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Identification
NameIpilimumab
Accession NumberDB06186
TypeBiotech
GroupsApproved
DescriptionIpilimumab, a recombinant human monoclonal antibody (IgG1 kappa immunoglobin), is an antineoplastic agent developed by Bristol-Myers Squibb and Medarex for the treatment of unresectable or metastatic melanoma in adults. Ipilimumab received FDA approved on March 25, 2011. In October 2015, the FDA approved expanded the indications for Ipilimumab, allowing it to be used to reduce the risk of the deadly skin cancer returning after surgery.
Protein structureDb06186
Related Articles
Protein chemical formulaC6572H10126N1734O2080S40
Protein average weight148000.0 Da
Sequences
>Ipilimumab heavy chain (patent appl. US20150283234) 
QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYTMHWVRQAPGKGLEWVTFISYDGNNKYY
ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAIYYCARTGWLGPFDYWGQGTLVTVSSAS
TKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL
YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPS
VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST
YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELT
KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQ
GNVFSCSVMHEALHNHYTQKSLSLSPGK
>Ipilimumab light chain 
EIVLTQSPGTLSLSPGERATLSCRASQSVGSSYLAWYQQKPGQAPRLLIYGAFSRATGIP
DRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPWTFGQGTKVEIKRTVAAPSVFIFP
PSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTL
TLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
Download FASTA Format
Synonyms
MDX-010
MDX-101
MDX-CTLA-4
MOAB-CTLA-4
External Identifiers Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
YervoyLiquid5 mgIntravenousBristol Myers Squibb Canada2012-03-08Not applicableCanada
YervoyInjection5 mg/mLIntravenousE.R. Squibb & Sons, L.L.C.2011-03-25Not applicableUs
YervoyInjection5 mg/mLIntravenousE.R. Squibb & Sons, L.L.C.2011-03-25Not applicableUs
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixturesNot Available
SaltsNot Available
Categories
UNII6T8C155666
CAS number477202-00-9
Pharmacology
IndicationIpilimumab is indicated for the treatment of unresectable or metastatic melanoma in adults. It is also used to reduce the risk of the deadly skin cancer returning after surgery.
Structured Indications
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 IgG1κ 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.
TargetKindPharmacological actionActionsOrganismUniProt ID
Cytotoxic T-lymphocyte protein 4ProteinyesNot AvailableHumanP16410 details
Related Articles
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 distribution

Volume of distribution at steady state = 7.21 L

Protein bindingNot Available
Metabolism

The 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.

Route of eliminationNot Available
Half lifeTerminal Elimination Half-life: 14.7 -15.4 days
Clearance

Clearance 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 on clearance: Age (range 26-86 years), gender, creatinine clearance (if ≥29ml/min), baseline AST, total bilirubin, ALT levels, concomitant use of budesonide, performance status, HLA-A2*0201 status, positive anti-ipilimumab antibody status, prior use of systemic anticancer therapy, baseline lactate dehydrogenase levels.

