Adalimumab (Anti-Human TNF-alpha, Human Antibody)
(Synonyms: 阿达木单抗; Anti-Human TNF-alpha, Human Antibody) 目录号 : GC34214
阿达木单抗（Adalimumab 抗人TNFα，人抗体）是治疗类风湿关节炎的主要疗法之一。
Cas No.:331731-18-1
Sample solution is provided at 25 µL, 10mM.
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| Pharmacokinetic experiment [1]: | |
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Preparation Method |
Using double-antigen enzyme-linked immunosorbent TNF-¦Á Adalimumab -coated plates and their detection by peroxidase-conjugated IgG. |
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Reaction Conditions |
These patients received 40 mg adalimumab subcutaneously every other week combined with methotrexate and follow-up was done for 1 year. |
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Applications |
Thirty patients treated for RA were analysed. The following pharmacokinetic and PK-PD parameters were estimated (interidividual coefficient of variation): apparent volume of distribution (Vd /F) = 10.8 l (92%); apparent clearance (CL/F) = 0.32 l day(-1) (17%); first-order absorption rate (ka ) = 0.28 day(-1) ; CRP input (kin ) = 22.0 mg l(-1) day(-1) (65%); adalimumab concentration leading to a 50% decrease in kin (C50 ) = 3.6 mg l(-1) (88%); baseline DAS28 (DAS0 ) = 5.5 mg l(-1) (11%); and adalimumab concentration leading to 50% decrease of DAS0 (IC50 ) = 11.0 mg l(-1) (71%). Simulations showed that a 160 mg loading dose should reduce the time to reach efficacy in terms of both CRP and DAS28 after the first injection. |
| Cell experiment [2]: | |
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Cell lines |
THP-1 monocytes |
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Preparation Method |
CellTracker green-labelled THP-1 monocytes on a HUVECs monolayer after incubation with conditioned media from oxLDL-stimulated THP-1 macrophages (oxLDL CM) with or without adalimumab (ada) for 4 hours followed by the addition of CellTracker green-labelled THP-1 monocytes. |
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Reaction Conditions |
1 ¦̧/mL Adalimumab (Anti-Human TNF-alpha, Human Antibody) for 4 hours |
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Applications |
The TNF-¦Á inhibitor adalimumab suppresses adhesion of THP-1 monocytes to endothelial cells. |
| Animal experiment [3]: | |
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Animal models |
Rd10 mice |
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Preparation Method |
To evaluate the effect of Adalimumab (Anti-Human TNF-alpha, Human Antibody), each rd10 mouse received one intraperitoneal injection of Adalimumab (Anti-Human TNF-alpha, Human Antibody) aline solution at 3 mg/kg every three days starting at P9 and until P17. |
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Dosage form |
3 mg/kg Adalimumab (Anti-Human TNF-alpha, Human Antibody)every three days |
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Applications |
intraperitoneal administration of Adalimumab (Anti-Human TNF-alpha, Human Antibody) significantly decreased the number of TUNEL-positive cells in the ONL at P18 (2.7?¡À?0.4 TUNEL-positive cells) compared to vehicle-treated rd10 retinas (12.5?¡À?2.4 TUNEL-positive cells) |
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References: [1]. Ternant D, Ducourau E, et,al. Pharmacokinetics and concentration-effect relationship of adalimumab in rheumatoid arthritis. Br J Clin Pharmacol. 2015 Feb;79(2):286-97. doi: 10.1111/bcp.12509. PMID: 25223394; PMCID: PMC4309634. [2]. Oberoi R, Schuett J, et,al. Targeting Tumor Necrosis Factor-¦Á with Adalimumab: Effects on Endothelial Activation and Monocyte Adhesion. PLoS One. 2016 Jul 28;11(7):e0160145. doi: 10.1371/journal.pone.0160145. PMID: 27467817; PMCID: PMC4965117. [3].Mart¨ªnez-Fern¨¢ndez de la C¨¢mara C, Hern¨¢ndez-Pinto AM, et,al. Adalimumab Reduces Photoreceptor Cell Death in A Mouse Model of Retinal Degeneration. Sci Rep. 2015 Jul 14;5:11764. doi: 10.1038/srep11764. PMID: 26170250; PMCID: PMC4501000. |
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Adalimumab (Anti-Human TNF-alpha, Human Antibody) is one of the leading therapies for the treatment of rheumatoid arthritis. It is a humanized monoclonal antibody that binds to TNF-α and blocks its interaction with the TNF receptor [1]. It neutralizes both soluble as well as transmembrane TNF-α[2].
Adalimumab (Anti-Human TNF-alpha, Human Antibody) prevents major inflammatory effects of TNF-α on endothelial activation, endothelial monocyte adhesion, endothelial leakage[3].
