Ipilimumab
Identification
- Name
- Ipilimumab
- Accession Number
- DB06186
- Type
- Biotech
- Groups
- Approved
- Biologic Classification
- Protein Based Therapies
Monoclonal antibody (mAb) - Description
Ipilimumab is a monoclonal antibody, more specifically a fully humanized IgG1 antibody produced in mammalian cell culture, to the cytotoxic T lymphocyte antigen-4 (CTLA-4) which activates antitumor immunity by inhibiting this major checkpoint.[2, 3] This antineoplastic agent was developed by Bristol-Myers Squibb and Medarex and FDA approved on March 25, 2011, for the treatment of melanoma.[8] On October 2015, the FDA approved expanded the indications for Ipilimumab, allowing it to be used to reduce the risk of relapsed skin cancer after surgery.[9] On July 11, 2018, the FDA approved an additional indication for the combination of low dose ipilimumab and Nivolumab for the treatment of previously treated microsatellite instability-high/deficient mismatch repair (MSI-H/dMMR) metastatic colorectal cancer.[10]
- 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
- Adjuvants, Immunologic
- Amino Acids, Peptides, and Proteins
- Antibodies
- Antibodies, Monoclonal
- Antibodies, Monoclonal, Humanized
- Antineoplastic Agents
- Antineoplastic and Immunomodulating Agents
- Blood Proteins
- CTLA-4-directed Blocking Antibody
- Globulins
- Immunoglobulin G
- Immunoglobulins
- Immunoproteins
- Proteins
- Serum Globulins
- UNII
- 6T8C155666
- CAS number
- 477202-00-9
Pharmacology
- Indication
Ipilimumab is approved for different conditions such as:
- Treatment of unresectable or metastatic melanoma in patients 12 years and older.
- Adjuvant treatment of patients with cutaneous melanoma with the pathologic involvement of regional lymph nodes of more than 1 mm who have undergone complete resection, including total lymphadenectomy.[Label]
In combination with Nivolumab, ipilimumab is approved for:
- Treatment of patients with intermediate or poor risk, previously untreated advanced renal cell carcinoma
- Treatment of 12 years and older patients with MSI-H/dMMR metastatic colorectal cancer with progression after treatment with fluoropyrimidine, oxaliplatin, and irinotecan.[Label]
- Associated Conditions
- Pharmacodynamics
In preclinical trials, ipilimumab was shown to inhibit tumor growth in mice, eradicate primary and metastatic melanomas, it has also been shown that it decreases serum prostate-specific antigens in prostate cancer patients and it produces a dose-dependent increase in T-cell activation.[4]
Ipilimumab has been shown to present an overall survival benefit in metastatic melanoma. The objective response rate of this gent has been studied to be in the range between 5-20% with disease control rates of 15-30%.[3] In clinical trials, in prostate cancer patients produce a decrease of >50% in PSA levels with a dose-response relationship between ipilimumab and CD8 T-cell activation which derived in an increase in interferon-gamma as well as lytic activity.[4]
The use of ipilimumab in combination with Nivolumab was based on the reports that indicated significant improvement in overall survival and objective response rate of 42%.[10] This combination was also confirmed by trials with progression after therapy colorectal cancer which obtained an overall response rate of 46% and 89% of those has a response duration of over 6 months.[11]
- Mechanism of action
The cytotoxic T-lymphocyte antigen-4 (CTLA-4) is a cell surface molecule that plays an essential role in regulating the adaptative immune response. The activation of T-cells is tightly controlled by two main signals 1) initial binding of tumor-associated antigens on antigen presenting cells to T-cell receptors and 2) subsequent binding of B7 molecules on the antigen presenting cells to CD28 receptors on T cells. After T-cell activation, CTLA-4 will be upregulated and it will compete on the binding between CD28 and B7. The binding between CTLA-4 and B7 interrupts the stimulatory signal which in order blunts T-cell proliferation response.[6]
The action of ipilimumab produces an exacerbated autoimmunity.[3] This is explained as 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 a potent T-cell response against tumor cells.[4]