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 pruritus) may be treated symptomatically. If no improvement is seen in 1 week administer topical or systemic corticosteroids. In one study of endocrinopathies, severe to life threatening endocrinopathies occurred in 1.8% (n=9) of patients, with all 9 patients having hyopituitarism and some having adrenal insufficiency, hypogonadism, and hypothyroidism. Six of the 9 patients were hospitalized. Moderate endocrinopathies occurred in 2.3% of patients (n=12) and required hormone replacement or medical intervention. The median time of onset was 11 weeks. In symptomatic patients, withhold ipilimumab, and initiate 1-2mg/kd/day of prednisone or equivalent and appropriate hormone replacement therapy. In one study of enterocolitis in 511 patients, diarrhea of ≥7 stools above baseline, fever, ileus and peritoneal signs (Grade 3-5, severe, potentially fatal enterocolitis) occured in 7% (n=34) of patients treated with ipilimumab. Diarrhea of up to 6 stools above baseline, abdominal pain, mucus or blood in stool (Grade 2, moderate enterocolitis) occurred in 5% of patients (n=28). Intestinal perforation occurred in 1% (n=5). Death as a result of complications occurred in 0.8% (n=4). Hospitalization for severe enterocolitis occurred in 5% (n=26). Grade 3-5 enterocolitis had a median time of onset of 7.4 weeks (with a range of 1.6-13.4 weeks). Grade 2 entercolitis had a median time of onset of 6.3 weeks (with a range of 0.3- 18.9 weeks). Treatment of 85% (n=29) of patients with Grade 3-5 enterocolitis (n=34) included high dose corticosteroids (≥40mg/day prednisone equivalent). Median dose used was 80mg/day of prednisone/equivalent for a median duration of 2.3 weeks (up to 13.9 weeks). Of the 34 patients, 74% experienced complete resolution, 3% progressed to Grade 2 severity, and 24% exhibited no improvement. In treatment of 28 patients with a Grade 2 enterocolitis: 25% received high dose corticosteroids for a median of 10 days; 29% of patients received a non-high dose of corticosteroids (<40mg/day of prednisone/equivalent) for a median duration of 5.1 weeks; 46% did not receive systemic corticosteroids. Of the 28 patients, 79% of patients experienced complete resolution, 11% improved in severity, 11% exhibited no improvement. In patients with severe enterocolitis, permanently discontinue ipilimumab, and initiate 1-2 mg/kd/day of prednisone or an equivalent. Once patient improvement to Grade 1 or less is seen, taper the corticosteroid over at least one month. In patients with moderate enterocolitis, hold dose of ipilimumab, and initiate 0.5 mg/kd/day of prednisone or an equivalent. In another study examining immune mediated hepatitis, AST or ALT elevation of ≥3 times the upper limit of normal (ULN) (severe and potentially fatal hepatotoxicity) was seen in 2% (n=8) of patients on ipilimumab. Fatal hepatic failure occurred in 0.2%. Hospitalization occurred in 0.4%. Additionally, moderate hepatotoxicity (2.5xULN >ALT or AST> 5xULN, or 1.5xULN>bilirubin>3xULN ) occurred in 2.5% (n=13). In Grade 3-5 hepatotoxicity, permanently discontinue ipilimumab, and initiate 1-2mg/kd/day of prednisone or equivalent. Once LFT show sustained improvement taper corticosteroid over 1 month. In Grade 2 hepatotoxicity, withhold ipilimumab. In pregnancy, use only if potential benefit justifies potential risk to fetus (Category C). In studies done in monkeys, severe toxicities were observed including abortion, stillbirth, low birth weight and infant mortality. Additionally, ipilimumab has the potential to cross the placental barrier, and it is unknown if secretion into breast milk occurs. No studies have been performed to study carcinogenesis, mutagenesis, and impairment of fertility.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
Interactions
Drug Interactions
DrugInteractionDrug group
AcetyldigitoxinAcetyldigitoxin may decrease the cardiotoxic activities of Ipilimumab.Approved
ALT-110The therapeutic efficacy of ALT-110 can be decreased when used in combination with Ipilimumab.Investigational
AnvirzelAnvirzel may decrease the cardiotoxic activities of Ipilimumab.Investigational
BelimumabThe risk or severity of adverse effects can be increased when Ipilimumab is combined with Belimumab.Approved
BevacizumabBevacizumab may increase the cardiotoxic activities of Ipilimumab.Approved, Investigational
CabazitaxelThe risk or severity of adverse effects can be increased when Cabazitaxel is combined with Ipilimumab.Approved
CDX-110The therapeutic efficacy of CDX-110 can be decreased when used in combination with Ipilimumab.Investigational
CyclophosphamideCyclophosphamide may increase the cardiotoxic activities of Ipilimumab.Approved, Investigational
DeslanosideDeslanoside may decrease the cardiotoxic activities of Ipilimumab.Approved
DigitoxinDigitoxin may decrease the cardiotoxic activities of Ipilimumab.Approved
DigoxinDigoxin may decrease the cardiotoxic activities of Ipilimumab.Approved
DocetaxelThe risk or severity of adverse effects can be increased when Docetaxel is combined with Ipilimumab.Approved, Investigational
G17DTThe therapeutic efficacy of G17DT can be decreased when used in combination with Ipilimumab.Investigational
GI-5005The therapeutic efficacy of GI-5005 can be decreased when used in combination with Ipilimumab.Investigational
INGN 201The therapeutic efficacy of INGN 201 can be decreased when used in combination with Ipilimumab.Investigational
INGN 225The therapeutic efficacy of INGN 225 can be decreased when used in combination with Ipilimumab.Investigational
OuabainOuabain may decrease the cardiotoxic activities of Ipilimumab.Approved
PaclitaxelThe risk or severity of adverse effects can be increased when Paclitaxel is combined with Ipilimumab.Approved, Vet Approved
Rabies vaccineThe therapeutic efficacy of Rabies vaccine can be decreased when used in combination with Ipilimumab.Approved
SRP 299The therapeutic efficacy of SRP 299 can be decreased when used in combination with Ipilimumab.Investigational
TG4010The therapeutic efficacy of TG4010 can be decreased when used in combination with Ipilimumab.Investigational
TrastuzumabTrastuzumab may increase the cardiotoxic activities of Ipilimumab.Approved, Investigational
VemurafenibIpilimumab may increase the hepatotoxic activities of Vemurafenib.Approved
Food InteractionsNot Available
References
Synthesis ReferenceNot Available
General References
  1. Ribas A: Tumor immunotherapy directed at PD-1. N Engl J Med. 2012 Jun 28;366(26):2517-9. doi: 10.1056/NEJMe1205943. Epub 2012 Jun 2. [PubMed:22658126 ]
External Links
ATC CodesL01XC11
AHFS Codes
  • 10:00
PDB EntriesNot Available
FDA labelDownload (374 KB)
MSDSDownload (479 KB)
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
InjectionIntravenous5 mg/mL
LiquidIntravenous5 mg
PricesNot Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
CA2381770 No2007-08-072020-08-08Canada
Properties
StateSolid
Experimental PropertiesNot Available
Taxonomy
DescriptionNot Available
KingdomOrganic Compounds
Super ClassOrganic Acids
ClassCarboxylic Acids and Derivatives
Sub ClassAmino Acids, Peptides, and Analogues
Direct ParentPeptides
Alternative ParentsNot Available
SubstituentsNot Available
Molecular FrameworkNot Available
External DescriptorsNot Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
General Function:
Not Available
Specific Function:
Inhibitory receptor acting as a major negative regulator of T-cell responses. The affinity of CTLA4 for its natural B7 family ligands, CD80 and CD86, is considerably stronger than the affinity of their cognate stimulatory coreceptor CD28.
Gene Name:
CTLA4
Uniprot ID:
P16410
Molecular Weight:
24655.63 Da
References
  1. Yang JC, Hughes M, Kammula U, Royal R, Sherry RM, Topalian SL, Suri KB, Levy C, Allen T, Mavroukakis S, Lowy I, White DE, Rosenberg SA: Ipilimumab (anti-CTLA4 antibody) causes regression of metastatic renal cell cancer associated with enteritis and hypophysitis. J Immunother. 2007 Nov-Dec;30(8):825-30. [PubMed:18049334 ]
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Drug created on March 19, 2008 10:16 / Updated on August 17, 2016 12:24