Ipilimumab

Identification

Summary

Ipilimumab is a human cytotoxic T-lymphocyte antigen 4 (CTLA-4) blocking antibody used to treat metastatic or unresectable melanoma.

Brand Names

Yervoy

Generic Name

Ipilimumab

DrugBank Accession Number

DB06186

Background

Ipilimumab is a fully humanized IgG1 monoclonal antibody that blocks cytotoxic T lymphocyte antigen-4 (CTLA-4).⁵ Blocking CTLA-4 removes an inhibitory signal from reducing the activity of T lymphocytes.^1,2,5 Ipilimumab was developed by Bristol-Myers Squibb and Medarex.⁵

Ipilimumab was granted FDA approval on 25 March 2011.⁵

Type

Biotech

Groups

Approved

Biologic Classification

Protein Based Therapies
Monoclonal antibody (mAb)

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

Ipilimumab

External IDs

BMS-734016
MDX-010
MDX-101
MDX-CTLA-4
MOAB-CTLA-4

Pharmacology

Indication

Ipilimumab is indicated to treat unresectable or metastatic melanoma, as an adjuvant in the treatment of cutaneous melanoma, to treat microsatellite-high or mismatch repair deficient metastatic colorectal cancer, or to treat hepatocellular carcinoma.⁵ Ipilimumab with nivolumab is indicated to treat advanced renal cell carcinoma.⁵

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Drug Discovery

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Associated Conditions

Contraindications & Blackbox Warnings

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Pharmacodynamics

Ipilimumab is a human IgG1 that binds CTLA-4, preventing 1 T-cell inhibition signal pathway.³ It has a long duration of action as it is given every 3 to 4 weeks.⁵ Patients should be counselled regarding the risk of immune-mediated adverse effects, infusion related reactions, and embryo-fetal toxicity.⁵

Mechanism of action

Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is an inhibitory molecule that competes with the stimulatory CD28 for binding to B7 on antigen presenting cells.³ CTLA-4 and CD28 are both presented on the surface of T-cells.³ Ipilimumab is a human IgG1 that binds CTLA-4, preventing the inhibition of T-cell mediated immune responses to tumors.³

Target	Actions	Organism
ACytotoxic T-lymphocyte protein 4	inhibitor antibody	Humans

Absorption

C_max was 65.8µg/mL for 2-6 year olds, 70.1µg/mL for 6-<12 year olds, and 73.3µg/mL in patients 12 years and older.⁵ Data regarding the AUC and T_max of ipilumumab are not readily available.^3,5

Volume of distribution

The volume of distribution at steady-state of ipilimumab is 7.21L.³

Protein binding

Data regarding the protein binding of ipilimumab is not readily available.⁵

Metabolism

The metabolism of ipilimumab does not involve the cytochrome P450 enzyme system.^5,6 Because ipilimumab is a protein, it is expected to be degraded into small peptides and amino acids by proteolytic enzymes.⁴

Route of elimination

Data regarding the route of elimination of ipilimumab is not readily available.⁵

Half-life

Ipilimumab has a half life of 14.7 days.³

Clearance

Ipilimumab has a clearance of 15.3 mL/hr.³ Systemic clearance increases proportionally with body weight.⁶

Adverse Effects

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Toxicity

Data regarding ipilumumab overdose is not readily available.⁵ However, the most common adverse reactions to ipilumumab are fatigue, diarrhea, pruritus, rash, and colitis.⁵

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

Drug	Interaction
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Abacavir	Abacavir may decrease the excretion rate of Ipilimumab which could result in a higher serum level.
Abciximab	The risk or severity of adverse effects can be increased when Abciximab is combined with Ipilimumab.
Aceclofenac	Aceclofenac may decrease the excretion rate of Ipilimumab which could result in a higher serum level.
Acemetacin	Acemetacin may decrease the excretion rate of Ipilimumab which could result in a higher serum level.
Acetaminophen	Acetaminophen may decrease the excretion rate of Ipilimumab which could result in a higher serum level.
Acetazolamide	Acetazolamide may increase the excretion rate of Ipilimumab which could result in a lower serum level and potentially a reduction in efficacy.
Acetylsalicylic acid	Acetylsalicylic acid may decrease the excretion rate of Ipilimumab which could result in a higher serum level.
Aclidinium	Ipilimumab may decrease the excretion rate of Aclidinium which could result in a higher serum level.
Acrivastine	Ipilimumab may decrease the excretion rate of Acrivastine which could result in a higher serum level.
Acyclovir	Acyclovir may decrease the excretion rate of Ipilimumab which could result in a higher serum level.

