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| Primary information |
|---|
| ID | 13885 |
| Therapeutic ID | Th1444 |
| Protein Name | Anifrolumab |
| Sequence | >Th1444_Anifrolumab
EVQLVQSGAEVKKPGESLKISCKGSGYIFTNYWIAWVRQMPGKGLESMGIIYPGDSDIRYSPSFQGQVTISADKSITTAYLQWSSLKASDTAMYYCARHDIEGFDYWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
|
| Molecular Weight | 148000 |
| Chemical Formula | NA |
| Isoelectric Point | NA |
| Hydrophobicity | NA |
| Melting point | NA |
| Half-life | The serum elimination half life anifrolumab in a phase 1 trial in patients with scleroderma was 0.84 days for a 0.1 mg/kg single dose, 1.24 days for a 0.3 mg/kg single dose, 2.96 days for a 1.0 mg/kg single dose, 4.07 days for a 3.0 mg/kg single dose, and 7.70 days for a 10.0 mg/kg single dose.[A237044] |
| Description | Anifrolumab, or MEDI-546, is a type 1 interferon receptor (IFNAR) inhibiting IgG1 monoclonal antibody indicated in the treatment of adults with moderate to severe systemic lupus erythematosus.[A237074,L34929] The standard therapy for systemic lupus erythematosus consists of antimalarials like [hydroxychloroquine], glucocorticoids like [dexamethasone], and disease modifying antirheumatic drugs like [methotrexate].[A237079,L34929] Three monoclonal antibodies (anifrolumab, [rontalizumab], and [sifalimumab]) that target the type 1 interferon pathway entered clinical trials as potential treatments for systemic lupus erythematosus, but so far only anifrolumab has been approved.[A237054] The design of early clinical trials of anti-interferon treatments such as anifrolumab, rontalizumab, and sifalimumab have come under criticism.[A237054] The design of the clinical trials use different definitions of autoantibody positivity, making comparison between trials difficult; all trials involve large portions of patients also using corticosteroids, which may alter patient responses in the experimental and placebo groups; and patient populations were largely homogenous, which may have increased the odds of success of the trial.[A237054] Anifrolumab has also been investigated for the treatment of Scleroderma.[A237044] Anifrolumab was granted FDA approval on 30 July 2021.[L34929] |
| Indication/Disease | Anifrolumab is indicated in the treatment of adults with moderate to severe systemic lupus erythematosus.[L34929] |
| Pharmacodynamics | Anifrolumab is a type 1 interferon receptor (IFNAR) inhibiting IgG1 monoclonal antibody indicated in the treatment of adults with moderate to severe systemic lupus erythematosus.[A237074,L34929] It has a long duration of action as it is given every 4 weeks.[L34929] Patients should be counselled regarding the risks of serious infections, hypersensitivity reactions, and malignancies.[L34929] |
| Mechanism of Action | Systemic lupus erythematosus (SLE) is an autoimmune disorder affecting multiple systems in the body.[A237059] SLE may manifest as a rash on the skin, and can progress to life-threatening autoimmune reactions in the kidney or nervous system.[A237069] Type 1 interferon pathway activation has been identified as a mediator of pathogenesis in SLE, and the level of type 1 interferon expression is correlated with severity of SLE.[A237059,A237069,A237084] Activation of the type 1 interferon receptor (INFAR1) by interferons alpha, beta, epsilon, kappa, and omega lead to stimulation of gene transcription.[A237059] Activation of INFAR1 and INFAR2 lead to phosphorylation of STAT1 and STAT2, which are translocated with interferon regulatory factor 9 (IRF9) to the cell nucleus to activate the interferon-stimulated response element (ISRE).[A237069] Activation of ISRE leads to the expression of many proinflammatory and immunomodulatory proteins, as well as the activation of a positive feedback loop that produces more type 1 interferons.[A237069] Interferon alpha stimulates monocytes to mature into myeloid dendritic cells that express self antigens.[A237084] CD4+ and CD8+ T-cells, as well as B cells, that are autoreactive will respond to the self antigens and induce inflammmation and apoptosis in cells.[A237084] This self-reactive immune response damages otherwise healthy tissue throughout the body.[A237084] Anifrolumab is an immunoglobulin gamma 1 kappa (IgG1) monoclonal antibody that selectively binds to subunit 1 of INFAR1.[A237049,L34929] The binding of anifrolumab to IFNAR1 inhibits the activity of the receptor, decreasing downstream signalling and gene transcription of inflammatory mediators.[A237059,L34929] The Fc region of anifrolumab carries the triple mutaion L234F/L235E/P331S to prevent binding of the Fc region of the antibody to cell surface Fc receptors.[A237069] In a phase IIb clinical trial, the primary endpoint was reached by 34.3% of patients in the 300 mg treatment group, 28.8% of patients in the 1000 mg treatment group, and 17.6% of patients in the placebo group.[A237059] Patients with higher interferon-stimulated gene transcription at baseline showed a greater response to treatment.[A237059] |
| Toxicity | Data regarding overdose is not readily available.[L34929] In a phase 1 clinical trial, patients given a single dose of 20.0 mg/kg experienced upper respiratory tract infections, headache, diarrhea, and nausea.[A237044] 2 patients in the 3.0 mg/kg single dose group experienced osteomyelitis and skin ulcer.[A237044] A single patient in the 1.0 mg/kg/week group developed chronic myelogenous leukemia.[A237044] The frequency and severity of adverse effects does not appear to be closely related to dose.[A237044] In the event of an overdose, treat patients with symptomatic and supportive measures. |
| Metabolism | Monoclonal antibodies are mainly catabolized to smaller oligopeptides and individual amino acids.[A40006,L34929] |
| Absorption | A 300 mg intravenous dose reaches a mean Cmax of 82.4 µg/mL, with a Tmax of 0.03 days, and an AUC of 907 day |
| The estimated volume of distribution of anifrolumab at steady state is 6.23 L for a 69.1 kg patient.[L34929] |
| Clearance | The estimated systemic clearance of anifrolumab is 0.193 L/day.[L34929] |
| Categories | Antibodies |
| Patents Number | NA |
| Date of Issue | NA |
| Date of Expiry | NA |
| Drug Interaction | NA |
| Target | Interferon alpha/beta receptor 1 |
| Brand Name | NA |
| Company | NA |
| Brand Description | NA |
| Prescribed For | NA |
| Chemical Name | NA |
| Formulation | NA |
| Physical Appearance | NA |
| Route of Administration | NA |
| Recommended Dosage | NA |
| Contraindication | NA |
| Side Effects | NA |
| Useful Link 1 | Link |
| Useful Link 2 | NA |
| Remarks | NA |