Abatacept
(Synonyms: CTLA4lg; BMS-188667) 目录号 : GC38130
Abatacept (CTLA4lg) 是一种可溶性融合蛋白，由人 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。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。
Cas No.:332348-12-6
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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Purity: >95.00%
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Abatacept (CTLA4lg) is a soluble fusion protein consisting of the extra-cellular domain of human CTLA4 and a fragment of the Fc portion of human IgG1 (hinge and CH2 and 3 domains)[1]. Abatacept is a selective T-cell co-stimulation modulator and a protein drug for the treatment of autoimmune diseases[2].
Abatacept reduces paw edema, and the SC Multiple-dose group shows significantly greater (tobs = 2.50) paw edema reduction compared with the IV dose group[2]. Abatacept exhibits linear PK across the studied doses. The NCA clearance (CL) is 20.8 mL/day/kg, volume (Vss) is 146 mL/kg, and bioavailability (F) of the SC dose dosing is 57.7%[2]. Abatacept (oral; 10 mg/kg; every 2 days) reduces the proportion of activated T cells (CD44highCD62L-) and inhibits the up-regulation of ICOS and CD71 in homozygous DO11.10 RAG-2-/- BALB/c (H-2d/d) mice[3]. Animal Model: Male Lewis rats (6-9 weeks old) with weights of 150-175 g[2]
[1]. Kiykim A, et al. Abatacept as a Long-Term Targeted Therapy for LRBA Deficiency. J Allergy Clin Immunol Pract. 2019 Jun 22. [2]. Lon HK, et al. Modeling pharmacokinetics/pharmacodynamics of abatacept and disease progression in collagen-induced arthritic rats: a population approach. J Pharmacokinet Pharmacodyn. 2013 Dec;40(6):701-12. [3]. Patakas A, 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. Arthritis Rheumatol. 2016 Mar;68(3):627-38.
| Cas No. | 332348-12-6 | SDF | |
| 别名 | CTLA4lg; BMS-188667 | ||
| Canonical SMILES | [Abatacept] | ||
| 分子式 | 分子量 | ||
| 溶解度 | Soluble in water | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
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工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Trial of Upadacitinib or Abatacept in Rheumatoid Arthritis
N Engl J Med 2020 Oct 15;383(16):1511-1521.PMID:33053283DOI:10.1056/NEJMoa2008250.
Background: Upadacitinib is an oral selective Janus kinase inhibitor to treat rheumatoid arthritis. The efficacy and safety of upadacitinib as compared with Abatacept, a T-cell costimulation modulator, in patients with rheumatoid arthritis refractory to biologic disease-modifying antirheumatic drugs (DMARDs) are unclear. Methods: In this 24-week, phase 3, double-blind, controlled trial, we randomly assigned patients in a 1:1 ratio to receive oral upadacitinib (15 mg once daily) or intravenous Abatacept, each in combination with stable synthetic DMARDs. The primary end point was the change from baseline in the composite Disease Activity Score for 28 joints based on the C-reactive protein level (DAS28-CRP; range, 0 to 9.4, with higher scores indicating more disease activity) at week 12, assessed for noninferiority. Key secondary end points at week 12 were the superiority of upadacitinib over Abatacept in the change from baseline in the DAS28-CRP and the percentage of patients having clinical remission according to a DAS28-CRP of less than 2.6. Results: A total of 303 patients received upadacitinib, and 309 patients received Abatacept. From baseline DAS28-CRP values of 5.70 in the upadacitinib group and 5.88 in the Abatacept group, the mean change at week 12 was -2.52 and -2.00, respectively (difference, -0.52 points; 95% confidence interval [CI], -0.69 to -0.35; P<0.001 for noninferiority; P<0.001 for superiority). The percentage of patients having remission was 30.0% with upadacitinib and 13.3% with Abatacept (difference, 16.8 percentage points; 95% CI, 10.4 to 23.2; P<0.001 for superiority). During the treatment period, one death, one nonfatal stroke, and two venous thromboembolic events occurred in the upadacitinib group, and more patients in the upadacitinib group than in the Abatacept group had elevated hepatic aminotransferase levels. Conclusions: In patients with rheumatoid arthritis refractory to biologic DMARDs, upadacitinib was superior to Abatacept in the change from baseline in the DAS28-CRP and the achievement of remission at week 12 but was associated with more serious adverse events. Longer and larger trials are required in order to determine the effect and safety of upadacitinib in patients with rheumatoid arthritis. (Funded by AbbVie; SELECT-CHOICE Clinicaltrials.gov number, NCT03086343.).
Abatacept: A Review in Rheumatoid Arthritis
Drugs 2017 Jul;77(11):1221-1233.PMID:28608166DOI:10.1007/s40265-017-0775-4.
