Drug Database: VRC07-523LS

Pharmacology Pharmacology

Pharmacology

Mechanism of Action

Broadly neutralizing antibody (bNAb). VRC07-523LS is a recombinant human IgG1 monoclonal antibody belonging to the VRC01 antibody class. It is an optimized version of the bNAb VRC07 and contains an LS mutation which prolongs its plasma half-life. VRC07-523LS is a next-generation bNAb that targets the CD4 binding site on HIV envelope gp120 and has broad and potent neutralizing activity against 96% of a large panel of viral strains.^4–7

Next-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.^8,11

VRC07-523LS is being studied for HIV prevention and is also being developed as a possible component to HIV treatment or cure.^2,3

Half-life (T_½)

In a Phase 1 study (NCT03387150) of VRC07-523LS administered via different routes and doses in healthy adults without HIV, the estimated median half-life of VRC07-523LS was approximately 40 days.^12,13

Select Clinical Trials Select Clinical Trials

Select Clinical Trials

Study Identifier: NCT04357821

Sponsor: University of California, San Francisco
Phase: 1/2 
Status: This study is ongoing, but not recruiting participants. 
Study Purpose: The purpose of this open-label study is to evaluate whether a combination regimen can control viral load levels in participants who undergo an analytical treatment interruption (ATI) of ART. The combination regimen includes (1) therapeutic HIV vaccines (Gag conserved element [CE]-targeted DNA+IL-12 prime/MVA boost vaccination), (2) bNAbs VRC07-523LS and 10-1074, and (3) the TLR9 agonist lefitolimod.
Study Population:

• Participants are adults with HIV who have been on a continuous ART regimen for at least 12 months and a stable ART regimen that does not include an NNRTI for at least 4 weeks.
• Participants have had undetectable HIV RNA in the past 24 months and have CD4 counts ≥500 cells/mm³ at screening.^14,15

Selected Study Results: Results presented at CROI 2023 indicated that most participants (seven out of 10) who received combination therapy had a least partial virologic control after ART interruption. The average time to viral rebound following ART interruption was 15 weeks.¹⁵

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 Identifier: NCT05275998

Sponsor: TaiMed Biologics Inc.
Phase: 1b/2a 
Status: This study is currently recruiting participants. 
Study Purpose: The purpose of this open-label, dose-escalation trial is to evaluate the safety, pharmacokinetics, and antiviral activity of the antibodies TMB-365 and TMB-380 (VRC07-523LS) in individuals with viral suppression on ART.
Study Population:

• Participants are adults with asymptomatic HIV who have been on continuous suppressive ART for 6 months prior to screening.
• Participants have undetectable HIV RNA at screening and one documented result of undetectable HIV RNA within 3 months of screening.
• Participants have CD4 counts >350 cells/mm³.¹⁷

Study Identifiers: ACTG A5357; NCT03739996

Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Phase: 2 
Status: This study is ongoing, but not recruiting participants. 
Study Purpose: The purpose of this open-label study is to evaluate the safety, tolerability, pharmacokinetics, and antiviral activity of long-acting cabotegravir (CAB LA) plus VRC07-523LS in adults with viral suppression.  
Study Population:

• Participants are adults with HIV who are clinically stable for at least 8 weeks prior to study entry on a three-drug ART regimen (a boosted PI, an NNRTI, or an INSTI plus two NRTIs). Participants have no history of a switch due to virologic failure.
• Participants have HIV RNA <50 copies/mL at screening and have had HIV RNA <50 copies/mL within the 2 years prior to study entry. Participants have at least two documented results of HIV RNA <50 copies/mL within 12 months of study entry.
• Participants have CD4 counts ≥350 cells/mm³ at screening.
• Participants have viral sensitivity to VRC07-523LS.¹⁸

Selected Study Results: Results presented at CROI 2024 demonstrated that CAB LA plus VRC07-523LS was safe and capable of maintaining viral suppression in most participants. Eleven (15%) participants had a Grade 3 or higher adverse event (AE) that was at least possibly related to CAB LA or VRC07-523LS, and one participant discontinued treatment due to a Grade 1 infusion-related reaction. Five out of 71 participants experienced virologic failure (defined as viral load of 200 copies/mL or higher at or prior to Week 44 of Step 2).¹⁹

