Drug Database: 3BNC117

Pharmacology

Pharmacology

Mechanism of Action

Broadly neutralizing antibody (bNAb). 3BNC117 is a recombinant human IgG1 kappa monoclonal antibody cloned from an HIV-infected viremic controller. It is a next-generation bNAb that targets the CD4 binding site on HIV envelope gp160.^2,6

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.^6–9 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.^6,10

3BNC117 and long-acting versions of 3BNC117 (called 3BNC117-LS and 3BNC117-LS-J) are being developed for HIV prevention and/or as a possible component to HIV treatment or cure.^3,5 

Half-life (T_½)

A Phase 1 study (NCT02018510) investigated a single intravenous (IV) infusion of 3BNC117 at four different dose levels (1, 3, 10, and 30 mg/kg) in adults with and without HIV and found that the average half-life of 3BNC117 was approximately 9 days in the HIV-infected group and 17 days in the HIV-uninfected group.¹⁰ In a Phase 2a trial (NCT02446847) of multiple IV infusions of 3BNC117 (30 mg/kg) in adults with HIV, the half-life of 3BNC117 ranged from 14.1 days in adults receiving four doses of 3BNC117 to 19.6 days in adults receiving two doses of 3BNC117.²

The half-life of 3BNC117-LS relative to 3BNC117 was measured in a study of macaques administered single IV infusions. 3BNC117-LS was found to have a median half-life of 2.8 weeks, an increase of 2.0-fold when compared to the half-life of 3BNC117 (median 1.4 weeks).¹¹

Resistance

HIV has developed resistance to 3BNC117 in both a Phase 1 (NCT02018510) and 2a (NCT02446847) trial of 3BNC117.^2,10 In the Phase 1 study, high-level resistance to 3BNC117 developed in some, although not all, participants by 28 days after a single 3BNC117 dose.¹⁰

In the Phase 2a study, eight out of 13 participants with HIV had rebound viruses that were more resistant to 3BNC117 when compared to pre-infusion viruses. In the majority of participants, viral rebound occurred at high 3BNC117 concentrations. Of eight participants who had sequence analysis performed on rebound viruses, six participants had viral genotypes indicating resistance to 3BNC117. Notably, five out of eight participants had rebound viruses that appeared to arise from a single reactivated virus from the latent reservoir. In all but two participants, rebound viruses did not demonstrate increased resistance to the investigational bNAb 10-1074.²

Select Clinical Trials

Select Clinical Trials

Study Identifier: NCT02588586

Sponsor: Rockefeller University
Phase: 2 
Status: This study has been completed.
Study Purpose: The purpose of this open-label study was to evaluate the safety of 3BNC117 and its ability to delay or prevent viral rebound during an analytical treatment interruption of ART.
Study Population:

• Participants were adults with HIV who had HIV RNA <50 copies/mL for at least 12 months while on ART and had HIV RNA <20 copies/mL at screening.
• Participants had CD4 counts >500 cells/mm³ and nadir CD4 counts >200 cells/mm³.¹²

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Study Identifier: NCT02446847

Sponsor: Rockefeller University
Phase: 2a
Status: This study has been completed.
Study Purpose: The purpose of this open-label, dose-escalation study was to evaluate the safety and pharmacokinetics of 3BNC117 and its ability to delay or prevent viral rebound during an analytical treatment interruption of ART.
Study Population:

• Participants were adults with HIV who had HIV RNA <50 copies/mL for at least 12 months while on ART and had HIV RNA <20 copies/mL at screening.
• Participants had CD4 counts >500 cells/mm³ and nadir CD4 counts ≥200 cells/mm³.
• Participants had 3BNC117-sensitive viruses.^2,13

Selected Study Results: Results published in Nature (2016) showed that 3BNC117 was safe and well tolerated. 3BNC117 was effective in delaying viral rebound following an analytical treatment interruption of ART.²

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Study Identifiers: ROADMAP; NCT02850016

Sponsor: Rockefeller University
Phase: 2a
Status: This study has been completed.
Study Purpose: The purpose of this open-label study was to compare the efficacy of the latency-reversing agent romidepsin plus 3BNC117 to the efficacy of romidepsin alone on delaying or preventing viral rebound during an analytical treatment interruption of ART.
Study Population:

