Division of Medical Genetics, Department of Pediatrics, Duke University Health System, Durham, NC, USA.
Division of Biologics Review and Research 3, Office of Biotechnology Products, Center for Drug Evaluation and Research, US FDA, Bethesda, MD, USA.
Clin Immunol. 2020 Oct;219:108541. doi: 10.1016/j.clim.2020.108541. Epub 2020 Jul 15.
Immune modulation with rituximab, methotrexate, and intravenous immunoglobulin (IVIG) has shown great success in inducing immune tolerance in a large cohort of enzyme replacement therapy (ERT)-naïve infantile Pompe disease patients. Antibody-dependent cellular cytotoxicity, the principal mechanism by which rituximab depletes B-cells, requires CD20 binding by Fab'2 of rituximab on B-cells and the concomitant binding of its Fc region to Fc receptors on effector cells or to complement. To protect patients against microbial infections when using rituximab, IVIG was added to the immunomodulation regimen used in Pompe disease. Administration of IVIG can saturate neonatal Fc receptors (FcRn), which recycle endogenous as well as administered polyclonal/monoclonal antibodies via the binding of the Fc moiety to FcRn. As such, the administration of IVIG prior to rituximab, a chimeric mouse-human monoclonal antibody, may sharply reduce the half-life of rituximab and in turn, its efficacy. Based on this understanding, it is vital to understand the optimal timing of IVIG administration in relation to rituximab administration for the purposes of inducing immune tolerance.
利妥昔单抗、甲氨蝶呤和静脉注射免疫球蛋白 (IVIG) 的免疫调节已在一大群未经酶替代治疗 (ERT) 的婴儿庞贝病患者中成功诱导免疫耐受。抗体依赖性细胞细胞毒性是利妥昔单抗消耗 B 细胞的主要机制，需要利妥昔单抗 Fab'2 上的 CD20 与 B 细胞结合，同时其 Fc 区与效应细胞上的 Fc 受体或补体结合。为了在使用利妥昔单抗时保护患者免受微生物感染，在庞贝病中使用的免疫调节方案中添加了 IVIG。IVIG 的给药可以饱和新生儿 Fc 受体 (FcRn)，该受体通过 Fc 部分与 FcRn 的结合来循环内源性和给予的多克隆/单克隆抗体。因此，在给予嵌合鼠 - 人单克隆抗体利妥昔单抗之前给予 IVIG 可能会大大缩短利妥昔单抗的半衰期，从而降低其疗效。基于这种理解，了解 IVIG 给药与利妥昔单抗给药之间的最佳时间对于诱导免疫耐受至关重要。
