Ibalizumab

Identification

Summary

Ibalizumab is a CD4-specific antibody used to treat HIV infections.

Brand Names
Trogarzo
Generic Name
Ibalizumab
DrugBank Accession Number
DB12698
Background

Ibalizumab (also known as ibalizumab-uiyk and formerly known as TNX-355) is a monoclonal antibody that binds to CD4 receptors on the surface of CD4-positive cells, preventing HIV particle entry into the lymphocytes. It is an advanced and current antibody in development for the treatment of HIV/AIDS. It has been developed by Taimed biologics and Theratechnologies 8,5.

This drug was approved in March 2018 for the management of treatment-resistant HIV 5. In October 2022, the FDA approved the administration of Trogarzo (ibalizumab-uiyk) by intravenous push, allowing for a faster drug administration.11,12

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Protein Chemical Formula
Not Available
Protein Average Weight
Not Available
Sequences
Not Available
Synonyms
  • Ibalizumab
  • Ibalizumab-uiyk
External IDs
  • TMB 355
  • TMB-355
  • TNX 355
  • TNX-355

Pharmacology

Indication

Indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in highly treatment-experienced adults with multidrug-resistant HIV-1 infection failing their current antiretroviral regimen Label.

The approval of Trogarzo was supported by a clinical trial of 40 treatment-experienced adults with MDR HIV-1 infection who persistently had elevated levels of HIV RNA in their blood despite heavy antiretroviral therapy. The majority of study patients had previously been treated with ≥10 antiretroviral medications 5.

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Used in combination to treatMultidrug resistant hiv-1 infection•••••••••••••••••••••••• ••••••• •••••••••••••• •••••••• ••••••••• ••••••••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Trogarzo safety and effectiveness have been confirmed in a clinical trial of 40 patients who suffer multidrug-resistant HIV. The majority of these patients experienced a substantial decrease in their HIV-RNA levels within 7 days after receiving the drug. Approximately 43 percent of patients continued to experience HIV-RNA inhibition after 24 weeks of taking Trogarzo 5.

Trogarzo inhibits viral entry into cells, effectively managing HIV-1 infection in those who have attempted other therapies to no avail 5.

Mechanism of action

Ibalizumab is a monoclonal antibody and viral-entry inhibitor that coats CD4-positive cells, the main target of HIV infection. By blocking viral entry into CD4 cells, ibalizumab creates a barrier for HIV, which is a different mechanism from those of entry inhibitors that target viral proteins or chemokine co-receptors.

Ibalizumab is a CD4 domain 2-directed post-attachment HIV-1 inhibitor. This binding specificity of ibalizumab-uiyk to domain 2 of CD4 allows ibalizumab-uiyk to prevent viral entry into host cells without causing immunosuppression. Epitope mapping studies confirm that ibalizumab-uiyk binds to a conformational epitope located mainly in domain 2 of the extracellular region of the CD4 receptor. This epitope is located on the surface of CD4 opposite to the site in domain 1 that is essential for CD4 binding of the MHC class II molecules. This drug, therefore, does not interfere with CD4 cell-mediated immune functions. In addition, ibalizumab-uiyk does not interfere with gp120 attachment to CD4 Label. Ibalizumab’s post-binding conformational effects block the gp120-CD4 complex from interacting with CCR5 or CXCR4 and thus prevents viral entry and fusion 6.

CD4 is an integral cell surface glycoprotein that is able to enhance T cell-specific antigen responses when it interacts with its physiological ligand, class II major histocompatibility (MHC) molecules. In addition, CD4 is a specific cell-surface receptor for the human immunodeficiency virus-1 (HIV-1).

The entry of human immunodeficiency virus (HIV) into cells requires the sequential binding of the viral exterior envelope glycoprotein, gp120, with the CD4 glycoprotein and a chemokine receptor on the cell surface. In addition, the CD4/gp120 interaction may directly inhibit T cell function 3.

In addition to the above mechanism of action, it was found in one study that ibalizumab-uiyk inhibits the replication of CCR5- and CXCR4- receptor laboratory strains and primary isolates of HIV-1 in phytohemagglutinin-stimulated peripheral blood lymphocytes, further confirming its action 9.