• Participants were adults with HIV who had been on ART for at least 18 months.
• Participants on a PI- or NNRTI-based ART regimen or on a cobicistat-containing regimen were willing to switch to an INI-based regimen prior to enrollment.
• Participants had HIV RNA <50 copies/mL for at least 12 months and had CD4 counts >500 cells/mm³ at screening.^14,15

Selected Study Results: Results published in The Lancet Microbe (2022) showed that romidepsin plus 3BNC117 and romidepsin administered alone had no substantial effect on reducing latent HIV reservoir size in participants on suppressive ART. Additionally, romidepsin plus 3BNC117, compared to romidepsin administered alone, was not effective in delaying the time to viral rebound during analytical treatment interruption. The observed time to viral rebound was not clinically meaningful in either group.¹⁵

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Study Identifiers: eCLEAR; NCT03041012

Sponsor: Aarhus University Hospital
Phase: 1b/2a 
Status: This study is ongoing, but not recruiting participants.
Study Purpose: The purpose of this open-label study is to evaluate whether the early administration of romidepsin and/or 3BNC117 in treatment-naive individuals who are initiating ART can reduce the time to viral suppression, limit the size of the latent HIV reservoir, and delay the time to viral rebound during an analytical treatment interruption of ART.
Study Population:

• Participants have HIV but have never received ART.
• Participants have CD4 counts >200 cells/mm³ prior to study entry.^16,17

Selected Study Results: Results presented at CROI 2022 showed that 3BNC117 administered to participants initiating ART led to faster viral load decline during the second phase of viral decay (10–24 days after ART initiation) and significantly enhanced the elimination of infected cells, as compared to what was observed in participants receiving ART only. After one year, latent HIV reservoir size was reduced from baseline in all treatment groups, with the greatest reduction seen in those receiving 3BNC117 plus ART. Among participants who had 3BNC117-sensitive virus, 80% maintained viral control during treatment interruption of ART. In contrast, among participants who had 3BNC117-resistant virus or did not receive 3BNC117, only 20% maintained viral control during treatment interruption.¹⁷

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Study Identifiers: TITAN; NCT03837756

Sponsor: University of Aarhus
Phase: 2a
Status: This study is ongoing, but not recruiting participants.
Study Purpose: The purpose of this study is to evaluate the safety and efficacy of the TLR9 agonist lefitolimod plus the bNAbs 3BNC117 and 10-1074 in delaying the time to viral rebound during an analytical treatment interruption of ART.
Study Population:

• Participants are adults with HIV who have been on ART for at least 18 months.
• Participants have had HIV RNA <50 copies/mL for at least 15 months and have CD4 counts >500 cells/mm³ at screening.
• Participants have HIV that is sensitive to 3BNC117 and 10-1074.¹⁸

Selected Study Results: Results presented at CROI 2023 showed that the groups receiving dual bNAb treatment had a significant delay in the time to viral rebound during ART interruption, as compared to groups receiving placebos only or lefitolimod plus placebo. The addition of lefitolimod to dual bNAb treatment did not confer any additional effect on viral control compared to dual bNAb treatment alone.¹⁹

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Study Identifier: NCT03719664

Sponsor: Frontier Biotechnologies Inc.
Phase: 2
Status: See the ClinicalTrials.gov record for this study's status.
Study Purpose: The purpose of this open-label study is to determine an optimal dosage of 3BNC117 and the HIV fusion inhibitor albuvirtide and evaluate the safety and efficacy of this combination as long-acting maintenance treatment.
Study Population:

• Participants are adults with HIV who have been receiving oral ART for the last 24 weeks.
• Participants have been on a stable ART regimen for the past 4 weeks prior to screening and during the time between the screening visit and first treatment visit.
• Participants have at least two alternative antiretroviral drug options available.
• Participants have had HIV RNA <50 copies/mL within the 24 weeks prior to screening and at screening.
• Participants have CD4 counts >300 cells/mm³ at screening.²⁰

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Study Identifiers: RIO; NCT04319367

Sponsor: Imperial College London
Phase: 2
Status: This study is currently recruiting participants.
Study Purpose: The purpose of this study is to determine whether the combination of the two long-acting bNAbs 3BNC117-LS and 10-1074-LS can prevent viral rebound during an analytical treatment interruption of ART.
Study Population:

