==== Reference: Usmani SS, Bedi G, Samuel JS, Singh S, Kalra S, Kumar P, et al. (2017) THPdb: Database of FDA-approved peptide and protein therapeutics. PLoS ONE 12(7) e0181748.====

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Primary information
ThPP IDTh1117
Therapeutic Peptide/Protein NameIpilimumab
SequenceHeavy chain:QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYTMHWVR view full sequnce in fasta
Functional ClassificationIIIc
Molecular Weight148000
Chemical FormulaC6572H10126N1734O2080S40
Isoelectric PointN.A.
HydrophobicityN.A.
Melting Point (℃)N.A.
Half LifeTerminal Elimination Half-life: 14.7 -15.4 days
DescriptionRecombinant, human monoclonal IgG1 kappa immunoglobin. It is an antineoplastic agent developed by Bristol-Myers Squibb and Medarex for the treatment of unresectable or metastatic melanoma in adults. Ipilimumab received FDA approval on March 25, 2011.
Indication/DiseaseIpilimumab is indicated for the treatment of unresectable or metastatic melanoma in adults.
PharmacodynamicsThe pharmacodynamics of Ipilimumab are not completely understood. In melanoma patients receiving Ipilimumab, the mean peripheral blood absolute lymphocyte counts (ALC) increased throughout the induction dosing period. This increase occurred in a dose-dependent fashion in Phase 2 studies. Ipilimumab given with or without gp100 at 3 mg/kg increased ALC throughout the induction dosing period, but no meaningful change in ALC occurred in the control group who received an investigational peptide vaccine alone. Furthermore, ipilimumab binds to CTLA-4 with high affinity (Kd = 5.24 ± 3.62 nM). As a result, ligands CD80 and CD86 are blocked from binding to CTLA-4 with a minimum EC50 value of 0.2 μg/mL.
Mechanism of ActionIpilimumab is a fully human IgG1K antibody that binds to CTLA-4 (cytotoxic T lymphocyte-associated antigen 4), a molecule on T-cells that is indicated for unresectable or metastatic melanoma. The absence or presence of CTLA-4 can augment or suppress the immune system's T-cell response in fighting disease. Ipilimumab is designed to block the activity of CTLA-4, thereby sustaining an active immune response in its attack on cancer cells. The proposed mechanism of action is indirect, and may be through T-cell - mediated anti-tumor immune responses.
ToxicityTherapy with Ipilimumab can result in severe and fatal immune reactions due to T-cell proliferation and activation. These reactions may occur in multiple organ systems, but common reactions include enterecolitis, dermatitis (including toxic necrolysis), neuropathy, and endocrinopathy. Patients should be assessed for signs and symptoms of enterocolitis (diarrhea, abdominal pain, mucus/blood in stool), bowel perforation (petitoneal signs and ileus), hepatitis, dermatitis (rash and pruritus), motor or sensory neuropathy (unilateral/bilateral weakness, sensory alterations, or paresthesia) , hypophysitis/adrenal insufficiency including adrenal crisis/hyper- or hypothyroidism (fatigue, mental status change, abdominal pain, unusual bowel habits, hypotension) and should have liver function tests and thyroid function tests performed at baseline and prior to each dose. Typically immune mediated adverse reactions manifest during therapy, however, a minority of reactions occurred after discontinuation of ipilimumab. In one study of neuropathies, one case of fatal Guillain-Barré syndrome occurred, and once case of severe peripheral neuropathy (Grade 3) was reported. During clinical development of ipilimumab additional cases of Guillain-Barré and myasthenia gravis have been reported. In severe neuropathy, permanently discontinue ipilimumab, and initiate 1-2mg/kd/day of prednisone or equivalent. In one study, severe or potentially fatal dermatitis (eg, Steven-Johnsons syndrome (SJS) or toxic epidermal necrolysis (TEN)) occured in 2.5% (n=13). The median time of onset of moderate to potentially fatal dermatitis was 3.1 weeks (up to 17.3 weeks). Treatment of 54% of severe dermatitis cases (n=7) involved high dose topical corticosteriods. 6 patients had complete resolution in up to 15.6 weeks. Permanently discontinue ipilimumab in patients with SJS or TEN, and withhold the dose in patients with moderate to severe signs and symptoms. Mild- moderate dermatitis (localized rash and
MetabolismThe metabolism of ipilimumab does not involve the cytochrome P450 enzyme system. Because ipilimumab is a protein it is expected to be degraded into small peptides and amino acids by proteolytic enzymes.
AbsorptionIn one pharmacokinetic study of patients with unresectable or metastatic melanoma peak concentrations, trough concentrations, and area under the curve (AUC) were found to be dose proportional in the dosage range examined (0.3, 3, or 10mg/kg every 3 weeks for four doses).
Volume of DistributionVolume of distribution at steady state = 7.21 L
ClearanceClearance was measured to be 15.3mL/hr-16.8 mL/hr.In one pharmacokinetic study examining ipilimumab administered every 3 weeks, clearance was found to be time invariant. Minimal systemic accumulation was observed (accumulation index of 1.5 fold or less).Steady state concentrations was reached by the third dose.Clearance will increase with increasing body weight; however, no dose adjustment is needed if administration occurs on a mg/kg basis. The following had no clinically meaningful influence o
CategoriesAntineoplastic Agents and Monoclonal antibodies
Patents NumberCA2381770
Date of Issue08/08/11
Date of Expiry09/08/24
Drug InteractionN.A.
TargetCytotoxic T-lymphocyte protein 4
Information of corresponding available drug in the market
Brand NameYERVOY
CompanyBristol-Myers Squibb
Brand DiscriptionYERVOY (ipilimumab) is a recombinant, human monoclonal antibody that binds to the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). Ipilimumab is an IgG1 kappa immunoglobulin with an approximate molecular weight of 148 kDa. Ipilimumab is produced in mammalian (Chinese hamster ovary) cell culture.
Prescribed forYERVOY is a human cytotoxic T-lymphocyte antigen 4 (CTLA-4)-blocking antibody indicated for the treatment of unresectable or metastatic melanoma
Chemical NameN.A.
FormulationIt is supplied in single-use vials of 50 mg/10 mL and 200 mg/40 mL. Each milliliter contains 5 mg of ipilimumab and the following inactive ingredients: diethylene triamine pentaacetic acid (DTPA) (0.04 mg), mannitol (10 mg), polysorbate 80 (vegetable origin) (0.1 mg), sodium chloride (5.85 mg), tris hydrochloride (3.15 mg), and Water for Injection, USP at a pH of 7.
Physcial AppearnceSterile, preservative-free, clear to slightly opalescent, colorless to pale-yellow solution
Route of AdministrationN.A.
Recommended DosageThe recommended dose of YERVOY is 3 mg/kg administered intravenously over 90 minutes every 3 weeks for a total of 4 doses.
ContraindicationImmune-mediated adverse reactions: Permanently discontinue for severe reactions. Less than 7.5 mg prednisone or equivalent per day is administered or systemic high-dose corticosteroids are adminstered for severe, persistent, or recurring immune-mediated reactions.
Side EffectsMost common adverse reactions (≥5%) are fatigue, diarrhea, pruritus, rash, and colitis.
Useful Linkhttp://www.rxlist.com/yervoy-drug.htm http://packageinserts.bms.com/pi/pi_yervoy.pdf http://www.yervoy.com/patient.aspx
PubMed ID25658618, 25658617, 25649350, 25647225, 25641691
3-D StructureTh1117 Heavy chain or (Download), Th1117 Light chain (View) or (Download)