Identification
- Summary
Etrolizumab is a humanized IgG1κ anti-β7 integrin subunit monoclonal antibody under investigation for use in ulcerative colitis and Crohn's disease.
- Generic Name
- Etrolizumab
- DrugBank Accession Number
- DB12189
- Background
Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, is typified by a chronic gastrointestinal inflammatory microenvironment, driven in part by the excessive infiltration and retention of intestinal-homing lymphocytes.1,2,4,5 A recent class of drugs designed to impair lymphocyte homing, so-called "anti-trafficking agents" (ATAs), have shown some success and include approved drugs such as natalizumab and vedolizumab, which target integrins and impair their interaction with adhesion molecules on epithelial cells.3 In the case of natalizumab, which targets the α4 integrin subunit, this has also resulted in undesirable blockade of lymphocyte CNS trafficking and reported cases of progressive multifocal leukoencephalopathy (PML).1,5 Etrolizumab is a humanized IgG1κ monoclonal antibody directed against the β7 subunit of gastrointestinal α4β7 and αEβ7 integrins that, due to its target specificity, appears as or more efficacious than vedolizumab and without the CNS effects of natalizumab.1,2,3,5
Etrolizumab is currently under investigation for the treatment of ulcerative colitis and Crohn's disease.
- Type
- Biotech
- Groups
- Investigational
- Biologic Classification
- Protein Based Therapies
Monoclonal antibody (mAb) - Protein Chemical Formula
- Not Available
- Protein Average Weight
- Not Available
- Sequences
- Not Available
- Synonyms
- Etrolizumab
Pharmacology
- Indication
Not Available
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Etrolizumab is a humanized anti-β7 integrin subunit monoclonal antibody that impairs the targeting and retention of gut-specific lymphocytes contributing to an inflammatory microenvironment in ulcerative colitis and Crohn's disease.1 Studies in cynomolgus monkeys demonstrate that etrolizumab specifically increases the number of circulating β7high lymphocytes without significantly altering other lymphocyte populations.5 This is in good agreement with the observed β7 occupancy by etrolizumab in animal models and human blood samples during clinical trials. Early studies in mice and cynomolgus monkeys suggested etrolizumab serum concentrations of 1-10 μg/mL were required to maintain β7 saturation;5 data from human clinical studies revealed an EC90 for β7 occupancy of 1.3 μg/mL, and serum concentrations in the range of 1-3 μg/mL demonstrated complete or near-complete β7 saturation in adult and pediatric patients.6,7 Unlike natalizumab, which binds α4 integrin and hence disrupts the α4β1:VCAM-1 interactions required for CNS immune cell homing, there have been no associations thus far between etrolizumab and progressive multifocal leukoencephalopathy (PML).1,5
- Mechanism of action
Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, is characterized by chronic inflammation of the gastrointestinal tract. This inflammation is driven, at least in part, by excessive infiltration and retention of intestinal-homing lymphocytes.1,2,4,5 An adhesion cascade drives the infiltration of immune cells. The binding of immune cell glycoproteins to their corresponding epithelial cell selectins results in partial retention and the "rolling" of immune cells along the endothelium. A stable arrest is mediated by stronger interactions between immune cell integrins and cell adhesion molecules (CAMs) on the endothelial cell; once arrested, immune cells will extravasate and enter the target tissue.3,4 Tissue retention is mediated by similar interactions between cell-surface molecules within the target tissue, which impedes immune cells' re-entry into the systemic circulation.1
