Mechanism of Action
: HIV-1 entry inhibitor. Ibalizumab, a humanized monoclonal antibody (mAb), binds to extracellular domain 2 of the CD4 receptor. The ibalizumab binding epitope is located at the interface between domains 1 and 2, opposite from the binding site for major histocompatibility complex class II molecules and gp120 attachment.4,5
Ibalizumab’s post-binding conformational effects prevent viral entry and fusion.6
: 3 to 3.5 days on average (estimated from a multiple-dose study of weekly ibalizumab 10 mg/kg in one study arm and biweekly ibalizumab 25 mg/kg in another study arm, given via intravenous [IV] infusion in HIV-infected adults).5
: Reduced ibalizumab susceptibility is associated with mutations that disrupt potential N-linked glycosolation sites (PNGS) in variable region 5 (V5) of HIV-1 envelope glycoproteins.4,7
Loss of glycan on the V5 N-terminus of gp120 is considered a major determinant of ibalizumab resistance. An in vitro
study demonstrated that strategic placement of a glycan in the variable region of the ibalizumab L chain to create a modified antibody can restore ibalizumab’s activity against certain ibalizumab-resistant strains of HIV-1.8
A Phase Ib study indicated that cross-resistance between enfuvirtide and ibalizumab does not occur.6
Dosing in Clinical Trials
: Safety and efficacy study of ibalizumab compared with placebo
: HIV-infected, treatment-experienced (triple-class-experienced)
: Ibalizumab 10 mg/kg administered via intravenous (IV) infusion weekly for 8 weeks, followed by either 10 mg/kg or 15 mg/kg every 2 weeks, versus placebo. All study participants also received an optimized background regimen.6,9,10
See references cited above for information on study results.)
: TMB-202; NCT0078414711
: Dose-response study of ibalizumab to determine optimal dose and regimen
: HIV-infected, treatment-experienced with documented resistance to at least one nucleoside reverse transcriptase inhibitor (NRTI), one non-nucleoside reverse transcriptase inhibitor (NNRTI), and one protease inhibitor (PI)
: Ibalizumab 800 mg administered via IV infusion every 2 weeks or 2000 mg every 4 weeks for 24 weeks. All participants also received an optimized background regimen.11,12
* Participants who demonstrated successful virologic response in Study TMB-202 could extend ibalizumab treatment beyond 24 weeks under a separate study protocol (NCT01056393).13
See references cited above for information on study results.)
Ibalizumab has also been investigated as an agent for HIV prevention. A Phase I safety study of ibalizumab given via subcutaneous injection in HIV-uninfected, at-risk participants has been completed.14
The most common treatment-emergent adverse events occurring in a Phase IIb trial were rash, diarrhea, headache, and nausea. Most events were mild to moderate. No drug-related deaths, serious adverse events, or discontinuations occurred. Laboratory and vital sign abnormalities were determined not to be clinically relevant.12
Ibalizumab drug interactions are currently unknown.
- United States National Library of Medicine. ChemIDplus Advanced. Available at: http://chem.sis.nlm.nih.gov/chemidplus/rn/680188-33-4. Last accessed on July 28, 2014.
- National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. Available at: http://chemdb.niaid.nih.gov/DrugDevelopmentHIV.aspx. Last accessed on July 28, 2014.
- University of Colorado, Denver. Compassionate Use of Dolutegravir and Ibalizumab for the Treatment of HIV Infection. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on January 3, 2014. NLM Identifier: NCT02028819. Available at: http://www.clinicaltrials.gov/ct2/show/NCT02028819. Last accessed on July 28, 2014.
- Toma J, Weinheimer SP, Stawiski E, et al. Loss of Asparagine-Linked Glycosylation Sites in Variable Region 5 of Human Immunodeficiency Virus Type 1 Envelope is Associated with Resistance to CD4 Antibody Ibalizumab. J Virol. 2011 Apr;85(8):3872-80. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3126132. Last accessed on July 28, 2014.