Adalimumab (Anti-Human TNF-alpha, Human Antibody) prevented TNFα upregulation, reduced photoreceptor cell death, slowed microglial and MÜller cell activation, improved antioxidant response and ameliorated the energetic and metabolic dysfunction at P18[4]. VaD rats treated with Adalimumab (Anti-Human TNF-alpha, Human Antibody) exhibited significant improvements in memory. In addition, Adalimumab (Anti-Human TNF-alpha, Human Antibody) treatment significantly alleviated neuronal loss in the hippocampi of VaD rats[5]. The important role of TNF-α for atherosclerotic plaque development in experimental models is well documented, different TNF-α-deficient mice models consistently showed reduced plaque burden[6,7]. Adalimumab (Anti-Human TNF-alpha, Human Antibody) has demonstrated a good prognosis and improvement of physical function in rheumatoid arthritis [8].
References:
[1]. HÜrlimann D, Forster A, et,al. Anti-tumor necrosis factor-alpha treatment improves endothelial function in patients with rheumatoid arthritis. Circulation. 2002 Oct 22;106(17):2184-7. doi: 10.1161/01.cir.0000037521.71373.44. PMID: 12390945.
[2]. Ternant D, Ducourau E, et,al. Pharmacokinetics and concentration-effect relationship of adalimumab in rheumatoid arthritis. Br J Clin Pharmacol. 2015 Feb;79(2):286-97. doi: 10.1111/bcp.12509. PMID: 25223394; PMCID: PMC4309634.
[3]. Oberoi R, Schuett J, et,al. Targeting Tumor Necrosis Factor-α with Adalimumab: Effects on Endothelial Activation and Monocyte Adhesion. PLoS One. 2016 Jul 28;11(7):e0160145. doi: 10.1371/journal.pone.0160145. PMID: 27467817; PMCID: PMC4965117.
[4]. MartÍnez-FernÁndez de la CÁmara C, HernÁndez-Pinto AM, et,al. Adalimumab Reduces Photoreceptor Cell Death in A Mouse Model of Retinal Degeneration. Sci Rep. 2015 Jul 14;5:11764. doi: 10.1038/srep11764. PMID: 26170250; PMCID: PMC4501000.
[5]. Xu JJ, Guo S, et,al. Adalimumab ameliorates memory impairments and neuroinflammation in chronic cerebral hypoperfusion rats. Aging (Albany NY). 2021 May 24;13(10):14001-14014. doi: 10.18632/aging.203009. Epub 2021 May 24. PMID: 34030135; PMCID: PMC8202885.
[6]. BrÅnÉn L, Hovgaard L, et,al. Inhibition of tumor necrosis factor-alpha reduces atherosclerosis in apolipoprotein E knockout mice. Arterioscler Thromb Vasc Biol. 2004 Nov;24(11):2137-42. doi: 10.1161/01.ATV.0000143933.20616.1b. Epub 2004 Sep 2. PMID: 15345516.
[7]. Ohta H, Wada H, et,al. Disruption of tumor necrosis factor-alpha gene diminishes the development of atherosclerosis in ApoE-deficient mice. Atherosclerosis. 2005 May;180(1):11-7. doi: 10.1016/j.atherosclerosis.2004.11.016. Epub 2005 Jan 20. PMID: 15823270.
[8]. Toussirot E, Wendling D. The use of TNF-alpha blocking agents in rheumatoid arthritis: an update. Expert Opin Pharmacother. 2007 Sep;8(13):2089-107. doi: 10.1517/14656566.8.13.2089. PMID: 17714062.
