Classical Complement Pathway Inhibition in a “Human‐On‐A‐Chip” Model of Autoimmune Demyelinating Neuropathies

• Published in: Advanced therapeutics Vol. 5; no. 6
• Main Authors: Rumsey, John W., Lorance, Case, Jackson, Max, Sasserath, Trevor, McAleer, Christopher W., Long, Christopher J., Goswami, Arindom, Russo, Melissa A., Raja, Shruti M., Gable, Karissa L., Emmett, Doug, Hobson‐Webb, Lisa D., Chopra, Manisha, Howard, James F., Guptill, Jeffrey T., Storek, Michael J., Alonso‐Alonso, Miguel, Atassi, Nazem, Panicker, Sandip, Parry, Graham, Hammond, Timothy, Hickman, James J.
• Format: Journal Article
• Language: English
• Published: Germany 01.06.2022
• Subjects: autoimmune demyelinating neuropathies; complement inhibition; drug efficacy; human‐on‐a‐chip; rare diseases; drug efficacy; human-on-a-chip; autoimmune demyelinating neuropathies; complement inhibition; Rare disease
• ISSN: 2366-3987; 2366-3987
• DOI: 10.1002/adtp.202200030

Chronic autoimmune demyelinating neuropathies are a group of rare neuromuscular disorders with complex, poorly characterized etiology. Here the authors describe a phenotypic, human‐on‐a‐chip (HoaC) electrical conduction model of two rare autoimmune demyelinating neuropathies, chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN), and explore the efficacy of TNT005, a monoclonal antibody inhibitor of the classical complement pathway. Patient sera is shown to contain anti‐GM1 IgM and IgG antibodies capable of binding to human primary Schwann cells and induced pluripotent stem cell‐derived motoneurons (MNs). Patient autoantibody binding is sufficient to activate the classical complement pathway, resulting in detection of C3b and C5b‐9. A HoaC model, using a microelectrode array with directed axonal outgrowth over the electrodes treated with patient sera, exhibits reductions in MN action potential frequency and conduction velocity. TNT005 rescued the serum‐induced complement deposition and functional deficits while treatment with an isotype control antibody has no rescue effect. These data indicate that complement activation by CIDP and MMN patient serum is sufficient to mimic neurophysiological features of each disease and that complement inhibition with TNT005 is sufficient to rescue these pathological effects and provide efficacy data included in an investigational new drug application, demonstrating the model's translational potential. This manuscript presents a novel in vitro human‐on‐a‐chip system to 1) investigate multifocal motor neuropathy and chronic inflammatory demyelinating polyneuropathy patient sera‐mediated changes in peripheral motoneuron conduction velocity due to complement deposition. 2) A novel C1s inhibitor's ability to prevent complement deposition and reverse the conduction block. 3) An IND to the FDA is filed utilizing these results, which led to an authorization of a clinical trial.