- Jacobson JM, Kuritzkes DR, Godofsky E, et al. 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. Antimicrob Agents Chemother. 2009 Feb;53(2):450-7. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2630626. Last accessed on July 28, 2014.
- Bruno CJ, Jacobson JM. Ibalizumab: an anti-CD4 monoclonal antibody for the treatment of HIV-1 infection. J Antimicrob Chemother. 2010 Sep;65(9):1839-41. Available at: http://jac.oxfordjournals.org/content/65/9/1839.long. Last accessed on July 28, 2014.
- Toma J, Weinheimer SP, Stawiski E, et al. Loss of Asparagine-Linked Glycosylation Sites in Variable Region Five of Human Immunodeficiency Virus Type 1 Envelope is Associated with Resistance to CD4 Antibody Ibalizumab. Poster presented at: 18th Conference on Retroviruses and Opportunistic Infections (CROI); February 27-March 2, 2011; Boston, MA. Poster 586. Available at: http://retroconference.org/2011/PDFs/586.pdf. Last accessed on May 22, 2013.
- Song R, Oren DA, Franco D, Seaman MS, Ho DD. Strategic addition of an N-linked glycan to a monoclonal antibody improves its HIV-1-neutralizing activity. Nat Biotechnol. 2013 Nov;31(11):1047-52. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3825789. Last accessed on July 28, 2014.
- Tanox. A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Three-Arm Study of the Anti-CD4 Monoclonal Antibody TNX-355 With Optimized Background Therapy in Treatment-Experienced Subjects Infected With HIV-1. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on August 10, 2004. NLM Identifier: NCT00089700. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00089700. Last accessed on July 28, 2014.
- Norris D, Morales J, Gathe J, et al. Phase 2 efficacy and safety of the novel entry inhibitor, TNX-355, in combination with optimized background regimen (OBR). Abstract presented at: 16th International AIDS Conference; August 13-18, 2006; Toronto, Canada. Abstract TUPE0058. Available at: http://www.iasociety.org/Default.aspx?pageId=11&abstractId=2195524. Last accessed on July 28, 2014.
- TaiMed Biologics Inc. A Phase 2b, Randomized, Double-Blinded, 48-Week, Multicenter, Dose-Response Study of Ibalizumab Plus an Optimized Background Regimen in Treatment-Experienced Patients Infected With HIV-1 (Amended to 24-Weeks). In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on October 30, 2008. NLM Identifier: NCT00784147. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00784147. Last accessed on July 28, 2014.
- Khanlou H, Gathe J Jr, Schrader S, Towner W, Weinheimer S, Lewis S. Safety, Efficacy, and Pharmacokinetics of Ibalizumab in Treatment-Experienced HIV-1 Infected Patients: a Phase 2b Study. Abstract presented at: 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); September 17-20, 2011; Chicago, IL; Abstract H2-794b. Available at: http://www.abstractsonline.com/Plan/ViewAbstract.aspx?sKey=553b562f-106a-48ff-b263-3cf82d20946e&cKey=214ca279-ad2f-4c51-8226-6747ca35bbab&mKey=%7b0C918954-D607-46A7-8073-44F4B537A439%7d. Last accessed on July 28, 2014.
- Kaiser Permanente. Investigator-Sponsored Protocol - Continued Use of Ibalizumab. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on January 22, 2010. NLM Identifier: NCT01056393. Available at: http://www.clinicaltrials.gov/ct2/show/NCT01056393. Last accessed on July 28, 2014.
- TaiMed Biologics Inc. A Phase 1, Randomized, Double-Blinded, Placebo-Controlled, Sequential Dose-Escalation Study of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Subcutaneously Administered Ibalizumab in HIV-Negative, At-Risk Volunteers. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on Feb 7, 2011. NLM Identifier: NCT01292174. Available at: http://www.clinicaltrials.gov/ct2/show/NCT01292174. Last accessed on July 28, 2014.
Last Reviewed: July 28, 2014
Last Updated: July 30, 2014