阿达木单抗（抗人 TNF-α，人抗体）是治疗类风湿性关节炎的主要疗法之一。它是一种与 TNF-α 结合的人源化单克隆抗体；并阻断其与 TNF 受体 [1] 的相互作用。它中和可溶性和跨膜 TNF-α；[2]。
阿达木单抗（抗人 TNF-α，人抗体）可预防 TNF-α 的主要炎症作用;对内皮活化、内皮单核细胞粘附、内皮渗漏的影响[3]。
阿达木单抗（抗人 TNF-α，人抗体）可预防 TNFα；上调、减少光感受器细胞死亡、减缓小胶质细胞和 MÜller 细胞活化、改善抗氧化反应并改善 P18[4] 的能量和代谢功能障碍。用阿达木单抗（抗人 TNF-α，人抗体）治疗的 VaD 大鼠在记忆力方面表现出显着改善。此外，阿达木单抗（抗人 TNF-α，人抗体）治疗显着减轻了 VaD 大鼠海马的神经元丢失[5]。 TNF-α的重要作用；对于实验模型中动脉粥样硬化斑块的发展，有据可查，不同的 TNF-α-缺陷小鼠模型始终显示斑块负荷减少 [6,7]。阿达木单抗（抗人 TNF-α，人抗体）在类风湿性关节炎中表现出良好的预后和身体机能的改善 [8]。
| Cas No. | 331731-18-1 | SDF | |
| 别名 | 阿达木单抗; Anti-Human TNF-alpha, Human Antibody | ||
| Canonical SMILES | [Adalimumab] | ||
| 分子式 | 分子量 | 145425.42 | |
| 溶解度 | 储存条件 | Store at -80°C | |
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1 mg | 5 mg | 10 mg |
| 1 mM | 0.0069 mL | 0.0344 mL | 0.0688 mL |
| 5 mM | 0.0014 mL | 0.0069 mL | 0.0138 mL |
| 10 mM | 0.0007 mL | 0.0034 mL | 0.0069 mL |
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Therapeutic effect of an anti-human-TNF-alpha antibody and itraconazole on feline infectious peritonitis
Arch Virol 2020 May;165(5):1197-1206.PMID:32236683DOI:10.1007/s00705-020-04605-7.
Feline infectious peritonitis (FIP) is a fatal disease in wild and domestic cat species. Although several drugs are expected to be useful as treatments for FIP, no drugs are available in clinical practice. In this study, we evaluated the therapeutic effect of combined use of Adalimumab (an anti-human-TNF-alpha monoclonal antibody, ADA) and itraconazole (ICZ), which are presently available to veterinarians. The neutralizing activity of ADA against fTNF-alpha-induced cytotoxicity was measured in WEHI-164 cells. Ten specific pathogen-free (SPF) cats were inoculated intraperitoneally with type I FIPV KU-2. To the cats that developed FIP, ADA (10 mg/animal) was administered twice between day 0 and day 4 after the start of treatment. ICZ (50 mg/head, SID) was orally administered daily from day 0 after the start of treatment. ADA demonstrated dose-dependent neutralizing activity against rfTNF-alpha. In an animal experiment, 2 of 3 cats showed improvements in FIP clinical symptoms and blood chemistry test results, an increase in the peripheral blood lymphocyte count, and a decrease in the plasma alpha 1-AGP level were observed after the beginning of treatment. One of the cats failed to respond to treatment and was euthanized, although the viral gene level in ascites temporarily decreased after the start of treatment. ADA was found to have neutralizing activity against rfTNF-alpha. The combined use of ADA and ICZ showed a therapeutic effect for experimentally induced FIP. We consider these drugs to be a treatment option until effective anti-FIPV drugs become available.
Characterization of a novel anti-human TNF-alpha murine monoclonal antibody with high binding affinity and neutralizing activity
Exp Mol Med 2008 Feb 29;40(1):35-42.PMID:18305396DOI:10.3858/emm.2008.40.1.35.
In order to develop an anti-human TNF-alpha mAb, mice were immunized with recombinant human TNF-alpha. A murine mAb, TSK114, which showed the highest binding activity for human TNF-alpha was selected and characterized. TSK114 specifically bound to human TNF-alpha without cross-reactivity with the homologous murine TNF-alpha and human TNF-beta. TSK114 was found to be of IgG1 isotype with kappa light chain. The nucleotide sequences of the variable regions of TSK114 heavy and light chains were determined and analyzed for the usage of gene families for the variable (V), diversity (D), and joining (J) segments. Kinetic analysis of TSK114 binding to human TNF-alpha by surface plasmon resonance technique revealed a binding affinity (K(D)) of approximately 5.3 pM, which is about 1,000- and 100-fold higher than those of clinically relevant infliximab (Remicade) and Adalimumab (Humira) mAbs, respectively. TSK114 neutralized human TNF-alpha-mediated cytotoxicity in proportion to the concentration, exhibiting about 4-fold greater efficiency than those of infliximab and Adalimumab in WEHI 164 cells used as an in vitro model system. These results suggest that TSK114 has the potential to be developed into a therapeutic TNF-alpha-neutralizing antibody with picomolar affinity.
New approaches to the treatment of inflammatory disorders small molecule inhibitors of p38 MAP kinase
Curr Top Med Chem 2006;6(2):113-49.PMID:16454763DOI:10.2174/156802606775270323.