Integrins are heterodimeric cell-surface receptors comprising transmembrane α and β subunits, of which multiple forms exist. Integrins primarily interact with CAMs, which are cell-surface members of the immunoglobulin superfamily expressed on vascular endothelial cells.1,4,5 Of primary importance to intestinal homing is the mucosal addressin cellular adhesion molecule (MAdCAM-1), which interacts strongly with α4β7 integrins, and vascular cell adhesion molecule (VCAM-1), which binds with lower affinity. MAdCAM-1 also binds to the CS-1 fragment of the extracellular matrix molecule fibronectin.1,3,4,5 α4β7 integrin is expressed at high levels on intestinal-homing lymphocytes but can also be found on natural killer cells, basophils, eosinophils, macrophages, activated monocytes, and mast cells.1,5 Another β7-containing integrin, αEβ7, is primarily expressed by lymphocytes, dendritic cells, mast cells, and innate lymphoid cells within the mucosal immune system, including the respiratory, gastrointestinal, and urogenital tracts, where it interacts with E-cadherin on mucosal tissue cells.1,3,4,5
The infiltration and retention of immune cells as a mechanism of IBD is suggested by observations across multiple studies of an increase in the number of, and alteration in the secreted cytokine profile of, α4β7+ and αEβ7+ immune cells in the gastrointestinal tract of IBD patients.1 These observations mirror an increase in the expression of the relevant CAMs, MAdCAM-1 and E-cadherin, in these patients.1,5 Although the mechanism has not been completely elucidated, it is clear that an increase in the number and retention of gut-homing immune cells capable of sustaining an inflammatory microenvironment is a crucial element of IBD pathophysiology.1
Etrolizumab is a humanized monoclonal antibody specific for the β7 integrin subunit;1,5 it has a Kd of 116 ± 11 pmol/L against human α4β7 and 1800 ± 170 pmol/L against human αEβ7, as assessed by transfection in HEK293 cells.1 This strong binding provides efficient inhibition of integrin/CAM interactions. Etrolizumab has an IC50 for the α4β7 interactions with MAdCAM-1, VCAM-1, and fibronectin of 0.075 ± 0.034, 0.089 ± 0.009, and 0.119 ± 0.056 nmol/L, respectively. Etrolizumab also inhibits the interaction of αEβ7 with E-cadherin, albeit less effectively (IC50 of 3.96 ± 1.78 nmol/L).1 While etrolizumab does not exhibit antibody-dependent cytotoxicity, it disrupts the integrin-CAM interactions involved in gut immune cell residence, in part by inducing the endocytic uptake of bound integrin receptors, and therefore reduces the inflammatory burden in IBD.1,2,5,6
Target Actions Organism AIntegrin beta-7 binderantibodyHumans - Absorption
Etrolizumab administered as a single 105 mg subcutaneous injection by prefilled syringe or autoinjector device in healthy adults aged 18-55 resulted in a geometric mean (%CV) Cmax of 12.2-12.5 μg/mL (28.3-32.0), AUClast of 319-325 μg*day/mL (33.1-35.3), and AUC0-∞ of 329-337 μg*day/mL (35.2-36.0). The median time to maximum serum concentration (Tmax) was 5.04 days (range 2.98-14.0) for the autoinjector and 6.97 days (range 3.00-14.0) for the syringe.8 Studies in adult patients with ulcerative colitis revealed approximately linear pharmacokinetics at doses >1.0 mg/kg and an accumulation ratio over three doses (four weeks apart) of 1.2-fold for intravenous dosing and 2.0-fold for subcutaneous dosing. The apparent bioavailability of subcutaneous etrolizumab was estimated at 67% at the 3 mg/kg level.9
Etrolizumab pharmacokinetics were also evaluated in pediatric patients aged 4-17 years with moderately to severely active ulcerative colitis or Crohn's disease given either 1.5 mg/kg etrolizumab every four weeks (q4w) for four doses or 3.0 mg/kg every eight weeks (q8w) for two doses by subcutaneous injection. The 1.5 mg/kg dose resulted in a mean Cmax of 7.7 ± 2.18 μg/mL after the first dose and 9.8 ± 4.86 μg/mL after the last dose and an AUC84-112d of 167 ± 86.9 μg*day/mL. The 3.0 mg/kg dose resulted in a mean Cmax of 19.0 ± 8.21 μg/mL after the first dose and 18.1 ± 6.25 μg/mL after the last dose and an AUC56-112d of 521 ± 306 μg*day/mL.7
- Volume of distribution
Modelling of etrolizumab pharmacokinetic data from adult patients with moderate to severe ulcerative colitis yielded a central volume of distribution of either 2570 mL (from the quasi-steady-state target-mediated drug disposition model) or 3200 mL (from the linear model).6 Subcutaneous administration of either 1.5 mg/kg q4w or 3.0 mg/kg q8w etrolizumab in pediatric patients with ulcerative colitis or Crohn's disease yielded an apparent volume of distribution of 4920 ± 2440 mL and 3910 ± 1830 mL, respectively.7
- Protein binding
Not Available
- Metabolism
Etrolizumab, as a monoclonal antibody, is expected to undergo proteolytic degradation in multiple locations throughout the body.
