Ilya Pharma AB, Uppsala, Sweden.
Division of Integrative Physiology, Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
Am J Physiol Gastrointest Liver Physiol. 2024 Aug 1;327(2):G140-G153. doi: 10.1152/ajpgi.00022.2024. Epub 2024 May 23.
Treatments of colitis, inflammation of the intestine, rely on induction of immune suppression associated with systemic adverse events, including recurrent infections. This treatment strategy is specifically problematic in the increasing population of patients with cancer with immune checkpoint inhibitor (ICI)-induced colitis, as immune suppression also interferes with the ICI-treatment response. Thus, there is a need for local-acting treatments that reduce inflammation and enhance intestinal healing. Here, we investigated the effect and safety of bacterial delivery of short-lived immunomodulating chemokines to the inflamed intestine in mice with colitis. Colitis was induced by dextran sulfate sodium (DSS) alone or in combination with ICI (anti-PD1 and anti-CTLA-4), and R2LC ( R2LC) genetically modified to express the chemokine CXCL12-1α (R2LC_CXCL12, emilimogene sigulactibac) was given perorally. In addition, the pharmacology and safety of the formulated drug candidate, ILP100-Oral, were evaluated in rabbits. Peroral CXCL12-producing R2LC significantly improved colitis symptoms already after 2 days in mice with overt DSS and ICI-induced colitis, which in benchmarking experiments was demonstrated to be superior to treatments with anti-TNF-α, anti-α4β7, and corticosteroids. The mechanism of action involved chemokine delivery to Peyer's patches (PPs), confirmed by local CXCR4 signaling, and increased numbers of colonic, regulatory immune cells expressing IL-10 and TGF-β1. No systemic exposure or engraftment could be detected in mice, and product feasibility, pharmacology, and safety were confirmed in rabbits. In conclusion, peroral CXCL12-producing R2LC efficiently ameliorates colitis, enhances mucosal healing, and has a favorable safety profile. Colitis symptoms are efficiently reduced by peroral administration of probiotic bacteria genetically modified to deliver CXCL12 locally to the inflamed intestine in several mouse models.
结肠炎（肠道炎症）的治疗方法依赖于诱导与全身不良事件相关的免疫抑制，包括反复感染。在越来越多的接受免疫检查点抑制剂（ICI）诱导结肠炎治疗的癌症患者中，这种治疗策略特别成问题，因为免疫抑制也会干扰 ICI 治疗反应。因此，需要局部作用的治疗方法来减轻炎症并促进肠道愈合。在这里，我们研究了将短寿命免疫调节趋化因子递送到结肠炎小鼠炎症肠道中的细菌传递对治疗的效果和安全性。单独使用葡聚糖硫酸钠（DSS）或与 ICI（抗 PD1 和抗 CTLA-4）联合诱导结肠炎，并用经遗传修饰表达趋化因子 CXCL12-1α 的 R2LC（R2LC_CXCL12， Emilimogene Sigulactibac）经口给予。此外，还在兔子中评估了配方候选药物 ILP100-Oral 的药理学和安全性。在明显的 DSS 和 ICI 诱导结肠炎的小鼠中，经口给予产生 CXCL12 的 R2LC 可显著改善结肠炎症状，在基准实验中，其效果优于抗 TNF-α、抗 α4β7 和皮质类固醇的治疗效果。作用机制涉及趋化因子递送至派尔集合淋巴结（PPs），通过局部 CXCR4 信号得到证实，并且表达 IL-10 和 TGF-β1 的结肠、调节性免疫细胞数量增加。在小鼠中未检测到系统暴露或移植，在兔子中证实了产品可行性、药理学和安全性。总之，经口给予产生 CXCL12 的 R2LC 可有效改善结肠炎，增强黏膜愈合，具有良好的安全性。通过向几种小鼠模型中经口给予遗传修饰以局部递送至炎症肠道的产生 CXCL12 的益生菌，可有效减轻结肠炎症状。
