Identification

Name
Ibalizumab
Accession Number
DB12698  (DB05435)
Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Description

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].

Protein chemical formula
Not Available
Protein average weight
Not Available
Sequences
Not Available
Synonyms
  • Ibalizumab-uiyk
External IDs
TNX-355
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
TrogarzoInjection, solution150 mg/1mLIntravenousTheratechnologies2018-04-20Not applicableUs
Categories
UNII
LT369U66CE
CAS number
680188-33-4

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].

Associated Conditions
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
UT-cell surface glycoprotein CD4
antagonist
Human
UC-C chemokine receptor type 5
antagonist
Human
UC-X-C chemokine receptor type 4
antagonist
Human
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].

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].

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AbciximabThe risk or severity of adverse effects can be increased when Abciximab is combined with Ibalizumab.
AbituzumabThe risk or severity of adverse effects can be increased when Ibalizumab is combined with Abituzumab.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Ibalizumab.
AdecatumumabThe risk or severity of adverse effects can be increased when Adecatumumab is combined with Ibalizumab.
AducanumabThe risk or severity of adverse effects can be increased when Aducanumab is combined with Ibalizumab.
AfelimomabThe risk or severity of adverse effects can be increased when Afelimomab is combined with Ibalizumab.
AlemtuzumabThe risk or severity of adverse effects can be increased when Alemtuzumab is combined with Ibalizumab.
AlirocumabThe risk or severity of adverse effects can be increased when Alirocumab is combined with Ibalizumab.
AmatuximabThe risk or severity of adverse effects can be increased when Ibalizumab is combined with Amatuximab.
AMG 108The risk or severity of adverse effects can be increased when AMG 108 is combined with Ibalizumab.
Food Interactions
Not Available

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. [PubMed:14722894]
  2. Vermeire K, Schols D, Bell TW: CD4 down-modulating compounds with potent anti-HIV activity. Curr Pharm Des. 2004;10(15):1795-803. [PubMed:15180541]
  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. [PubMed:1888898]
  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]
External Links
PubChem Substance
347911363
Wikipedia
Ibalizumab
FDA label
Download (491 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2CompletedTreatmentHuman Immunodeficiency Virus (HIV)1
2CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections1
2Unknown StatusTreatmentHuman Immunodeficiency Virus (HIV) Infections1
3CompletedTreatmentHuman Immunodeficiency Virus (HIV)1
3No Longer AvailableNot AvailableHuman Immunodeficiency Virus (HIV)1
3RecruitingTreatmentHuman Immunodeficiency Virus (HIV)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, solutionIntravenous150 mg/1mL
Prices
Not Available
Patents
Not Available

Properties

State
Not Available
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
Unknown
Actions
Antagonist
General Function
Zinc ion binding
Specific Function
Accessory protein for MHC class-II antigen/T-cell receptor interaction. May regulate T-cell activation. Induces the aggregation of lipid rafts.(Microbial infection) Acts as a receptor for human imm...
Gene Name
CD4
Uniprot ID
P01730
Uniprot Name
T-cell surface glycoprotein CD4
Molecular Weight
51110.205 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Antagonist
General Function
Virus receptor activity
Specific Function
Receptor for a number of inflammatory CC-chemokines including MIP-1-alpha, MIP-1-beta and RANTES and subsequently transduces a signal by increasing the intracellular calcium ion level. May play a r...
Gene Name
CCR5
Uniprot ID
P51681
Uniprot Name
C-C chemokine receptor type 5
Molecular Weight
40523.645 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Antagonist
General Function
Virus receptor activity
Specific 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. Acts as a receptor for extracellular ubiq...
Gene Name
CXCR4
Uniprot ID
P61073
Uniprot Name
C-X-C chemokine receptor type 4
Molecular Weight
39745.055 Da

Drug created on October 20, 2016 17:40 / Updated on November 02, 2018 07:28