- Route of elimination
Not Available
- Half-life
Etrolizumab administered as a single 105 mg subcutaneous injection by prefilled syringe or autoinjector device in healthy adults aged 18-55 resulted in a similar mean half-life of 11.8 ± 3.85 days for the injector and 12.2 ± 4.39 days for the syringe.8 In adult ulcerative colitis patients, the half-life was similar at higher doses (10.6-13.1 days for 3-10 mg/kg) but shorter at smaller doses (4.8-7.4 days at 0.3-1.0 mg/kg).9 The half-life in pediatric patients was similar at 7.3 ± 1.76 days at the 1.5 mg/kg q4w level and 8.7 ± 3.74 at the 3.0 mg/kg q8w level.7
- Clearance
Etrolizumab has a mean clearance in adult patients of ~300 mL/day, which appears higher in pediatric patients (385-505 mL/day).6,7,8
- Adverse Effects
Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!Improve decision support & research outcomes with our structured adverse effects data.- Toxicity
Not Available
- 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 Integrate drug-drug
interactions in your softwareAbciximab The risk or severity of adverse effects can be increased when Abciximab is combined with Etrolizumab. Adalimumab The risk or severity of adverse effects can be increased when Adalimumab is combined with Etrolizumab. Aducanumab The risk or severity of adverse effects can be increased when Etrolizumab is combined with Aducanumab. Alemtuzumab The risk or severity of adverse effects can be increased when Alemtuzumab is combined with Etrolizumab. Alirocumab The risk or severity of adverse effects can be increased when Alirocumab is combined with Etrolizumab. - Food Interactions
- Not Available
Categories
- Drug Categories
- Chemical TaxonomyProvided by Classyfire
- 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
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- I2A72G2V3J
- CAS number
- 1044758-60-2
References
- General References
- Tang MT, Keir ME, Erickson R, Stefanich EG, Fuh FK, Ramirez-Montagut T, McBride JM, Danilenko DM: Review article: nonclinical and clinical pharmacology, pharmacokinetics and pharmacodynamics of etrolizumab, an anti-beta7 integrin therapy for inflammatory bowel disease. Aliment Pharmacol Ther. 2018 Jun;47(11):1440-1452. doi: 10.1111/apt.14631. Epub 2018 Mar 30. [Article]
- Lichnog C, Klabunde S, Becker E, Fuh F, Tripal P, Atreya R, Klenske E, Erickson R, Chiu H, Reed C, Chung S, Neufert C, Atreya I, McBride J, Neurath MF, Zundler S: Cellular Mechanisms of Etrolizumab Treatment in Inflammatory Bowel Disease. Front Pharmacol. 2019 Feb 1;10:39. doi: 10.3389/fphar.2019.00039. eCollection 2019. [Article]
- Zundler S, Wiendl M, Neurath MF: Anti-trafficking agents in the treatment of inflammatory bowel disease. Curr Opin Gastroenterol. 2019 Nov;35(6):499-506. doi: 10.1097/MOG.0000000000000579. [Article]
- Biswas S, Bryant RV, Travis S: Interfering with leukocyte trafficking in Crohn's disease. Best Pract Res Clin Gastroenterol. 2019 Feb - Apr;38-39:101617. doi: 10.1016/j.bpg.2019.05.004. Epub 2019 May 28. [Article]
- Stefanich EG, Danilenko DM, Wang H, O'Byrne S, Erickson R, Gelzleichter T, Hiraragi H, Chiu H, Ivelja S, Jeet S, Gadkari S, Hwang O, Fuh F, Looney C, Howell K, Albert V, Balazs M, Refino C, Fong S, Iyer S, Williams M: A humanized monoclonal antibody targeting the beta7 integrin selectively blocks intestinal homing of T lymphocytes. Br J Pharmacol. 2011 Apr;162(8):1855-70. doi: 10.1111/j.1476-5381.2011.01205.x. [Article]