TargetActionsOrganism
AC-C chemokine receptor type 5
antagonist
Humans
AC-X-C chemokine receptor type 4
antagonist
Humans
AT-cell surface glycoprotein CD4
antagonist
Humans
Absorption

Not Available

Volume of distribution

4.8 L Label

Protein binding

Not Available

Metabolism

Metabolized by CD4 receptor internalization, ibalizumab has no significant impact on liver or kidney metabolism 10.

Route of elimination

Not Available

Half-life

The half-life of ibalizumab is 3 to 3.5 days on average. The half-life was estimated from a multiple-dose study evaluating weekly ibalizumab 10 mg/kg in 1 study arm and biweekly ibalizumab 25 mg/kg in another study arm, given via intravenous (IV) infusion in adults with HIV 6. In one clinical trial, the elimination half-life increased from 2.7 to 64 hours as the dose increased from 0.3 to 25 mg/kg (0.01 to 0.9 times the approved recommended loading dose based on a 70 kg patient) Label.

Clearance

Following single-dose administrations of ibalizumab-uiyk as 0.5 to 1.5-hour infusions, the area under the concentration-time curve increased in a greater than dose-proportional manner, clearance decreased from 9.54 to 0.36 mL/h/kg and elimination half-life increased from 2.7 to 64 hours as the dose increased from 0.3 to 25 mg/kg Label.

Adverse Effects
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Toxicity

Immune reconstitution inflammatory syndrome has been reported in one patient treated with TROGARZO in combination with other antiretrovirals. During the initial phase of combination antiretroviral therapies, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections, which may necessitate further evaluation and treatment Label.

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.
DrugInteraction
AbciximabThe risk or severity of adverse effects can be increased when Abciximab is combined with Ibalizumab.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Ibalizumab.
Adenovirus type 7 vaccine liveThe therapeutic efficacy of Adenovirus type 7 vaccine live can be decreased when used in combination with Ibalizumab.
AducanumabThe risk or severity of adverse effects can be increased when Aducanumab is combined with Ibalizumab.
AlemtuzumabThe risk or severity of adverse effects can be increased when Alemtuzumab is combined with Ibalizumab.
Food Interactions
No interactions found.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
TrogarzoInjection, solution, concentrate200 mgIntravenousTheratechnologies2021-01-282019-07-25EU flag
TrogarzoInjection, solution150 mg/1mLIntravenousTheratechnologies2018-04-20Not applicableUS flag

Categories

ATC Codes
J05AX23 — Ibalizumab
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
Not Available

Chemical Identifiers

UNII
LT369U66CE
CAS number
680188-33-4

References

General References
  1. Kuritzkes DR, Jacobson J, Powderly WG, Godofsky E, DeJesus E, Haas F, Reimann KA, Larson JL, Yarbough PO, Curt V, Shanahan WR Jr: Antiretroviral activity of the anti-CD4 monoclonal antibody TNX-355 in patients infected with HIV type 1. J Infect Dis. 2004 Jan 15;189(2):286-91. Epub 2004 Jan 8. [Article]
  2. Vermeire K, Schols D, Bell TW: CD4 down-modulating compounds with potent anti-HIV activity. Curr Pharm Des. 2004;10(15):1795-803. [Article]
  3. Silberman SL, Goldman SJ, Mitchell DB, Tong AT, Rosenstein Y, Diamond DC, Finberg RW, Schreiber SL, Burakoff SJ: The interaction of CD4 with HIV-1 gp120. Semin Immunol. 1991 May;3(3):187-92. [Article]
  4. FDA label Trogarzo [Link]
  5. Trogarzo Approved to Treat Multidrug Resistant HIV-1 Infection [Link]
  6. Ibalizumab [Link]
  7. Safety, Pharmacokinetics, and Antiretroviral Activity of Multiple Doses of Ibalizumab (formerly TNX-355), an Anti-CD4 Monoclonal Antibody, in Human Immunodeficiency Virus Type 1-Infected Adults [Link]
  8. Ibalizumab [Link]
  9. Ibalizumab Targeting CD4 Receptors, An Emerging Molecule in HIV Therapy [Link]
  10. Monotherapy With Anti-CD4 Monoclonal Antibody Cuts Viral Load 10-Fold in 7 Days [Link]
  11. FDA Approved Drug Products: TROGARZO (ibalizumab-uiyk) injection, for intravenous use (October 2022) [Link]
  12. Globe Newswire: Theratechnologies’ Trogarzo Approved by FDA for 30-Second Intravenous (IV) Push, Simplifying HIV Treatment for Heavily Treatment-Experienced Population [Link]
PubChem Substance
347911363
Wikipedia
Ibalizumab
FDA label
Download (491 KB)

