Hall Christopher, Pleasance Jill, Hickman Oliver, Kirkham Bruce, Panayi Gabriel S, Eggleton Paul, Corrigall Valerie M
Academic Department of Rheumatology, Centre for Inflammation Biology and Cancer Immunology (CIBCI), King's College London Faculty of Life Sciences and Medicine, Guy's Hospital Campus, London SE1 1UL, UK.
Revolo Biotherapeutics, London SE1 9AP, UK.
Int J Mol Sci. 2024 Apr 16;25(8):4394. doi: 10.3390/ijms25084394.
A homologue of binding immunoglobulin protein/BiP-IRL201805 alters the function of immune cells in pre-clinical in vivo and in vitro studies. The aim of the study was to select biomarkers that clearly delineate between RA patients who respond to IRL201805 and placebo patients and reveal the immunological mode of action of IRL201805 driving the extended pharmacodynamics observed in responding patients. Biomarkers that distinguished between responding patients and placebo patients included downregulation of serum interferon-γ and IL-1β; upregulation of anti-inflammatory mediators, serum soluble CTLA-4, and intracellular monocyte expression of IDO; and sustained increased CD39 expression on CD3CD4CD25 CD127 regulatory T cells. In the responding patients, selected biomarkers verified that the therapeutic effect could be continuous for at least 12 weeks post-infusion. In secondary co-culture, pre-infusion PBMCs cultured 1:1 with autologous PBMCs, isolated at later time-points during the trial, showed significantly inhibited IL-6 and IL-1β production upon anti-CD3/CD28 stimulation demonstrating IRL201805 alters the function of immune cells leading to prolonged pharmacodynamics confirmed by biomarker differences. IRL201805 may be the first of a new class of biologic drug providing long-term drug-free therapy in RA.
结合免疫球蛋白蛋白/ BiP-IRL201805的同源物在临床前体内和体外研究中改变免疫细胞功能。本研究的目的是选择能够清晰区分对IRL201805有反应的类风湿关节炎（RA）患者和接受安慰剂治疗患者的生物标志物，并揭示IRL201805的免疫作用模式，这种作用模式导致在有反应的患者中观察到药效动力学延长。区分有反应患者和安慰剂患者的生物标志物包括血清干扰素-γ和IL-1β下调；抗炎介质、血清可溶性细胞毒性T淋巴细胞相关抗原4（CTLA-4）以及吲哚胺2,3-双加氧酶（IDO）细胞内单核细胞表达上调；以及CD3CD4CD25 CD127调节性T细胞上CD39表达持续增加。在有反应的患者中，所选生物标志物证实治疗效果在输注后至少12周内可持续。在二次共培养中，输注前外周血单核细胞（PBMC）与在试验后期分离的自体PBMC按1:1培养，在抗CD3/CD28刺激下显示IL-6和IL-1β产生受到显著抑制，这表明IRL201805改变免疫细胞功能，导致药效动力学延长，这一点通过生物标志物差异得到证实。IRL201805可能是一类新型生物药物中的首个药物，可在类风湿关节炎中提供长期无药治疗。