Study Identifiers: GS-US-382-5445; NCT05281510

Sponsor: Gilead Sciences
Phase: 2a 
Status: This study is ongoing, but not recruiting participants. 
Study Purpose: The purpose of this open-label trial is to evaluate the safety and tolerability of the bNAbs VRC07-523LS and CAP256V2LS with the TLR7 agonist vesatolimod in early ART-treated women with clade C HIV.
Study Population:

• Participants are adult females with HIV who are recruited from the Females Rising through Education, Support, and Health (FRESH) acute HIV infection cohort. 
• Participants have been receiving ART for at least 12 consecutive months prior to screening.
• Participants have HIV RNA <50 copies/mL at screening and have had HIV RNA <50 copies/mL for 12 consecutive months prior to screening.
• Participants have documented viral sensitivity to VRC07-523LS or CAP256V2LS.²⁰

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.²¹

Additional studies evaluating VRC07-523LS for HIV treatment have been completed or are being conducted, including the following early-phase trials:

• VOR-07 study (NCT03803605): A Phase 1 trial that evaluated the effects of the latency-reversing agent vorinostat plus VRC07-523LS on persistent HIV infection. This study has been completed, and results are available from IAS 2021 and The Journal of Infectious Diseases (2022).²²
• VRC 607/ACTG A5378 (NCT02840474): A Phase 1 trial that evaluated the safety and antiviral effects of the bNAbs VRC01LS and VRC07-523LS in treatment-naive adults with HIV. This study has been completed, and results are available from IAS 2019.²³
• IAVI T003 (NCT03721510): A Phase 1/2a study that evaluated a triple bNAb regimen consisting of PGT121, VRC07-523LS, and PGDM1400. Initially, the safety, tolerability, and pharmacokinetics of the triple bNAb regimen was assessed in adults with and without HIV. Thereafter, the antiviral activity of the combination bNAb regimen was evaluated in adults with HIV undergoing an ATI of ART. This study has been completed, and results are available from CROI 2024.^24,25
• IAVI T002 (NCT03205917): A Phase 1 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).²⁶
• ACTG A5386 (NCT04340596): A Phase 1 trial investigating the safety and efficacy of N-803 (an IL-15 superagonist), administered with and without the bNAbs VRC07-523LS and 10-1074, in controlling viral load during a treatment interruption of ART. This study is currently recruiting participants.²⁷
• RV 582 (NCT05769569): A Phase 1 study evaluating the safety and efficacy of VRC07-523LS, PGDM1400LS, and N-803 in combination with the therapeutic HIV vaccines Ad26.Mos4.HIV, MVA-BN-HIV, and A244d11 gp120/ALFQ for the induction of HIV remission. See the ClinicalTrials.gov record for this study’s status.²⁸ 

Adverse Events Adverse Events

Adverse Events

NCT04357821

In this Phase 1/2 trial, 10 participants received a combination regimen consisting of therapeutic HIV vaccination (Gag conserved element [CE]-targeted DNA+IL-12 prime/MVA boost vaccination), bNAbs VRC07-523LS and 10-1074, and the TLR9 agonist lefitolimod. Two participants experienced ALT elevations (Grade 3 and 4) which were attributed to external causes rather than to trial interventions.^14,15

ACTG A5357 (NCT03739996)

In this Phase 2 trial, 75 participants initially received oral CAB plus two NRTIs for 4 weeks (Step 1). Thereafter, 71 participants who tolerated the oral CAB regimen and maintained viral suppression discontinued oral CAB and NRTIs and switched to intramuscular (IM) CAB LA plus intravenous (IV) VRC07-523LS for up to 48 weeks (Step 2). During Step 2, one participant discontinued treatment due to a Grade 1 infusion reaction that started and resolved on the day of their third VRC07-523LS infusion. Eleven (15%) participants experienced Grade 3 AEs that were considered at least possibly related to CAB LA or VRC07-523LS. Grade 3 AEs that were at least possibly related to VRC07-523LS included chills, feeling unwell, fatigue, generalized aching, vasospasm, hypotension, myalgia, and headache. Grade 3 AEs that were at least possibly related to CAB LA included muscle pain and decreased creatinine clearance. One participant had Grade 3 elevated ALT levels, which was possibly related to both CAB LA and VRC07-523LS. No Grade 4 AEs were reported.^19,29