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Food Interactions

No interactions found.

Products

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International/Other Brands

Yervoy

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Yervoy	Injection, solution, concentrate	5 mg/ml	Intravenous	Bristol Myers Squibb Pharma Eeig	2020-12-22	Not applicable
Yervoy	Injection	5 mg/1mL	Intravenous	E.R. Squibb & Sons, L.L.C.	2011-03-25	Not applicable
Yervoy	Injection	5 mg/1mL	Intravenous	Baxter Pharmaceutical Solutions, LLC	2011-03-25	2016-04-11
Yervoy	Injection, solution, concentrate	5 mg/ml	Intravenous	Bristol Myers Squibb Pharma Eeig	2020-12-22	Not applicable
Yervoy	Injection	5 mg/1mL	Intravenous	E.R. Squibb & Sons, L.L.C.	2011-03-25	Not applicable
Yervoy	Liquid	5 mg / mL	Intravenous	Bristol Myers Squibb	2012-03-08	Not applicable
Yervoy	Injection	5 mg/1mL	Intravenous	Baxter Pharmaceutical Solutions, LLC	2011-03-25	2016-04-11

Chemical Identifiers

UNII: 6T8C155666
CAS number: 477202-00-9

References

General References

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. [Article]
Thumar JR, Kluger HM: Ipilimumab: a promising immunotherapy for melanoma. Oncology (Williston Park). 2010 Dec;24(14):1280-8. [Article]
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. [Article]
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. [Article]
FDA Approved Drug Products: Yervoy Ipilimumab Intravenous Injection [Link]
BC Cancer Agency: Yervoy Monograph [Link]

External Links

KEGG Drug: D04603
PubChem Substance: 347910341
RxNav: 1094833
ChEMBL: CHEMBL1789844
RxList: RxList Drug Page
Drugs.com: Drugs.com Drug Page
Wikipedia: Ipilimumab

FDA label

Download (1.13 MB)

MSDS

Download (479 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Active Not Recruiting	Treatment	Lung Cancers	1
4	Active Not Recruiting	Treatment	Melanoma, Malignant	1
4	Active Not Recruiting	Treatment	Renal Cell Adenocarcinoma	1
4	Not Yet Recruiting	Treatment	Renal Cancers	1
4	Terminated	Treatment	Metastatic Melanoma	1
3	Active Not Recruiting	Treatment	Advanced Renal Cell Carcinoma / Metastatic Renal Cell Carcinoma	1
3	Active Not Recruiting	Treatment	Gastroesophageal Junction Cancer / Malignant Neoplasm of Stomach	1
3	Active Not Recruiting	Treatment	Head and Neck Carcinoma	2
3	Active Not Recruiting	Treatment	Lung Cancers	1
3	Active Not Recruiting	Treatment	Melanoma of Unknown Primary / Recurrent Melanoma / Stage IIIB Cutaneous Melanoma AJCC v7 / Stage IIIC Cutaneous Melanoma AJCC v7 / Stage IV Cutaneous Melanoma AJCC v6 and v7	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Injection	Intravenous	5 mg/1mL
Injection, solution, concentrate	Intravenous	5 mg/ml
Injection, solution, concentrate	Intravenous; Parenteral
Liquid	Intravenous	5 mg / mL
Injection, solution, concentrate	Intravenous
Solution	Intravenous	50 mg
Solution	Intravenous	5 mg/1ml

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
CA2381770	No	2007-08-07	2020-08-08

Properties

State

Liquid

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.

Targets

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Details1. Cytotoxic T-lymphocyte protein 4

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Inhibitor
Antibody

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. [Article]

Drug created on March 19, 2008 16:16 / Updated on July 24, 2021 14:57

Ipilimumab

Identification

Pharmacology

Interactions

Products

Categories

Chemical Identifiers

References

Clinical Trials

Pharmacoeconomics

Properties

Targets

References