Objective: LYS241, a first-in-class, humanized, and optimized monoclonal antibody, designed to inhibit the interaction between tissue plasminogen activator (tPA) and N-methyl-D-aspartate receptor (NMDAr), has demonstrated therapeutic potential across multiple neurological disease models. tPA plays a key role in brain function in both health and disease, with growing evidence implicating it in Parkinson’s disease (PD) pathophysiology. In this study, we investigated the effects of LYS241 and its murinized version, mLYS241, in in vitro and in vivo rodent models of multiple system atrophy (MSA), a rapidly progressive neurodegenerative synucleinopathy.

Background: In an AAV-human α-synuclein (hα-syn) mouse model of PD, both genetic tPA deficiency and repeated intravenous administration of glunomab, the murine parental antibody of LYS241, even at a late disease stage, prevents tPA-induced neuroinflammation and dopaminergic neurodegeneration, resulting in improved sensorimotor function. These data highlight the role of the tPA-NMDAr pathway in PD pathology and more broadly in alpha-synucleinopathies, supporting its potential as a novel therapeutic strategy to slow disease progression.

Method: The dose-response effects of LYS241 were evaluated in an in vitro model of MSA using rotenone-induced injury in central neurons & oligodendrocytes (OLs). In vivo, two-month-old male and female proteolipid protein (PLP)-hα-syn transgenic mice received weekly intraperitoneal injections of mLYS241 or vehicle for five months, while vehicle-treated wild-type mice served as controls. Motor function was assessed with challenging beam and notched bar tests. Immunohistochemistry was used to analyze the tPA expression, α-syn-positive inclusions and blood brain barrier (BBB) disruption, and circulating biomarkers were also measured.

Results: In an in vitro model of MSA, LYS241 pre-treatment dose dependently protected OLs and prevented α-syn aggregation. In vivo, PLP-hα-syn mice treated with mLYS241 for five months exhibited motor performance comparable to healthy controls. tPA expression, α-syn inclusions, BBB integrity, and plasma biomarkers were also evaluated.

Conclusion: LYS241 is a novel disease-modifying therapeutic candidate targeting synucleinopathies, including PD and MSA. The program is currently advancing through IND/CTA-enabling studies in preparation for first-in-human clinical trials.

References: The interaction of tPA with NMDAR1 drives neuroinflammation and neurodegeneration in α-synuclein-mediated neurotoxicity.
Torrente D, Su EJ, Citalán-Madrid AF, Schielke GP, Magaoay D, Warnock M, Stevenson T, Mann K, Lesept F, Delétage N, Blanc M, Norris EH, Vivien D, Lawrence DA.
J Neuroinflammation. 2025 Jan 14;22(1):8. doi: 10.1186/s12974-025-03336-3.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-novel-therapeutic-targeting-the-tpa-nmdar-interaction-for-multiple-system-atrophy/