Ipilimumab
Identification
- Name
- Ipilimumab
- Accession Number
- DB06186
- Type
- Biotech
- Groups
- Approved
- Biologic Classification
- Protein Based Therapies
Monoclonal antibody (mAb) - Description
Ipilimumab, 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 structure
- Protein chemical formula
- C6572H10126N1734O2080S40
- Protein average weight
- 148000.0 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
- Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Yervoy Liquid 5 mg Intravenous Bristol Myers Squibb 2012-03-08 Not applicable Canada 
Yervoy Injection 5 mg/mL Intravenous E.R. Squibb & Sons, L.L.C. 2011-03-25 Not applicable US 
Yervoy Injection 5 mg/mL Intravenous E.R. Squibb & Sons, L.L.C. 2011-03-25 Not applicable US - Categories
- UNII
- 6T8C155666
- CAS number
- 477202-00-9
Pharmacology
- Indication
Ipilimumab 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
- Pharmacodynamics
The 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 action
Ipilimumab 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.
Target Actions Organism ACytotoxic T-lymphocyte protein 4 Not Available Human - Absorption
In 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 binding
- Not 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 elimination
- Not Available
- Half life
Terminal 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.
- Toxicity
Therapy 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
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
Drug Interaction Drug group Acetyldigitoxin Acetyldigitoxin may decrease the cardiotoxic activities of Ipilimumab. Approved Acetyldigoxin Acetyldigoxin may decrease the cardiotoxic activities of Ipilimumab. Experimental Ancestim The risk or severity of cytotoxicity can be increased when Ancestim is combined with Ipilimumab. Approved, Investigational, Withdrawn Anthrax immune globulin human The therapeutic efficacy of Anthrax immune globulin human can be decreased when used in combination with Ipilimumab. Approved Bacillus calmette-guerin substrain connaught live antigen The therapeutic efficacy of Bacillus calmette-guerin substrain connaught live antigen can be decreased when used in combination with Ipilimumab. Approved, Investigational Bacillus calmette-guerin substrain tice live antigen The therapeutic efficacy of Bacillus calmette-guerin substrain tice live antigen can be decreased when used in combination with Ipilimumab. Approved BCG vaccine The therapeutic efficacy of BCG vaccine can be decreased when used in combination with Ipilimumab. Investigational Belimumab The risk or severity of adverse effects can be increased when Ipilimumab is combined with Belimumab. Approved Bevacizumab Bevacizumab may increase the cardiotoxic activities of Ipilimumab. Approved, Investigational Cabazitaxel The risk or severity of adverse effects can be increased when Cabazitaxel is combined with Ipilimumab. Approved Clostridium tetani toxoid antigen (formaldehyde inactivated) The therapeutic efficacy of Clostridium tetani toxoid antigen (formaldehyde inactivated) can be decreased when used in combination with Ipilimumab. Approved Corynebacterium diphtheriae toxoid antigen (formaldehyde inactivated) The therapeutic efficacy of Corynebacterium diphtheriae toxoid antigen (formaldehyde inactivated) can be decreased when used in combination with Ipilimumab. Approved Cyclophosphamide Cyclophosphamide may increase the cardiotoxic activities of Ipilimumab. Approved, Investigational Cymarin Cymarin may decrease the cardiotoxic activities of Ipilimumab. Experimental Deslanoside Deslanoside may decrease the cardiotoxic activities of Ipilimumab. Approved Digitoxin Digitoxin may decrease the cardiotoxic activities of Ipilimumab. Approved, Investigational Digoxin Digoxin may decrease the cardiotoxic activities of Ipilimumab. Approved Digoxin Immune Fab (Ovine) Digoxin Immune Fab (Ovine) may decrease the cardiotoxic activities of Ipilimumab. Approved Docetaxel The risk or severity of adverse effects can be increased when Docetaxel is combined with Ipilimumab. Approved, Investigational G17DT The therapeutic efficacy of G17DT can be decreased when used in combination with Ipilimumab. Investigational GI-5005 The therapeutic efficacy of GI-5005 can be decreased when used in combination with Ipilimumab. Investigational Gitoformate Gitoformate may decrease the cardiotoxic activities of Ipilimumab. Experimental Hepatitis A Vaccine The therapeutic efficacy of Hepatitis A Vaccine can be decreased when used in combination with Ipilimumab. Approved Hepatitis B Vaccine (Recombinant) The therapeutic efficacy of Hepatitis B Vaccine (Recombinant) can be decreased when used in combination with