Drug Database: PGT121

Pharmacology

Pharmacology

Mechanism of Action

Broadly neutralizing antibody (bNAb). PGT121 is a recombinant human IgG1 monoclonal antibody. It is a second-generation bNAb that targets a V3 glycan-dependent epitope site on the HIV-1 envelope glycoprotein. PGT121 has potent neutralizing activity against 66% of a panel of 118 multi-clade pseudoviruses.^5,6 A derivative of PGT121, known as PGT121.414.LS, was designed for improved manufacturability, stability, and in vivo half-life.³

Second-generation HIV bNAbs are naturally occurring antibodies with potent neutralizing activity against a broad array of HIV strains. The utility of bNAbs is being researched for both HIV prevention and treatment/cure. By binding to sites on HIV envelope and through Fc receptor interactions, bNAbs can potentially 1) inhibit cell-free and cell-to-cell viral entry, 2) induce cellular phagocytosis and destruction by macrophages or antibody dependent cellular cytotoxicity (ADCC) by natural killer (NK) cells, and 3) promote the maturation and activity of dendritic cells.^7–10 Because it is difficult to induce in vivo generation of bNAbs using conventional vaccination techniques, bNAbs may need to be given by passive transfer, whereby a bNAb is directly administered to an individual.^7,11

PGT121 and PGT121.414.LS are being studied for HIV prevention and/or as a possible component to HIV treatment or cure.^1,4

Half-life (T_½)

A two-part Phase 1 trial (NCT02960581) initially evaluated a single intravenous (IV) or subcutaneous (SC) dose (3, 10, or 30 mg/kg) of PGT121 in adults without HIV and with HIV on ART. Thereafter, a single IV dose (30 mg/kg) of PGT121 in participants with HIV who were off ART and viremic was assessed. The elimination half-life of PGT121 was 22 days in participants without HIV, 16 days in participants with HIV and on ART, and 14 days in participants with HIV who were off ART and viremic.⁶

In a Phase 1/2a trial (IAVI T003; NCT03721510) evaluating triple bNAb therapy with PGT121, PGDM1400, and VRC07-523LS administered via IV infusion in adults with and without HIV, the median elimination half-life of PGT121 was approximately 19.9 days.^12,13

In a Phase 1 study (NCT04212091) of IV or SC infusions of PGT121.414.LS in healthy adults without HIV, PGT121.414.LS demonstrated a half-life ranging from 53.6 to 74.3 days.^14,15

Resistance

The IAVI T003 study (NCT03721510) evaluated monthly infusions of triple bNAb therapy (PGT121, PGDM1400, and VRC07-523LS) in 12 participants with viral suppression. Two participants who had viral rebound early in the study were found to have pre-existing baseline virus that was resistant to PGT121 and PGDM1400. In one of the two participants, the rebound virus selected for new PGT121 and VRCC07-523LS mutations, which were not present at baseline. Five participants experienced late viral rebound with low plasma levels of PGT121 and PGDM1400 but high levels of VRC07-523LS. One of the five participants received only three doses of triple bNAb infusions, and late rebound occurred despite having virus that was susceptible to the three bNAbs. In a second participant, the virus at rebound was found to be fully resistant to PGT121 and PGDM1400. In a third participant, rebound occurred with virus that had intermediate resistance to PGT121 and PGDM1400.^12,13

Select Clinical Trials

Select Clinical Trials

Study Identifiers: IAVI T003; NCT03721510

Sponsor: International AIDS Vaccine Initiative
Phase: 1/2a
Status: This study has been completed. 
Study Purpose: The purpose of this open-label study was to evaluate the safety, tolerability, pharmacokinetics, and antiviral activity of the bNAbs PGT121, VRC07-523LS, and PGDM1400 in adults with and without HIV.
Study Population: 

• Participants were adults without and with HIV.
• Participants with HIV had been on ART for at least 24 months, had HIV RNA <50 copies/mL for at least 12 months and at screening, and had CD4 counts ≥400 cells/mm³.¹²

Selected Study Results: Results presented at CROI 2024 showed that triple bNAb therapy with PGT121, VRC07-523LS, and PGDM1400 was generally safe and well tolerated. Most participants (83%) who received bNAb therapy while undergoing an analytical treatment interruption of ART maintained viral suppression for at least 28 weeks (duration of the dosing period). Although bNAb concentrations declined to low or undetectable levels during the follow-up period, 36% of the participants who completed follow-up had viral suppression through the end of the study (Week 44).¹³ 