Clinical Trials

Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package
PhaseStatusPurposeConditionsCountStart DateWhy Stopped100+ additional columns
Not AvailableCompletedNot AvailableHuman Immunodeficiency Virus Type 1 (HIV-1) Infection1somestatusstop reasonjust information to hide
Not AvailableNo Longer AvailableNot AvailableHuman Immunodeficiency Virus (HIV) Infections1somestatusstop reasonjust information to hide
Not AvailableRecruitingNot AvailableHuman Immunodeficiency Virus (HIV) Infections / Multi-Antiviral Resistance1somestatusstop reasonjust information to hide
3CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections2somestatusstop reasonjust information to hide
3CompletedTreatmentHuman Immunodeficiency Virus Type 1 (HIV-1) Infection1somestatusstop reasonjust information to hide

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, solutionIntravenous150 mg/1mL
Injection, solution, concentrateIntravenous200 MG
Prices
Not Available
Patents
Not Available

Properties

State
Not Available
Experimental Properties
Not Available

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Receptor for a number of inflammatory CC-chemokines including CCL3/MIP-1-alpha, CCL4/MIP-1-beta and RANTES and subsequently transduces a signal by increasing the intracellular calcium ion level. May play a role in the control of granulocytic lineage proliferation or differentiation. Participates in T-lymphocyte migration to the infection site by acting as a chemotactic receptor (PubMed:30713770)
Specific Function
actin binding
Gene Name
CCR5
Uniprot ID
P51681
Uniprot Name
C-C chemokine receptor type 5
Molecular Weight
40523.645 Da
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Receptor for the C-X-C chemokine CXCL12/SDF-1 that transduces a signal by increasing intracellular calcium ion levels and enhancing MAPK1/MAPK3 activation (PubMed:10452968, PubMed:18799424, PubMed:24912431, PubMed:28978524). Involved in the AKT signaling cascade (PubMed:24912431). Plays a role in regulation of cell migration, e.g. during wound healing (PubMed:28978524). Acts as a receptor for extracellular ubiquitin; leading to enhanced intracellular calcium ions and reduced cellular cAMP levels (PubMed:20228059). Binds bacterial lipopolysaccharide (LPS) et mediates LPS-induced inflammatory response, including TNF secretion by monocytes (PubMed:11276205). Involved in hematopoiesis and in cardiac ventricular septum formation. Also plays an essential role in vascularization of the gastrointestinal tract, probably by regulating vascular branching and/or remodeling processes in endothelial cells. Involved in cerebellar development. In the CNS, could mediate hippocampal-neuron survival (By similarity)
Specific Function
actin binding
Gene Name
CXCR4
Uniprot ID
P61073
Uniprot Name
C-X-C chemokine receptor type 4
Molecular Weight
39745.055 Da
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Integral membrane glycoprotein that plays an essential role in the immune response and serves multiple functions in responses against both external and internal offenses. In T-cells, functions primarily as a coreceptor for MHC class II molecule:peptide complex. The antigens presented by class II peptides are derived from extracellular proteins while class I peptides are derived from cytosolic proteins. Interacts simultaneously with the T-cell receptor (TCR) and the MHC class II presented by antigen presenting cells (APCs). In turn, recruits the Src kinase LCK to the vicinity of the TCR-CD3 complex. LCK then initiates different intracellular signaling pathways by phosphorylating various substrates ultimately leading to lymphokine production, motility, adhesion and activation of T-helper cells. In other cells such as macrophages or NK cells, plays a role in differentiation/activation, cytokine expression and cell migration in a TCR/LCK-independent pathway. Participates in the development of T-helper cells in the thymus and triggers the differentiation of monocytes into functional mature macrophages
Specific Function
coreceptor activity
Gene Name
CD4
Uniprot ID
P01730
Uniprot Name
T-cell surface glycoprotein CD4
Molecular Weight
51110.205 Da

Drug created at October 20, 2016 23:40 / Updated at October 11, 2024 22:08