Drug Interactions Drug Interactions

Drug Interactions

Drug-drug interactions associated with VRC07-523LS are currently unknown.

References References

References

1. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. Accessed March 12, 2024
2. Treatment Action Group website. Research toward a cure trials. Accessed August 13, 2023
3. Jefferys R. The HIV vaccines and passive immunization pipeline report 2023. Treatment Action Group Pipeline Report 2023. Accessed March 12, 2024
4. Julg B, Stephenson KE, Wagh K, et al. Safety and antiviral activity of triple combination broadly neutralizing monoclonal antibody therapy against HIV-1: a Phase 1 clinical trial. Nat Med. 2022;28(6):1288-1296. doi:10.1038/s41591-022-01815-1. Accessed March 12, 2024
5. Gaudinski MR, Houser KV, Doria-Rose NA, et al. Safety and pharmacokinetics of broadly neutralising human monoclonal antibody VRC07-523LS in healthy adults: a Phase 1 dose-escalation clinical trial. Lancet HIV. 2019;6(10):e667-e679. doi:10.1016/S2352-3018(19)30181-X. Accessed March 12, 2024
6. Rudicell RS, Kwon YD, Ko SY, et al. Enhanced Potency of a broadly neutralizing HIV-1 antibody in vitro improves protection against lentiviral infection in vivo. J Virol. 2014;88(21):12669-12682. doi:10.1128/JVI.02213-14. Accessed March 12, 2024
7. 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 March 12, 2024
8. Halper-Stromberg A, Nussenzweig MC. Towards HIV-1 remission: potential roles for broadly neutralizing antibodies. J Clin Invest. 2016;126(2):415-423. doi:10.1172/JCI80561. Accessed March 12, 2024
9. Bruel T, Guivel-Benhassine F, Amraoui S, et al. Elimination of HIV-1-infected cells by broadly neutralizing antibodies. Nat Commun. 2016;7:10844. Accessed March 12, 2024
10. Stephenson KE, Barouch DH. Broadly Neutralizing Antibodies for HIV Eradication. Curr HIV/AIDS Rep. 2016;13(1):31-37. doi:doi:10.1007/s11904-016-0299-7. Accessed March 12, 2024
11. Caskey M Klein F, Lorenzi JC, et al. 3BNC117 a broadly neutralizing antibody suppresses viremia in HIV-1-infected humans. Nature. 2015;522(7557):487-491. Accessed March 12, 2024
12. National Institute of Allergy and Infectious Diseases (NIAID). A multicenter, randomized, partially blinded Phase 1 clinical trial to evaluate the safety and serum concentrations of a human monoclonal antibody, VRC-HIVMAB075-00-AB (VRC07-523LS), administered in multiple doses and routes to healthy, HIV-uninfected adults. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on December 21, 2017. NLM Identifier: NCT03387150. Accessed March 12, 2024
13. Walsh S, Gay C, Karuna S, et al. Safety and single-dose pharmacokinetics of VRC07-523LS administered via different routes and doses. Abstract presented at: HIV Research for Prevention Conference (HIVR4P); January 27-28 and February 3-4, 2021; Virtual. Abstract OA03.01. Accessed March 12, 2024
14. University of California, San Francisco. Combinatorial therapy with a therapeutic conserved element DNA vaccine, MVA vaccine boost, TLR9 agonist and broadly neutralizing antibodies: a proof-of-concept study aimed at inducing an HIV remission. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on April 18, 2020. NLM Identifier: NCT04357821. Accessed March 12, 2024
15. Peluso M, Deitchman A, Magombedze G, et al. Rebound dynamics following immunotherapy with an HIV vaccine, TLR-9 agonist, and broadly neutralizing antibodies. Poster presented at: Conference on Retroviruses and Opportunistic Infections (CROI); February 19-22, 2023; Seattle, WA. Poster 435. Accessed March 12, 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 March 12, 2024
