Bifunctional self-assembling peptides for selective inhibition of neuro-inflammatory autoantibodies in multiple sclerosis

Overview

Current multiple sclerosis (MS) therapeutics broadly deplete or sequester peripheral T- and/or B-cell populations, which inherently carry risks of opportunistic infections and off-target effects. This proposal introduces a bifunctional self-assembling peptide (SAP) platform that selectively targets and inhibits MS-specific autoantibodies rather than entire immune cell populations. By forming a physical molecular mask atop pathogenic autoantibodies, the peptides block antigen binding and downstream neuro-inflammatory cascades, potentially offering a more precise and safer therapeutic approach for MS and related autoimmune conditions.

Technical specifications

Core technology — Self-Assembling Peptides (SAPs):

• Each SAP incorporates a targeting domain fused to a self-assembling domain that spontaneously assembles into a β-sheet nanofiber in situ.
• The targeting domain is an immunogenic peptide (e.g., MBP83-99) designed to bind the autoantibody's antigen-binding pocket.
• Adjacent SAP domains co-assemble into a multi-dimeric "molecular mask" over the autoantibody, physically hindering its ability to engage antigen.

Proof-of-concept validation:

• In vitro model using a monoclonal IgG with a documented MBP82-87 epitope (model autoantibody) co-incubated with a non-immunogenic internal control IgG (anti-MBP150-304), in the presence or absence of SAP-MBP83-99.
• Western blot detection of MBP in brain lysate showed dose-dependent inhibition of the immunogenic antibody's antigen detection, while the non-immunogenic antibody's detection remained unaffected.

Planned characterization and in vivo validation:

• Aim 1 — Characterization: Purity (LC/MS), secondary structure (circular dichroism, FTIR), fibril formation (AFM, TEM), cytocompatibility, stability (4–25°C over 3 months), and IC50 determination.
• Aim 2 — In vivo efficacy and derisking: Subcutaneous administration in the MBP83-99-EAE mouse model, with assessment of pathology (tail paresis, motor deficit), biocompatibility and tolerable dose (10×, 100×, 1000× IC50), pharmacokinetics, and organ distribution.
• Aim 3 — Epitope spreading: Evaluation of SAP-MBP83-99 combined with SAP-PLP1139-151 to prevent documented epitope spreading in MBP-EAE and PLP178-191-EAE models beyond day 16.

Technology readiness level

The technology is at an early preclinical stage (TRL 3). Proof-of-concept has been demonstrated in vitro, showing selective, dose-dependent inhibition of an MS-relevant autoantibody's antigen binding without affecting non-immunogenic control antibodies in the same preparation. The research team is now advancing toward comprehensive biophysical characterization, in vivo efficacy testing in established MS animal models, and evaluation of the platform's ability to address epitope spreading — a key driver of disease progression. Further development, including formal toxicology, formulation optimization, and IND-enabling studies, would be required before clinical translation.