The biological DMARD (bDMARD) Abatacept (Orencia®), a recombinant fusion protein, selectively modulates a co-stimulatory signal necessary for T-cell activation. In the EU, Abatacept is approved for use in patients with highly active and progressive rheumatoid arthritis (RA) not previously treated with methotrexate. Abatacept is also approved for the treatment of moderate to severe active RA in patients with an inadequate response to previous therapy with at least one conventional DMARD (cDMARD), including methotrexate or a TNF inhibitor. In phase III trials, beneficial effects on RA signs and symptoms, disease activity, structural damage progression and physical function were seen with intravenous (IV) or subcutaneous (SC) Abatacept regimens, including Abatacept plus methotrexate in methotrexate-naive patients with early RA and poor prognostic factors, and Abatacept plus methotrexate or other cDMARDs in patients with inadequate response to methotrexate or TNF inhibitors. Benefits were generally maintained during longer-term follow-up. Absolute drug-free remission rates following withdrawal of all RA treatments were significantly higher with Abatacept plus methotrexate than with methotrexate alone. Both IV and SC Abatacept were generally well tolerated, with low rates of immunogenicity. Current evidence therefore suggests that Abatacept is a useful treatment option for patients with RA.
Abatacept for the treatment of rheumatoid arthritis
Expert Rev Clin Immunol 2019 Apr;15(4):319-326.PMID:30730220DOI:10.1080/1744666X.2019.1579642.
Rheumatoid arthritis (RA) is a complex disease in which different mechanisms are involved. Studies suggest a key role for aberrant pathways of T-cell activation in the initiation and perpetuation of disease. Abatacept is a fusion protein composed of the Fc region of the immunoglobulin G1 (IgG1) fused to the extracellular domain of cytotoxic T lymphocyte-associated antigen (CTLA4). It has the ability to modulate T-cell activation by interfering with co-stimulation of these cells, a necessary step to become activated. This suggests that Abatacept may play a role in the progression and/or even the initiation of RA. Areas covered: a review of the different studies carried out during clinical development of Abatacept was performed. Both formulations, intravenous (IV) and subcutaneous (SC), showed a similar and consistent efficacy and safety profile. Abatacept was effective both in RA patients not responding to methotrexate (MTX) and to tumor necrosis factor (TNF) inhibitors. Expert commentary: Abatacept, with its unique mechanism of action, proved to be a useful therapeutic alternative in RA, also having an acceptable safety profile. Evidence points out that Abatacept may be able to alter the RA disease course. Ongoing studies will clarify this issue.
Phase II Trial of Costimulation Blockade With Abatacept for Prevention of Acute GVHD
J Clin Oncol 2021 Jun 10;39(17):1865-1877.PMID:33449816DOI:10.1200/JCO.20.01086.
Purpose: Severe (grade 3-4) acute graft-versus-host disease (AGVHD) is a major cause of death after unrelated-donor (URD) hematopoietic cell transplant (HCT), resulting in particularly high mortality after HLA-mismatched transplantation. There are no approved agents for AGVHD prevention, underscoring the critical unmet need for novel therapeutics. ABA2 was a phase II trial to rigorously assess safety, efficacy, and immunologic effects of adding T-cell costimulation blockade with Abatacept to calcineurin inhibitor (CNI)/methotrexate (MTX)-based GVHD prophylaxis, to test whether Abatacept could decrease AGVHD. Methods: ABA2 enrolled adults and children with hematologic malignancies under two strata: a randomized, double-blind, placebo-controlled stratum (8/8-HLA-matched URD), comparing CNI/MTX plus Abatacept with CNI/MTX plus placebo, and a single-arm stratum (7/8-HLA-mismatched URD) comparing CNI/MTX plus Abatacept versus CNI/MTX CIBMTR controls. The primary end point was day +100 grade 3-4 AGVHD, with day +180 severe-AGVHD-free-survival (SGFS) a key secondary end point. Sample sizes were calculated using a higher type-1 error (0.2) as recommended for phase II trials, and were based on predicting that Abatacept would reduce grade 3-4 AGVHD from 20% to 10% (8/8s) and 30% to 10% (7/8s). ABA2 enrolled 142 recipients (8/8s, median follow-up = 716 days) and 43 recipients (7/8s, median follow-up = 708 days). Results: In 8/8s, grade 3-4 AGVHD was 6.8% (Abatacept) versus 14.8% (placebo) (P = .13, hazard ratio = 0.45). SGFS was 93.2% (CNI/MTX plus Abatacept) versus 82% (CNI/MTX plus placebo, P = .05). In the smaller 7/8 cohort, grade 3-4 AGVHD was 2.3% (CNI/MTX plus Abatacept, intention-to-treat population), which compared favorably with a nonrandomized matched cohort of CNI/MTX (30.2%, P < .001), and the SGFS was better (97.7% v 58.7%, P < .001). Immunologic analysis revealed control of T-cell activation in abatacept-treated patients. Conclusion: Adding Abatacept to URD HCT was safe, reduced AGVHD, and improved SGFS. These results suggest that Abatacept may substantially improve AGVHD-related transplant outcomes, with a particularly beneficial impact on HLA-mismatched HCT.
[Abatacept]
Nihon Rinsho 2016 Jun;74(6):968-73.PMID:27311187doi
Abatacept (ABT) is a recombinant fusion protein comprising the extracellular domain of human CTLA4, which inhibits the activation of T cells. Several clinical trials have provided evidence of efficacy and safety of ABT in the patients with rheumatoid athritis (RA) with various clinical characteristics such as MTX inadequate responders (IR), TNF inhibitor-IR. Moreover, indirect comparison of ABT to other biologics reported in Cochrane review revealed that ABT has better safety profile in serious adverse events and serious infection Thus the features of ABT in the treatment of RA have gradually become apparent and knowledge of these features is helpful for better use of biologics. In this review we will discuss the efficacy and safety of ABT in the management of RA.