine-learning applied to large-plex proteomics. 20 such tests were used for drug characterization, safety and efficacy when incorporated in clinical drug trials at Pharma/Biotech and 17 different multivariate tests were validated and translated into regulated healthcare uses. Prior to SomaLogic, Dr. Williams was at Pfizer in the UK and the USA as a clinical triallist in Translational Medicine, and subsequently as VP, Global Clinical Technology. He sat on the National Advisory Council for the National Institute of Biomedical Imaging and Bioengineering, the Executive Committee for the FNIH Biomarkers Consortium, and worked with FDA and PhRMA on developing evidentiary standards for biomarker qualification. Dr. William’s medical training was in London, at Charing Cross and Westminster Medical School, followed by a PhD in medicine/physiology at the same institution and training in Radiology at the University of Newcastle Upon Tyne. Steve is co-inventor on 26 proteomics patents and author/coauthor on multiple foundational proteomics manuscripts.

Justin McAnear

CFO

Mr. McAnear serves as the company’s Chief Financial Officer. He brings over 25 years of operational and financial leadership experience across various sectors and was instrumental in taking 10x Genomics public in 2019, serving as its CFO for over five years. Mr. McAnear served for over 3 years as Tesla’s VP of Worldwide Finance and Operations, supporting landmark initiatives such as the Model X and Model 3 launches and Solar City acquisition. He also held various roles at Apple and J&J earlier in his career and served as a naval officer and aviator for over 9 years.