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| Primary information |
|---|
| ID | 13548 |
| Therapeutic ID | Th1415 |
| Protein Name | Durvalumab |
| Sequence | >Th1415_Durvalumab
EVQLVESGGGLVQPGGSLRLSCAASGFTFSRYWMSWVRQAPGKGLEWVANIKQDGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGWFGELAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
|
| Molecular Weight | 146300 |
| Chemical Formula | C6502H10018N1742O2024S42 |
| Isoelectric Point | NA |
| Hydrophobicity | NA |
| Melting point | NA |
| Half-life | Based on baseline clearance rate, the geometric mean terminal half-life is 18 days.[L12621,L12627] |
| Description | Durvalumab is a human immunoglobulin G1 kappa (IgG1) monoclonal antibody and a novel immune-checkpoint inhibitor for cancer treatment.[A192789] Produced by recombinant DNA technology in Chinese Hamster Ovary (CHO) cell suspension culture,[L12621] durvalumab is a programmed death-ligand 1 (PD-L1) blocking antibody that works to promote normal immune responses that attack tumour cells.[L12621,L12627] Durvalumab is marketed under the brand name Imfinzi, which is available for intravenous injections. It was granted accelerated approval by the FDA in May 2017 [A192807] for the treatment of selected patients with locally advanced or metastatic urothelial carcinoma.[L12621] In September 2018, durvalumab was approved by the EMA for the treatment of adult patients with locally advanced, unresectable non-small cell lung cancer (NSCLC), only if PD-L1 is expressed in = 1% of tumour cells and there was no observable disease progression following platinum-based chemoradiation therapy.[A192789,L12627] On March 27, 2020, durvalumab was approved by the FDA for use in combination with [etoposide] and either [carboplatin] or [cisplatin] as first-line treatment of patients with extensive-stage small cell lung cancer (ES-SCLC).[L12624] |
| Indication/Disease | Durvalumab is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.[L12621] Durvalumab is indicated for the treatment of patients with unresectable Stage III non-small cell lung cancer (NSCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy.[L12621] It is also approved for the treatment of patients with extensive-stage small cell lung cancer (ES-SCLC) in combination with [etoposide] and either [carboplatin] or [cisplatin] as first-line therapy.[L12624] Durvalumab is indicated as monotherapy used for the treatment of locally advanced, unresectable non-small cell lung cancer (NSCLC) in adults whose tumours express PD-L1 on = 1% of tumour cells and whose disease has not progressed following platinum-based chemoradiation therapy.[L12627] |
| Pharmacodynamics | Durvalumab is an anticancer antibody that works to promote the antitumour responses mediated by immune cells. By blocking the action of PD-L1, durvalumab exerts its anticancer effects by increasing T-cell activation, enhancing detection and ablation of tumour cells.[L12621] In _in vitro_ assays, durvalumab inhibited the activity of PD-L1 in a concentration-dependent manner.[A192807] In co-engrafted human tumor and immune cell xenograft mouse models, durvalumab was effective in decreasing tumour size. Durvalumab does not mediate antibody-dependent cell-mediated cytotoxicity (ADCC).[L12621] |
| Mechanism of Action | Because cancer cells express antigens that are recognized and taken up by antigen-presenting cells (APCs), the immune responses prime and activate cytotoxic T cells, and allow them to travel to the site of tumour to destroy cancer cells. However, tumours often evade T cell-mediated immune responses to enhance their survival.[A192798] Inflammatory mediators, such as IFN-gamma, induce the expression of programmed cell death ligand-1 (PD-L1), which is a type 1 transmembrane protein expressed on tumour cells and tumour-associated immune cells in the tumour microenvironment.[A192789,L12621] PD-L1 acts as an immune checkpoint to regulate immune responses. PD-L1 is a ligand to PD-1, which is a cell surface receptor expressed on activated T cells in peripheral tissues following antigen exposure.[A192789,A192801] Both PD-L1 and PD-1 are co-inhibitory molecules involved in blocking T cell-mediated immune responses. PD-L1 also interacts with CD-80, which is a receptor constitutively expressed by T cells and is upregulated early after T cell activation.[A193005] The expression of PD-L1 is an adaptive immune response by tumour cells, resulting in over-expression of the molecule in some cancers.[A192801] PD-L1 interacts with PD-1 and CD80, which leads to blocked cytotoxic T cell activation, T cell proliferation, and cytokine production.[L12621] By binding to PD-L1 and preventing its association with PD-1 and CD80, durvalumab activates the immune responses mediated by cytotoxic T cells that attack tumour cells.[L12621] Durvalumab displays selective and high affinity toward PD-L1 but not PD-L2, which is a regulatory ligand expressed in tumour cells to a lesser extent and involved in regulating inflammation and differentiation of T cells.[A192789] |
| Toxicity | There is limited information about the overdose profile and LD50 of durvalumab. In case of overdose, the patient should be closely monitored for drug-related adverse events, and appropriate symptomatic treatment should be immediately initiated.[L12627] Based on the findings of clinical studies, durvalumab had a risk of causing immune-mediated reactions, such as pneumonitis, hepatitis, and other serious infections. In animal reproductive studies, durvalumab caused fetal harm and this fetal toxicity may be possible in humans.[L12621] |
| Metabolism | Durvalumab is subject to protein catabolism via reticuloedothelial system or target-mediated disposition.[L12627] |
| Absorption | Durvalumab exhibits a dose-proportional pharmacokinetic profile that is non-linear at doses <3 mg/kg and linear at doses =3 mg/kg. Following intravenous administration in patients with solid tumours, the steady-state plasma concentrations were reached at approximately 16 weeks.[L12621] |
| In patients receiving the dose range of = 10 mg/kg every 2 weeks, the mean steady state volume of distribution (Vss) was 5.64 L.[L12621,L12627] |
| Clearance | Clearance of durvalumab decreases over time, resulting in a mean steady-state clearance (CLss) of 8.2 mL/h following 365 days of initial drug administration. However, the decrease in CLss is not considered clinically relevant.[L12621,L12627] |
| Categories | Amino Acids, Peptides, and Proteins |
| Patents Number | NA |
| Date of Issue | NA |
| Date of Expiry | NA |
| Drug Interaction | NA |
| Target | Programmed cell death 1 ligand 1 |
| Brand Name | Imfinzi |
| Company | Astra Zeneca Ab |
| Brand Description | Astra Zeneca Ab |
| Prescribed For | Intravenous |
| Chemical Name | 50 mg/ml |
| Formulation | None. |
| Physical Appearance | fatigue, musculoskeletal pain, constipation, decreased appetite, nausea, swelling of extremities, urinary tract infection, abdominal pain, diarrhea/colitis, fever, shortness of breath, cough, and rash. |
| Route of Administration | Imfinzi is a cancer medicine that works with your immune system to interfere with the growth and spread of cancer cells in the body. Imfinzi is used to treat non-small cell lung cancer in patients whose tumors cannot be removed by surgery, and whose cancer has not progressed after treatment with chemotherapy... |
| Recommended Dosage | Imfinzi is a prescription medicine used to treat the symptoms of Urothelial Carcinoma, Non-small Cell Lung Cancer and Small Cell Lung Cancer. Imfinzi may be used alone or with other medications. |
| Contraindication | NA |
| Side Effects | Durvalumab is a programmed cell death ligand 1 (PD-L1) blocking antibody. Durvalumab is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that is produced by recombinant DNA technology in Chinese Hamster Ovary (CHO) cell suspension culture. |
| Useful Link 1 | Link |
| Useful Link 2 | Link |
| Remarks | NA |