{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T15:13:55Z","timestamp":1787238835325,"version":"build-2736575974"},"reference-count":26,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T00:00:00Z","timestamp":1761782400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"LAPIX Therapeutics Inc."}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background: Current disease-modifying therapies (DMTs) for multiple sclerosis (MS) attenuate pathogenic immune responses but are limited by safety and tolerability concerns. Antigen-specific tolerance approaches provide targeted immunomodulation yet remain constrained by their dependence on known autoantigens. LPX-TI641, an orally bioavailable, clinical-stage small-molecule agonist of Tim-3\/4, represents an antigen-independent strategy to restore immune tolerance by expanding regulatory T cells (Tregs). Methods: LPX-TI641 was evaluated in vitro for its ability to induce Treg populations in murine splenocytes. Therapeutic efficacy was assessed in vivo using MOG35\u201355- and PLP139\u2013151-induced experimental autoimmune encephalomyelitis (EAE) mouse models. Ex vivo, peripheral blood mononuclear cells (PBMCs) from people with MS (PwMS) were analyzed for Treg phenotype and function in response to LPX-TI641. Results: LPX-TI641 induced dose-dependent expansion of CD4+Foxp3+ and CD4+Foxp3+Tim-3+ Tregs in vitro. In EAE models, treatment significantly reduced disease severity, prevented relapses, and maintained clinical benefit after discontinuation. In PBMCs from patients with MS, LPX-TI641 restored diminished Tim-3+ Treg populations and reversed Treg dysfunction in recall assays. Efficacy in animal models was comparable to or exceeded that of high-efficacy DMTs, including natalizumab. Conclusions: LPX-TI641 promotes antigen-independent immune tolerance through Tim receptor agonism and Treg expansion. These findings support its potential as a novel therapeutic candidate for MS, addressing the limitations of current DMTs.<\/jats:p>","DOI":"10.3390\/pharmaceutics17111402","type":"journal-article","created":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T05:08:47Z","timestamp":1761800927000},"page":"1402","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["LPX-TI641, a Tim3\/4 Agonist, Induces Long-Term Immune Tolerance in Multiple Sclerosis Models"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1804-5840","authenticated-orcid":false,"given":"Anas M.","family":"Fathallah","sequence":"first","affiliation":[{"name":"LAPIX Therapeutics Inc., Cambridge, MA 021141, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdulraouf","family":"Ramadan","sequence":"additional","affiliation":[{"name":"LAPIX Therapeutics Inc., Cambridge, MA 021141, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Basel","family":"Karzoun","sequence":"additional","affiliation":[{"name":"LAPIX Therapeutics Inc., Cambridge, MA 021141, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Leahy","sequence":"additional","affiliation":[{"name":"LAPIX Therapeutics Inc., Cambridge, MA 021141, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nimita","family":"Dave","sequence":"additional","affiliation":[{"name":"LAPIX Therapeutics Inc., Cambridge, MA 021141, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5141-1510","authenticated-orcid":false,"given":"Raed","family":"Khashan","sequence":"additional","affiliation":[{"name":"Artelligence Therapeutics LLC, Philadelphia, PA 19114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saleh","family":"Allababidi","sequence":"additional","affiliation":[{"name":"LAPIX Therapeutics Inc., Cambridge, MA 021141, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiv","family":"Saidha","sequence":"additional","affiliation":[{"name":"Division of Neuroimmunology and Neurological Infections, Department of Neurology, Johns Hopkins University, Baltimore, MD 21218, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Madani","sequence":"additional","affiliation":[{"name":"LAPIX Therapeutics Inc., Cambridge, MA 021141, USA"},{"name":"Department of Neurology, Atrius Health, Boston, MA 02215, USA"},{"name":"Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1186\/s12974-017-0892-8","article-title":"Regulatory T cells in multiple sclerosis and myasthenia gravis","volume":"14","author":"Danikowski","year":"2017","journal-title":"J. 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