• Participants are adults with HIV who had previously been diagnosed with primary HIV infection and who had started ART during the primary HIV infection stage.
• Participants have been receiving continuous suppressive ART for at least 1 year.
• Participants have had undetectable HIV RNA for at least 1 year and have CD4 counts >500 cells/mm³. Participants have nadir CD4 counts >350 cells/mm³.
• Participants show no evidence of viral insensitivity to either 10-1074 or 3BNC117.²¹

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Study Identifier: NCT04819347

Sponsor: Frontier Biotechnologies Inc.
Phase: 2
Status: See the ClinicalTrials.gov record for this study’s status.
Study Purpose: The purpose of this open-label study is to evaluate the safety of combination therapy with albuvirtide plus 3BNC117 and determine whether this combination can control viral load levels during an analytical treatment interruption of ART.
Study Population:

• Participants are adults with HIV on a stable ART regimen who initiated ART either within 6 months of primary HIV infection (cohort 1) or after 6 months of primary HIV infection (cohort 2).
• Participants have had HIV RNA <50 copies/mL for at least 12 months prior to screening and have HIV RNA <20 copies/mL at screening.
• Participants have CD4 counts >500 cells/mm³.²²

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Study Identifier: NCT04560569

Sponsor: Frontier Biotechnologies Inc.
Phase: 2
Status: The status of this study is unknown.
Study Purpose: The purpose of this open-label study is to evaluate the safety and efficacy of combination therapy with albuvirtide plus 3BNC117 in participants with multidrug-resistant HIV. 
Study Population:

• Participants are adults with HIV who have received ART for at least 6 months. Participants have been on a failing ART regimen for at least 8 weeks prior to screening or had treatment failure within the past 8 weeks of screening and are off therapy.
• Participants have HIV that is resistant to at least one ARV drug from at least three different ARV drug classes and have difficulty in constructing a viable suppressive regimen. Participants must have at least one potential approved ARV drug available which can be used as part of an optimized background regimen.
• Participants have had HIV RNA >200 copies/mL within the last 3 months prior to screening and have HIV RNA ≥1,000 copies/mL at screening.²³

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Study Identifiers: RHIVIERA-02; NCT05300035

Sponsor: ANRS, Emerging Infectious Diseases
Phase: 2
Status: See the ClinicalTrials.gov record for this study’s status.
Study Purpose: The purpose of this study is to evaluate the efficacy of the long-acting bNAbs 3BNC117-LS and 10-1074-LS in controlling viral load levels during an analytical treatment interruption of ART.
Study Population: Participants are adults with primary HIV infection who are initiating ART.²⁴

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Additional studies evaluating 3BNC117 for HIV treatment have been or are being conducted, including the following early-phase trials of 3BNC117 and 10-1074:

• NCT03526848: A Phase 1b study that evaluated whether 3BNC117 and 10-1074 could control viral rebound in adults with HIV during a treatment interruption of ART. This study has been completed and results are available from Nature (2022).^25,26
• NCT03571204: A Phase 1 study that evaluated whether 3BNC117 and 10-1074 could control viral load levels in individuals with HIV who were not receiving ART and in individuals with HIV who stopped ART during a treatment interruption. This study was terminated early. Results are available from Nature (2022).^27,28
• BEAT-2 (NCT03588715): A Phase 1 study that evaluated whether peginterferon alfa-2b plus 3BNC117 and 10-1074 could control viral rebound and reduce the latent HIV reservoir in adults with HIV during an analytical treatment interruption of ART. This study has been completed, and primary outcome results are available from CROI 2023.^3,29
• NCT04811040: A Phase 1b study evaluating the safety and efficacy of 3BNC117-LS (teropavimab) and 10-1074-LS (GS-2872) in combination with the capsid inhibitor lenacapavir in controlling viral load levels in virologically suppressed adults with HIV. This study is ongoing, but not recruiting participants. Results were presented at CROI 2023.³⁰
• NCT05079451: A Phase 1 trial assessing the safety and ability of 3BNC117-LS and 10-1074-LS to prevent viral rebound in virologically suppressed adults during an analytical treatment interruption of ART. See the ClinicalTrials.gov record for this study’s status.³¹
• NCT05245292: A Phase 1 trial evaluating the safety and antiviral activity of 3BNC117-LS and 10-1074-LS in combination with N-803 (an IL-15 superagonist complex) in virologically suppressed adults during an analytical treatment interruption of ART. This study is currently recruiting participants.³²