17. TaiMed Biologics Inc. A Phase 1b/2a dose escalation study of the safety, pharmacokinetics, and efficacy of the combination of TMB-365 and TMB-380 in HIV-1 infected individuals suppressed with combination antiretroviral therapy. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 2, 2022. NLM Identifier: NCT05275998. Accessed March 12, 2024
18. National Institute of Allergy and Infectious Diseases (NIAID). A study of long-acting cabotegravir plus VRC01LS to maintain viral suppression in adults living with HIV-1. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on November 9, 2018. NLM Identifier: NCT03739996. Accessed March 12, 2024
19. Taiwo B, Zheng YE, Rodriguez K, et al. Safety and efficacy of VRC07-523LS plus long-acting cabotegravir in the Phase II ACTG A5357 trial. Abstract presented at: Conference on Retroviruses and Opportunistic Infections (CROI); March 3-6, 2024; Denver, CO. Abstract 119. Accessed March 12, 2024
20. Gilead Sciences. A Phase 2a study to evaluate the safety and tolerability of a regimen of dual anti-HIV envelope antibodies, VRC07-523LS and CAP256V2LS, in a sequential regimen with a TLR7 agonist, vesatolimod, in early antiretroviral-treated HIV-1 clade C-infected women. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 7, 2022. NLM Identifier: NCT05281510. Accessed March 12, 2024
21. 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 March 12, 2024
22. University of North Carolina, Chapel Hill. IGHID 11802 - Combination therapy with the novel clearance modality (VRC07-523LS) and the latency reversal agent (vorinostat) to reduce the frequency of latent, resting CD4+ T cell infection (the VOR-07 study). In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on: January 10, 2019. NLM Identifier: NCT03803605. Accessed March 12, 2024
23. National Institute of Allergy and Infectious Diseases (NIAID). VRC 607-ACTG A5378: a phase 1, single dose study of the safety and virologic effect of an HIV-1 specific broadly neutralizing human monoclonal antibody, VRC-HIVMAB080-00-AB (VRC01LS) or VRC-HIVMAB075-00-AB (VRC07-523LS), administered intravenously to HIV-infected adults. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered July 19, 2016. NLM Identifier: NCT02840474. Accessed March 12, 2024
24. 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 March 12, 2024
25. Juelg BD, Walker-Sperling VE, Wagh K, et al. Therapeutic efficacy of a triple combination of HIV-1 broadly neutralizing antibodies. Abstract presented at: Conference on Retroviruses and Opportunistic Infections (CROI); March 3-6, 2024; Denver, CO. Abstract 121. Accessed March 12, 2024 
26. 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 March 12, 2024
27. National Institute of Allergy and Infectious Diseases (NIAID). A Phase I clinical trial of the safety, tolerability, and efficacy of IL-15 superagonist (N-803) with and without combination broadly neutralizing antibodies to induce HIV-1 control during analytic treatment interruption. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 23, 2020. NLM Identifier: NCT04340596. Accessed March 12, 2024
28. Henry M. Jackson Foundation for the Advancement of Military Medicine. Safety and efficacy of broadly neutralizing antibodies followed by innate immune stimulation and therapeutic vaccination for the induction of HIV remission. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on February 15, 2023. NLM Identifier: NCT05769569. Accessed March 12, 2024
29. Taiwo B, Zheng YE, Rodriguez K, et al. Safety and efficacy of VRC07-523LS plus long-acting cabotegravir in the Phase II ACTG A5357 trial. Conference on Retroviruses and Opportunistic Infections (CROI); March 3-6, 2024; Denver, CO. Conference Reports for National AIDS Treatment Advocacy Project (NATAP); 2024. Accessed March 12, 2024