Mechanism of Action: HIV-1 entry inhibitor. PRO-140, a humanized IgG4 monoclonal antibody (mAb), binds to hydrophilic extracellular domains on CCR5, and via competitive mechanisms it inhibits CCR5-mediated HIV-1 viral entry, without preventing CC-chemokine signaling at antiviral concentrations.4,5,6 PRO-140 does not inhibit CXCR4-using viruses.7
T½: 3.4 and 3.7 days (multiple subcutaneous [SC] doses, 162 mg and 324 mg) 7; 3.13 and 3.33 days (single intravenous [IV] dose, 5 mg/kg and 10 mg/kg).8
Metabolism/Elimination: PRO-140 pharmacokinetic characteristics are consistent with a saturable, antigen-mediated clearance pathway.5
Resistance: In vitro, PRO-140 has exhibited activity against viruses resistant to maraviroc.9
Tropism shifts were observed in 5 out of 84 PRO-140-treated subjects in single-dose IV or multiple-dose SC studies. Three of the 5 subjects with tropism shifts were classified as having pre-existing minor variants of CXCR4-using HIV-1 (based on ES Trofile assay results), while analysis of the pre-treatment viruses of the other 2 subjects is being investigated. No emergence of viral resistance to PRO-140 was observed in these studies, as indicated by Monogram assay results.10
Dosing in Clinical Trials
PRO-140 can be administered via SC infusion.
- Phase IIa multiple-dose study (treatment-naive or –experienced, with no antiretroviral therapy for at least 12 weeks; only R5-HIV detectable):
- PRO-140 162 mg or 324 mg weekly; or 324 mg biweekly versus placebo.7,11
PRO-140 can be administered via IV infusion.
- Phase IIa single-dose study (treatment-naive or –experienced, with no antiretroviral therapy for at least 12 weeks; only R5-HIV detectable):
- PRO-140 5 mg/kg or 10 mg/kg versus placebo.8,12
The most frequent systemic adverse events occurring in a Phase IIa trial (associated with either placebo or SC PRO-140) were diarrhea, headache, lymphadenopathy, and hypertension. There were no drug-related serious adverse events or dose-limiting toxicities among participants. There were also no clinically relevant drug-related effects on ECG, including QTc intervals, among participants. Adverse events related to administration-site reactions were infrequent and described as mild, transient, and self-resolving. Administration-site reactions occurring in more than 5% of participants were induration, pain, and irritation.7
Adverse events associated with IV PRO-140 and occurring in more than two subjects in a Phase IIa trial were headache and nasal congestion. There were no clinically relevant changes in ECG parameters, including QTc intervals, or laboratory or vital sign abnormalities among the subjects.8
PRO-140 drug interactions are currently unknown.
1. United States National Library of Medicine. ChemIDplus Advanced
2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development
3. CytoDyn Inc.: Press Releases. CytoDyn Announces Acquisition of PRO 140
. Accessed May 15, 2013.
. Olson WC, Doshan H, Zhan C, et al. Prolonged Coating of CCR5 Lymphocytes by PRO 140, a Humanized CCR5 Monoclonal Antibody for HIV-1 Therapy
. Paper presented at: 13th
Conference on Retroviruses and Opportunistic Infections (CROI); February 5-8, 2006; Denver, CO. Paper 515.
. Jacobson JM, Saag MS, Thompson MA, et al. Antiviral activity of single-dose PRO 140, a CCR5 monoclonal antibody, in HIV-infected adults
. J Infect Dis
. 2008 Nov 1;198(9):1345-52.
. Trkola A, Ketas TJ, Nagashima KA, et al. Potent, broad-spectrum inhibition of human immunodeficiency virus type 1 by the CCR5 monoclonal antibody PRO 140
. J Virol
. 2001 Jan;75(2):579-88.
. Jacobson JM, Thompson MA, Lalezari JP, et al. Anti-HIV-1 activity of weekly or biweekly treatment with subcutaneous PRO 140, a CCR5 monoclonal antibody
. J Infect Dis
. 2010 May 15;201(10):1481-7.
. Jacobson JM, Lalezari JP, Thompson MA, et al. Phase 2a study of the CCR5 monoclonal antibody PRO 140 administered intravenously to HIV-infected adults
. Antimicrob Agents Chemother
. 2010 Oct;54(10):4137-42.
. Marozsan AJ, Ketas TJ, Huang W, et al. CCR5 monoclonal antibody PRO 140 inhibited HIV-1 resistant to maraviroc, a small molecule CCR5 antagonist
. Abstract presented at: 17th
International AIDS Conference; August 3-8, 2008; Mexico City, Mexico. Abstract TUAA0305.
. Jacobson J, Morris S, Carpenito J, et al. Co-receptor Tropism and Viral Resistance following Short-term Monotherapy with the Anti-CCR5 Monoclonal Antibody PRO 140
. Paper presented at: 17th
Conference on Retroviruses and Opportunistic Infections (CROI); February 16-19, 2010; San Francisco, CA. Paper 531.
. Thompson M, Lalezari J, Saag M, et al. Weekly and Biweekly Subcutaneous PRO 140 Demonstrates Potent, Sustained Antiviral Activity
. Paper presented at: 16th
Conference on Retroviruses and Opportunistic Infections (CROI); February 8-11, 2009; Montreal, Canada. Paper 571a.
. Jacobson J, Thompson M, Fischl M, et al. Phase 2a Study of PRO 140 in HIV-Infected Adults
. Abstract presented at: 49th
Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); September 12-15, 2009; San Francisco, CA. Abstract H-1229.
Last Reviewed: May 23, 2013
Last Updated: May 23, 2013