Abatacept (CTLA4Ig) is a soluble fusion protein composed of the extracellular domain of human cytotoxic T lymphocyte-associated protein 4 (CTLA4) and a fragment of the human IgG1 Fc portion (hinge, CH2 and 3 domains)[1]. Abatacept is a selective T cell co-stimulatory modulator and a protein drug used to treat autoimmune diseases[2]. CTLA4 is structurally similar to CD28, but binds to CD80 and CD86 with higher affinity, thereby inhibiting T cell activation[3]. Abatacept can be used to treat moderate to severe rheumatoid arthritis (RA), and is also used to treat psoriatic arthritis and juvenile idiopathic arthritis[4].
In vitro, Abatacept (0.5, 5, 50μM) treatment of human Burkitt lymphoma B (BJAB) wild-type, CD80 KO, and CD86 KO cells for 2h reduced the expression of CD86 and CD80 on the cell surface[5].
In vivo, subcutaneous administration of Abatacept (10mg/kg, once every 2 days) to DO11.10 RAG-2–/– mice inhibited T cell activation in the draining lymph nodes of mice, but did not induce T cell anergy or the generation of Treg cells[6]. Subcutaneous administration of Abatacept (20mg/kg) to rats with collagen-induced arthritis (CIA) significantly reduced paw edema[7].
References:
[1] Douthwaite J, Moisan J, Privezentzev C, et al. A CD80-biased CTLA4-Ig fusion protein with superior in vivo efficacy by simultaneous engineering of affinity, selectivity, stability, and FcRn binding[J]. The Journal of Immunology, 2017, 198(1): 528-537.
[2] Chitale S, Moots R. Abatacept: the first T lymphocyte co-stimulation modulator, for the treatment of rheumatoid arthritis[J]. Expert opinion on biological therapy, 2008, 8(1): 115-122.
[3] da Rosa L C, Scales H E, Benson R A, et al. The effect of abatacept on T-cell activation is not long-lived in vivo[J]. Discovery Immunology, 2024, 3(1): kyad029.
[4] Brunner H I, Wong R, Nys M, et al. Abatacept: a review of the treatment of polyarticular-course juvenile idiopathic arthritis[J]. Pediatric Drugs, 2020, 22: 653-672.
[5] Lorenzetti R, Janowska I, Smulski C R, et al. Abatacept modulates CD80 and CD86 expression and memory formation in human B-cells[J]. Journal of Autoimmunity, 2019, 101: 145-152.
[6] Patakas A, Ji R R, Weir W, et al. Abatacept inhibition of T cell priming in mice by induction of a unique transcriptional profile that reduces their ability to activate antigen‐presenting cells[J]. Arthritis & rheumatology, 2016, 68(3): 627-638.
[7] Lon H K, Liu D, DuBois D C, et al. Modeling pharmacokinetics/pharmacodynamics of abatacept and disease progression in collagen-induced arthritic rats: a population approach[J]. Journal of pharmacokinetics and pharmacodynamics, 2013, 40: 701-712.
Abatacept（CTLA4Ig）是一种可溶性融合蛋白，由人细胞毒性T淋巴细胞相关蛋白4（CTLA4）的胞外结构域和人IgG1 Fc部分的片段（铰链，CH2和3结构域）组成[1]。Abatacept是选择性T细胞共刺激调节剂，也是一种用于治疗自身免疫性疾病的蛋白药物[2]。CTLA4在结构上与CD28相似，但以更高的亲和力与CD80和CD86结合，从而抑制T细胞活化[3]。Abatacept能够用于治疗中度至重度类风湿性关节炎（RA），还用于治疗银屑病关节炎和幼年特发性关节炎[4]。
在体外，Abatacept（0.5, 5, 50μM）处理人类伯基特淋巴瘤B（BJAB）野生型、CD80 KO、CD86 KO细胞2h，减少了细胞表面CD86和CD80的表达[5]。
在体内，Abatacept（10mg/kg，2天一次）通过皮下注射处理DO11.10 RAG-2–/–小鼠，抑制了小鼠引流淋巴结的T细胞活化，但不会导致T细胞无能或导致Treg细胞的产生[6]。Abatacept（20mg/kg）通过皮下注射治疗胶原诱导性关节炎（CIA）大鼠，显著减轻了爪水肿[7]。