Karzoun Basel, Ramadan Abdulraouf, Allababidi Saleh, Fathallah Anas M
LAPIX Therapeutics Inc., Cambridge, MA 02141, USA.
Int J Mol Sci. 2025 Jun 10;26(12):5531. doi: 10.3390/ijms26125531.
Autoimmune diseases such as multiple sclerosis (MS) are characterized by a loss of self-tolerance, driven by diminished regulatory T cell (Treg) function and elevated Th1/Th17 responses. Existing therapies broadly suppress the immune system without correcting this imbalance, often leading to adverse effects. LPX3, a novel small-molecule T cell immunoglobulin and mucin domain-containing 3 and 4 (Tim-3/4) receptor agonist, was developed to restore immune tolerance via Treg induction. In this study, LPX3 was formulated into a liposomal oral delivery system, enabling efficient uptake through the gastrointestinal tract and lymphatic targeting. In vitro and in vivo analyses confirmed LPX3's ability to expand CD4Foxp3 Tregs in a dose-dependent manner. In a MOG-induced experimental autoimmune encephalomyelitis (EAE) mouse model of MS, both prophylactic and therapeutic oral administration of LPX3 significantly delayed disease onset, reduced symptom severity, and improved survival. Importantly, efficacy was achieved without antigen co-delivery, indicating an antigen-independent mechanism of immune modulation. LPX3 liposomes showed deep lymph node penetration and colocalization with immune cells, supporting its functional delivery to key immunological sites. These findings suggest LPX3 is a promising candidate for treating autoimmune diseases by re-establishing immune regulation through oral, antigen-agnostic tolerance induction.
自身免疫性疾病，如多发性硬化症（MS），其特征是自身耐受性丧失，这是由调节性T细胞（Treg）功能减弱和Th1/Th17反应增强所驱动的。现有的治疗方法广泛抑制免疫系统，但并未纠正这种失衡，常常导致不良反应。LPX3是一种新型小分子T细胞免疫球蛋白和含粘蛋白结构域3和4（Tim-3/4）受体激动剂，旨在通过诱导Treg来恢复免疫耐受性。在本研究中，LPX3被制成脂质体口服给药系统，能够通过胃肠道有效摄取并靶向淋巴系统。体外和体内分析证实LPX3能够以剂量依赖的方式扩增CD4Foxp3 Treg。在MS的髓鞘少突胶质细胞糖蛋白（MOG）诱导的实验性自身免疫性脑脊髓炎（EAE）小鼠模型中，预防性和治疗性口服LPX3均显著延迟疾病发作，减轻症状严重程度，并提高生存率。重要的是，在不共递送抗原的情况下实现了疗效，表明其免疫调节机制不依赖抗原。LPX3脂质体显示出深入淋巴结渗透并与免疫细胞共定位，支持其向关键免疫部位的功能性递送。这些发现表明，LPX3是通过口服、不依赖抗原的耐受性诱导来重建免疫调节从而治疗自身免疫性疾病的有前景的候选药物。