The therapy of chronic inflammatory diseases like rheumatoid arthritis (RA) and inflammatory bowel disease (IBD) has recently been enriched by the successful launch of the anti-cytokine biologicals Etanercept (tumor necrosis factor (TNF) receptor-p75 Fc fusion protein), Infliximab (chimeric anti-human TNF-alpha monoclonal antibody), Adalimumab (recombinant human anti-human TNF-alpha monoclonal antibody) and Anakinra (recombinant form of human interleukin 1beta (IL-1) receptor antagonist). The success of these novel treatments has impressively demonstrated the clinical benefit that can be gained from therapeutic intervention in cytokine signalling, highlighting the central role of proinflammatory cytokine systems like IL-1alpha and TNF-alpha to be validated targets. However, all of the anti-cytokine biologicals available to date are proteins, and therefore suffering to a varying degree from the general disadvantages associated with protein drugs. Therefore, small molecular, orally active anti-cytokine agents, which target specific pathways of proinflammatory cytokines, would offer an attractive alternative to anti-cytokine biologicals. A number of molecular targets have been identified for the development of such small molecular agents but p38 mitogen-activated protein (MAP) kinase occupies a central role in the regulation of IL-1beta and TNF-alpha signalling network at both the transcriptional and translational level. Since the mid-1990s, an immense number of inhibitors of p38 MAP kinase has been characterised in vitro, and to date several compounds have been advanced into clinical trials. This review will highlight the correlation between effective inhibition of p38 MAP kinase at the molecular target and cellular activity in functional assays of cytokine, particularly TNF-alpha and IL-1beta production. SAR will be discussed regarding activity at the enzyme target, but also with regard to properties required for efficient in vitro and in vivo activity.
Monoclonal antibodies in rheumatoid arthritis: comparative effectiveness of tocilizumab with tumor necrosis factor inhibitors
Biologics 2014 Apr 7;8:141-53.PMID:24741293DOI:10.2147/BTT.S37509.
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by persistent joint inflammation, systemic inflammation, and immunological abnormalities. Because cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-6 play a major role in the development of RA, their targeting could constitute a reasonable novel therapeutic strategy for treating RA. Indeed, worldwide clinical trials of TNF inhibiting biologic disease modifying antirheumatic drugs (bDMARDs) including infliximab, Adalimumab, golimumab, certolizumab pegol, and etanercept as well as the humanized anti-human IL-6 receptor antibody, tocilizumab, have demonstrated outstanding clinical efficacy and tolerable safety profiles, resulting in worldwide approval for using these bDMARDs to treat moderate to severe active RA in patients with an inadequate response to synthetic disease modifying antirheumatic drugs (sDMARDs). Although bDMARDs have elicited to a paradigm shift in the treatment of RA due to the prominent efficacy that had not been previously achieved by sDMARDs, a substantial percentage of patients failed primary or secondary responses to bDMARD therapy. Because RA is a heterogeneous disease in which TNF-α and IL-6 play overlapping but distinct pathological roles, further studies are required to determine the best use of TNF inhibitors and tocilizumab in individual RA patients.
Formatted anti-tumor necrosis factor alpha VHH proteins derived from camelids show superior potency and targeting to inflamed joints in a murine model of collagen-induced arthritis
Arthritis Rheum 2006 Jun;54(6):1856-66.PMID:16736523DOI:10.1002/art.21827.
Objective: The advent of tumor necrosis factor (TNF)-blocking drugs has provided rheumatologists with an effective, but highly expensive, treatment for the management of established rheumatoid arthritis (RA). Our aim was to explore preclinically the application of camelid anti-TNF VHH proteins, which are single-domain antigen binding (VHH) proteins homologous to human immunoglobulin V(H) domains, as TNF antagonists in a mouse model of RA. Methods: Llamas were immunized with human and mouse TNF, and antagonistic anti-TNF VHH proteins were isolated and cloned for bacterial production. The resulting anti-TNF VHH proteins were recombinantly linked to yield bivalent mouse and human TNF-specific molecules. To increase the serum half-life and targeting properties, an anti-serum albumin anti-TNF VHH domain was incorporated into the bivalent molecules. The TNF-neutralizing potential was analyzed in vitro. Mouse TNF-specific molecules were tested in a therapeutic protocol in murine collagen-induced arthritis (CIA). Disease progression was evaluated by clinical scoring and histologic evaluation. Targeting properties were evaluated by 99mTc labeling and gamma camera imaging. Results: The bivalent molecules were up to 500 times more potent than the monovalent molecules. The antagonistic potency of the anti-human TNF VHH proteins exceeded even that of the anti-TNF antibodies infliximab and Adalimumab that are used clinically in RA. Incorporation of binding affinity for albumin into the anti-TNF VHH protein significantly prolonged its serum half-life and promoted its targeting to inflamed joints in the murine CIA model of RA. This might explain the excellent therapeutic efficacy observed in vivo. Conclusion: These data suggest that because of the flexibility of their format, camelid anti-TNF VHH proteins can be converted into potent therapeutic agents that can be produced and purified cost-effectively.