Study Identifier: NCT04983030

Sponsor: Boris Juelg, MD PhD
Phase: 1/2a
Status: This study is currently recruiting participants.
Study Purpose: The purpose of this study is to evaluate the safety, immunogenicity, and efficacy of therapeutic HIV vaccines (Ad26.Mos4.HIV prime and MVA-BN-HIV boost) in combination with bNAbs (PGT121, PGDM1400, and VRC07-523LS) in adults on suppressive ART. Researchers will assess whether this combination strategy can control participants’ viral load levels during an ATI of ART.
Study Population: 

• Participants are adults with HIV who have been on a suppressive ART regimen for at least 48 weeks prior to screening.
• Participants have HIV RNA <50 copies/mL at screening and at least one documented result of HIV RNA <50 copies/mL after the last ART change.
• Participants have CD4 counts >450 cells/mm3 at screening and at least one documented result >300 cells/mm³ within the past 48 weeks prior to randomization.¹⁶

Study Identifiers: A5388; NCT05719441

Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Phase: 2
Status: See the ClinicalTrials.gov record for this study’s status. 
Study Purpose: The purpose of this study is to determine whether administration of the bNAbs VRC07-523LS and PGT121.414.LS in adults who are initiating ART during acute HIV infection is safe and to determine whether this combination strategy can induce HIV remission.
Study Population: The A5388 study is a multi-step trial.  Participants in Step 1 are treatment-naive adults with acute HIV infection who are willing to initiate ART at enrollment.¹⁷

Additional studies evaluating PGT121 for HIV treatment have been completed or are being conducted, including the following Phase 1 trials:

• IAVI T001 (NCT02960581): A study that evaluated the safety, tolerability, pharmacokinetics, and antiviral activity of PGT121 in adults with and without HIV. This study has been completed, and results are available from CROI 2019 and Nature Medicine (2021).¹⁸
• IAVI T002 (NCT03205917): A study that evaluated the safety, tolerability, pharmacokinetics, and antiviral activity of the bNAbs PGDM1400, PGT121, and VRC07-523LS in adults without HIV and adults with HIV who were not on ART. This study has been completed, and results are available from CROI 2022 and Nature Medicine (2022).¹⁹ 

Adverse Events

Adverse Events

IAVI T003; NCT03721510

In this Phase 1/2a trial, three participants without HIV received a single infusion of PGT121 and VRC07-523LS and three other participants without HIV received a single infusion of PGT121, VRC07-523LS, and PGDM1400. Thereafter, 12 participants with HIV received up to six monthly infusions of PGT121, VRC07-523LS, and PGDM1400. All three bNAbs studied were reported to be generally safe and well tolerated. There were four serious adverse events (SAEs) and/or a Grade 3 or higher adverse event (AE), all of which were considered unrelated to the study bNAbs.^12,13

Drug Interactions

Drug Interactions

Drug-drug interactions associated with PGT121 are currently unknown.