Ipilimumab. Approved, Withdrawn Human rabies virus immune globulin The therapeutic efficacy of Human rabies virus immune globulin can be decreased when used in combination with Ipilimumab. Approved INGN 201 The therapeutic efficacy of INGN 201 can be decreased when used in combination with Ipilimumab. Investigational INGN 225 The therapeutic efficacy of INGN 225 can be decreased when used in combination with Ipilimumab. Investigational Japanese encephalitis virus strain sa 14-14-2 antigen (formaldehyde inactivated) The therapeutic efficacy of Japanese encephalitis virus strain sa 14-14-2 antigen (formaldehyde inactivated) can be decreased when used in combination with Ipilimumab. Approved Lanatoside C Lanatoside C may decrease the cardiotoxic activities of Ipilimumab. Experimental Metildigoxin Metildigoxin may decrease the cardiotoxic activities of Ipilimumab. Experimental Oleandrin Oleandrin may decrease the cardiotoxic activities of Ipilimumab. Experimental, Investigational Ouabain Ouabain may decrease the cardiotoxic activities of Ipilimumab. Approved Paclitaxel The risk or severity of adverse effects can be increased when Paclitaxel is combined with Ipilimumab. Approved, Vet Approved Peruvoside Peruvoside may decrease the cardiotoxic activities of Ipilimumab. Experimental Proscillaridin Proscillaridin may decrease the cardiotoxic activities of Ipilimumab. Experimental Rabies virus inactivated antigen, A The therapeutic efficacy of Rabies virus inactivated antigen, A can be decreased when used in combination with Ipilimumab. Approved, Investigational Rindopepimut The therapeutic efficacy of Rindopepimut can be decreased when used in combination with Ipilimumab. Investigational Rotavirus Vaccine The therapeutic efficacy of Rotavirus Vaccine can be decreased when used in combination with Ipilimumab. Approved Rubella virus vaccine The therapeutic efficacy of Rubella virus vaccine can be decreased when used in combination with Ipilimumab. Approved, Investigational Salmonella typhi ty2 vi polysaccharide antigen The therapeutic efficacy of Salmonella typhi ty2 vi polysaccharide antigen can be decreased when used in combination with Ipilimumab. Approved Salmonella typhi ty21a live antigen The therapeutic efficacy of Salmonella typhi ty21a live antigen can be decreased when used in combination with Ipilimumab. Approved SRP 299 The therapeutic efficacy of SRP 299 can be decreased when used in combination with Ipilimumab. Investigational Tecemotide The therapeutic efficacy of Tecemotide can be decreased when used in combination with Ipilimumab. Investigational TG4010 The therapeutic efficacy of TG4010 can be decreased when used in combination with Ipilimumab. Investigational Trastuzumab Trastuzumab may increase the cardiotoxic activities of Ipilimumab. Approved, Investigational Varicella Zoster Vaccine (Live/Attenuated) The therapeutic efficacy of Varicella Zoster Vaccine (Live/Attenuated) can be decreased when used in combination with Ipilimumab. Approved Vemurafenib The risk or severity of increased transaminases can be increased when Vemurafenib is combined with Ipilimumab. Approved Yellow Fever Vaccine The therapeutic efficacy of Yellow Fever Vaccine can be decreased when used in combination with Ipilimumab. Approved, Investigational - Food Interactions
- Not Available
References
- General References
- 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
- KEGG Drug
- D04603
- PubChem Substance
- 347910341
- ChEMBL
- CHEMBL1789844
- RxList
- RxList Drug Page
- Drugs.com
- Drugs.com Drug Page
- Wikipedia
- Ipilimumab
- ATC Codes
- L01XC11 — Ipilimumab
- AHFS Codes
- 10:00.00 — Antineoplastic Agents
- FDA label
- Download (374 KB)
- MSDS
- Download (479 KB)
Clinical Trials
- Clinical Trials
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage forms
Form Route Strength Injection Intravenous 5 mg/mL Liquid Intravenous 5 mg - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) CA2381770 No 2007-08-07 2020-08-08 Canada
Properties
- State
- Solid
- Experimental Properties
- Not Available
Taxonomy
- Description
- Not Available
- Kingdom
- Organic Compounds
- Super Class
- Organic Acids
- Class
- Carboxylic Acids and Derivatives
- Sub Class
- Amino Acids, Peptides, and Analogues
- Direct Parent
- Peptides
- Alternative Parents
- Not Available
- Substituents
- Not Available
- Molecular Framework
- Not Available
- External Descriptors
- Not 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 t...
- Gene Name
- CTLA4
- Uniprot ID
- P16410
- Uniprot Name
- Cytotoxic T-lymphocyte protein 4
- Molecular Weight
- 24655.63 Da
References
- 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]
Drug created on March 19, 2008 10:16 / Updated on April 23, 2018 23:10