- Wei X, Gibiansky L, Wang Y, Fuh F, Erickson R, O'Byrne S, Tang MT: Pharmacokinetic and Pharmacodynamic Modeling of Serum Etrolizumab and Circulating beta7 Receptor Occupancy in Patients With Ulcerative Colitis. J Clin Pharmacol. 2018 Mar;58(3):386-398. doi: 10.1002/jcph.1031. Epub 2017 Nov 26. [Article]
- Zhang W, Scalori A, Fuh F, McBride J, She G, Kierkus J, Korczowksi B, Li R, Abouhossein M, Kadva A, Park KT, Tang MT: Pharmacokinetics, Pharmacodynamics, and Safety of Etrolizumab in Children With Moderately to Severely Active Ulcerative Colitis or Crohn's Disease: Results from a Phase 1 Randomized Trial. Inflamm Bowel Dis. 2021 Nov 29. pii: 6446094. doi: 10.1093/ibd/izab275. [Article]
- Zhang W, Tyrrell H, Ding HT, Pulley J, Boruvka A, Erickson R, Abouhossein M, Ravanello R, Tang MT: Comparable Pharmacokinetics, Safety, and Tolerability of Etrolizumab Administered by Prefilled Syringe or Autoinjector in a Randomized Trial in Healthy Volunteers. Adv Ther. 2021 May;38(5):2418-2434. doi: 10.1007/s12325-021-01661-6. Epub 2021 Mar 29. [Article]
- Rutgeerts PJ, Fedorak RN, Hommes DW, Sturm A, Baumgart DC, Bressler B, Schreiber S, Mansfield JC, Williams M, Tang M, Visich J, Wei X, Keir M, Luca D, Danilenko D, Egen J, O'Byrne S: A randomised phase I study of etrolizumab (rhuMAb beta7) in moderate to severe ulcerative colitis. Gut. 2013 Aug;62(8):1122-30. doi: 10.1136/gutjnl-2011-301769. Epub 2012 Jun 20. [Article]
- External Links
- PubChem Substance
- 347911296
- Wikipedia
- Etrolizumab
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 3 Completed Treatment Crohn's Disease (CD) 1 3 Completed Treatment Ulcerative Colitis 4 3 Terminated Treatment Crohn's Disease (CD) 1 3 Terminated Treatment Ulcerative Colitis 1 2 Completed Treatment Ulcerative Colitis 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
- Not Available
- Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Not Available
- Experimental Properties
- Not Available
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- BinderAntibody
- General Function
- Virus receptor activity
- Specific Function
- Integrin alpha-4/beta-7 (Peyer patches-specific homing receptor LPAM-1) is an adhesion molecule that mediates lymphocyte migration and homing to gut-associated lymphoid tissue (GALT). Integrin alph...
- Gene Name
- ITGB7
- Uniprot ID
- P26010
- Uniprot Name
- Integrin beta-7
- Molecular Weight
- 86902.415 Da
References
- Stefanich EG, Danilenko DM, Wang H, O'Byrne S, Erickson R, Gelzleichter T, Hiraragi H, Chiu H, Ivelja S, Jeet S, Gadkari S, Hwang O, Fuh F, Looney C, Howell K, Albert V, Balazs M, Refino C, Fong S, Iyer S, Williams M: A humanized monoclonal antibody targeting the beta7 integrin selectively blocks intestinal homing of T lymphocytes. Br J Pharmacol. 2011 Apr;162(8):1855-70. doi: 10.1111/j.1476-5381.2011.01205.x. [Article]
- Lichnog C, Klabunde S, Becker E, Fuh F, Tripal P, Atreya R, Klenske E, Erickson R, Chiu H, Reed C, Chung S, Neufert C, Atreya I, McBride J, Neurath MF, Zundler S: Cellular Mechanisms of Etrolizumab Treatment in Inflammatory Bowel Disease. Front Pharmacol. 2019 Feb 1;10:39. doi: 10.3389/fphar.2019.00039. eCollection 2019. [Article]
Drug created at October 20, 2016 21:34 / Updated at January 20, 2022 10:18