References

References

1. Treatment Action Group website. Research toward a cure trials. Accessed May 23, 2024
2. Mahomed S, Garrett N, Capparelli E, et al. Assessing the safety and pharmacokinetics of the monoclonal antibodies, VRC07-523LS and PGT121 in HIV negative women in South Africa: study protocol for the CAPRISA 012A randomised controlled phase I trial. BMJ Open. 2019;9(7):e030283. doi:10.1136/bmjopen-2019-030283. Accessed May 23, 2024
3. HIV Vaccine Trials Network and HIV Prevention Trials Network. Protocol HVTN 136/HPTN 092: a phase 1 dose-escalation clinical trial to evaluate the safety, tolerability, pharmacokinetics, and antiviral activity of the monoclonal antibody PGT121.414.LS administered alone and in combination with VRC07-523LS via intravenous or subcutaneous infusions in healthy, HIV-uninfected adult participants [Version 1.0]; October 8, 2019. Accessed May 23, 2024
4. Jefferys R. HIV vaccines & passive immunization. Treatment Action Group Pipeline Report 2023. Accessed May 23, 2024
5. Griffith SA, McCoy LE. To bnAb or not to bnAb: defining broadly neutralising antibodies against HIV-1. Front Immunol. 2021;12:708227. doi:10.3389/fimmu.2021.708227. Accessed May 23, 2024
6. Stephenson KE, Julg B, Tan CS, et al. Safety, pharmacokinetics and antiviral activity of PGT121, a broadly neutralizing monoclonal antibody against HIV-1: a randomized, placebo-controlled, phase 1 clinical trial. Nat Med. 2021;27(10):1718-1724. doi:10.1038/s41591-021-01509-0. Accessed May 23, 2024
7. Halper-Stromberg A, Nussenzweig MC. Towards HIV-1 remission: potential roles for broadly neutralizing antibodies. J Clin Invest. 126(2):415-423. doi:10.1172/JCI80561. Accessed May 23, 2024
8. Bruel T, Guivel-Benhassine F, Amraoui S, et al. Elimination of HIV-1-infected cells by broadly neutralizing antibodies. Nat Commun. 2016;7. doi:10.1038/ncomms10844. Accessed May 23, 2024
9. Stephenson KE, Barouch DH. Broadly Neutralizing Antibodies for HIV Eradication. Curr HIV/AIDS Rep. 2016;13(1):31-37. doi:10.1007/s11904-016-0299-7. Accessed May 23, 2024
10. Liu Y, Cao W, Sun M, Li T. Broadly neutralizing antibodies for HIV-1: efficacies, challenges and opportunities. Emerg Microbes Infect. 9(1):194-206. doi:10.1080/22221751.2020.1713707. Accessed May 23, 2024
11. Caskey M, Klein F, Lorenzi JCC, et al. 3BNC117 a broadly neutralizing antibody suppresses viremia in HIV-1-infected humans. Nature. 2015;522(7557):487-491. doi:10.1038/nature14411. Accessed May 23, 2024
12. International AIDS Vaccine Initiative. A Phase 1/2a open label study of the safety, tolerability, pharmacokinetics and antiviral activity of PGT121, VRC07-523LS and PGDM1400 monoclonal antibodies in HIV-uninfected and HIV-infected adults. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 16, 2018. NLM Identifier: NCT03721510. Accessed May 23, 2024
13. Juelg BD, Walker-Sperling VE, Wagh K, et al. Therapeutic efficacy of a triple combination of HIV-1 broadly neutralizing antibodies. Webcast presented at: Conference on Retroviruses and Opportunistic Infections (CROI); March 3-6, 2024; Denver, CO. Accessed May 23, 2024
14. National Institute of Allergy and Infectious Diseases (NIAID). A Phase 1 dose-escalation clinical trial to evaluate the safety, tolerability, pharmacokinetics, and antiviral activity of the monoclonal antibody PGT121.414.LS administered alone and in combination with VRC07-523LS via intravenous or subcutaneous infusions in healthy, HIV-uninfected adult participants. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on December 23, 2019. NLM Identifier: NCT04212091. Accessed May 23, 2024
15. Edupuganti S, Hurt C, Stephenson K, et al. First-in-human evaluation of safety and pharmacokinetics of intravenous or subcutaneous infusions of PGT121.141.LS, an anti-V3 HIV-1 broadly neutralizing antibody in healthy volunteers without HIV. Abstract presented at: International AIDS Conference; July 29 – August 2, 2022; Montreal, Canada and Virtual. Abstract PELBA02. Accessed May 23, 2024
16. Boris Juelg, MD PhD. A safety, immunogenicity and efficacy Phase 1/2a study of a heterologous Ad26.Mos4.HIV, MVA-BN-HIV vaccine regimen plus broadly neutralizing antibodies PGT121, PGDM1400, and VRC07-523LS in HIV-1-infected adults on suppressive ART. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on July 5, 2021. NLM Identifier: NCT04983030. Accessed May 23, 2024
17. National Institute of Allergy and Infectious Diseases (NIAID). A double-blind, randomized, placebo-controlled clinical trial of combination HIV-specific broadly neutralizing monoclonal antibodies combined with ART initiation during acute HIV infection to induce HIV remission. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on January 30, 2023. NLM Identifier: NCT05719441. Accessed May 23, 2024
18. International AIDS Vaccine Initiative. A Phase 1 randomized placebo-controlled clinical trial of the safety, pharmacokinetics and antiviral activity of PGT121 monoclonal antibody (mAb) in HIV-uninfected and HIV-infected adults. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on October 18, 2016. NLM Identifier: NCT02960581. Accessed May 23, 2024
19. International AIDS Vaccine Initiative. A Phase 1 randomized placebo-controlled clinical trial of the safety, pharmacokinetics and antiviral activity of PGDM1400 and PGT121 and VRC07-523LS monoclonal antibodies in HIV-uninfected and HIV-infected adults. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on May 12, 2017. NLM Identifier: NCT03205917. Accessed May 23, 2024
     

Last Reviewed: May 23, 2024