However, this mechanism of action presents a limited clinical benefit to a fraction of treated patients an thus, it is thought that there should be an unknown mechanism related to host-dependent factors.[5]
Target Actions Organism ACytotoxic T-lymphocyte protein 4 Not Available Human - Absorption
When administered once every 3 weeks for 4 cycles, the peak serum concentration and the AUC of ipilimumab are dose proportional within the dose range. The steady-state concentration is reached by the third dose and the accumulation rate was less or equal to 1.5.[6] In steady-state, the mean Cmin ranges from 19.4 mcg/ml to 58.1 mcg/ml when given in a dosage from 3-10 mg/kg.[Label] Once absorbed it is thought to be confined in the extracellular fluid due to its large molecular weight and it is not thought to be able to cross the blood-brain barrier.[12]
The combination of Nivolumab and ipilimumab are based on the fact that PD-1 and CTLA-4 checkpoints have nonredundant roles on T-cell modulation.[A35187]
- Volume of distribution
The volume of distribution at steady-state is determined to be of 7.21L.[6]
- Protein binding
No information regarding the plasma protein binding is 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.[7]
- Route of elimination
The main excretion is thought to be done in the urine. It is suggested that the systemic clearance increases proportionally with body weight.[12]
- Half life
It has been determined that the terminal half-life of ipilimumab is of 14.7 days.[6]
- Clearance
Clearance of ipilimumab was determined to be 15.3 mL/hr.[6]
- Toxicity
The toxicity effect of ipilimumab differs from other cytotoxic chemotherapies. The adverse reactions related to ipilimumab are only related to the immune response due to the mechanism of action of this agent. These adverse reactions are mainly related to certain organs such as skin, gastrointestinal tract and endocrine glands.[3]
The carcinogenic, genotoxic and fertility effect of ipilimumab has not been evaluated.[Label]
- 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 Typhoid Vaccine The therapeutic efficacy of Typhoid Vaccine can be decreased when used in combination with Ipilimumab. Approved 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]
- Johnson DB, Peng C, Abramson RG, Ye F, Zhao S, Wolchok JD, Sosman JA, Carvajal RD, Ariyan CE: Clinical Activity of Ipilimumab in Acral Melanoma: A Retrospective Review. Oncologist. 2015 Jun;20(6):648-52. doi: 10.1634/theoncologist.2014-0468. Epub 2015 May 11. [PubMed:25964307]
- Thumar JR, Kluger HM: Ipilimumab: a promising immunotherapy for melanoma. Oncology (Williston Park). 2010 Dec;24(14):1280-8. [PubMed:21294471]
- Authors unspecified: Ipilimumab. Drugs R D. 2010;10(2):97-110. doi: 10.2165/11584510-000000000-00000. [PubMed:20698719]
- Romano E, Kusio-Kobialka M, Foukas PG, Baumgaertner P, Meyer C, Ballabeni P, Michielin O, Weide B, Romero P, Speiser DE: Ipilimumab-dependent cell-mediated cytotoxicity of regulatory T cells ex vivo by nonclassical monocytes in melanoma patients. Proc Natl Acad Sci U S A. 2015 May 12;112(19):6140-5. doi: 10.1073/pnas.1417320112. Epub 2015 Apr 27. [PubMed:25918390]
- Trinh VA, Hagen B: Ipilimumab for advanced melanoma: a pharmacologic perspective. J Oncol Pharm Pract. 2013 Sep;19(3):195-201. doi: 10.1177/1078155212459100. Epub 2012 Oct 9. [PubMed:23047236]
- Fellner C: Ipilimumab (yervoy) prolongs survival in advanced melanoma: serious side effects and a hefty price tag may limit its use. P T. 2012 Sep;37(9):503-30. [PubMed:23066344]
- FDA approval [Link]
- FDA letters [Link]
- FDA news [Link]
- FDA news [Link]
- BCC Cancer [File]
- 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 (1.13 MB)
- 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
Property Value Source melting point (°C) 80-90 ºC (based on IgG properties) McConnell A., et al. (2014). MAbs. Sep-Oct; 6 (5); 1274-1282 boiling point (°C) Fab and Fc domains denaturates at 60 and 70 ºC respectively Arnoldus W. et al. (2000). Biophysical Journal. Vol 78. 394-404 water solubility 50 mg/ml Human IgG purified. Product Information isoelectric point 6.1-8.5 Agrisera Information about IgG antibodies.
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 August 14, 2018 04:31