Adverse Events

Adverse Events

NCT02446847

In this Phase 2a trial investigating multiple infusions of 3BNC117 in 13 individuals with HIV, most adverse events (AEs) that occurred during the study were transient and mild. Some participants experienced modest drops in CD4 counts during viral rebound, but most had their counts return to baseline by Week 12. Acute retroviral syndrome was not reported in any participants during rebound.²

ROADMAP (NCT02850016)

In this Phase 2a trial, 11 participants received romidepsin plus 3BNC117 and nine participants received romidepsin alone. All participants in both groups experienced AEs, most of which were mild to moderate in severity. Out of 267 reported AEs, 39 were considered drug-related and 159 were deemed at least possibly related to study treatments. Two severe AEs occurred in the romidepsin only group, one of which was related to romidepsin and resolved without intervention — increased direct bilirubin. The most common AEs associated with romidepsin were nausea, headache, chills, and vomiting. More drug-related AEs occurred with romidepsin than with 3BNC117. Transient QTc interval prolongation without associated clinical symptoms was seen in three participants one day after romidepsin infusion.¹⁵

eCLEAR (NCT03041012)

In the Phase 1b/2a eCLEAR study, 60 participants were enrolled to receive ART only; ART plus 3BNC117; ART plus romidepsin; or a combination of ART, 3BNC117, and romidepsin. The majority of AEs that occurred during the trial were mild and unrelated to study treatment.¹⁷

TITAN (NCT03837756)

In this Phase 2a trial, participants were randomized to receive placebo/placebo (n=11), lefitolimod/placebo (n=11), placebo/bNAbs (n=12), or lefitolimod/bNAbs (n=12). Two severe AEs occurred. One severe AE was unrelated to study treatment and the other (infusion reaction) was related to 3BNC117. Mild AEs occurred more frequently in the lefitolimod/bNAbs group than in other treatment groups.^18,19

Drug Interactions

Drug Interactions

Drug-drug interactions associated with 3BNC117 are currently unknown.

References

References

1. National Center for Biotechnology Information. PubChem compound summary for SID: 381127297, 3BNC117. Accessed March 20, 2023
2. Scheid JF, Horwitz JA, Bar-On Y, et al. HIV-1 antibody 3BNC117 suppresses viral rebound in humans during treatment interruption. Nature. 2016;535(7613):556-560. Accessed March 20, 2023
3. Treatment Action Group website. Research toward a cure trials. Accessed March 20, 2023
4. Gilead Sciences: press release, dated January 9, 2020. Gilead Sciences licenses portfolio of HIV antibodies from The Rockefeller University. Accessed March 20, 2023
5. Jefferys R. HIV vaccines & passive immunization. Treatment Action Group Pipeline Report 2022. Accessed March 20, 2023
6. Halper-Stromberg A, Nussenzweig MC. Towards HIV-1 remission: potential roles for broadly neutralizing antibodies. J Clin Invest. 126(2):415-423. Accessed March 20, 2023
7. Jefferys R, Jacobson J. Therapeutic vaccines and immune-based therapies. CUREiculum: HIV/AIDS and cure basics – Module 12. PowerPoint presentation available on the AIDS Vaccine Advocacy Coalition (AVAC) website. Accessed March 20, 2023
8. 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 20, 2023
9. Stephenson KE, Barouch DH. Broadly neutralizing antibodies for HIV eradication. Curr HIV/AIDS Rep. 2016;13:31-37. Accessed March 20, 2023
10. 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 20, 2023
11. Gautam R, Nishimura Y, Gaughan N, et al. A single injection of crystallizable fragment domain-modified antibodies elicits durable protection from SHIV infection. Nat Med. 2018;24(5):610-616. Accessed March 20, 2023
12. Rockefeller University. An open label, Phase 2 study of the safety and antiretroviral activity of 3BNC117 in HIV-infected individuals on combination antiretroviral therapy. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on October 26, 2015. NLM Identifier: NCT02588586. Accessed March 20, 2023
13. Rockefeller University. A Phase 2, open label study of the safety, antiretroviral activity and pharmacokinetics of 3BNC117 during a short analytical treatment interruption in HIV-infected subjects. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 17, 2015. NLM Identifier: NCT02446847. Accessed March 20, 2023
14. Rockefeller University. A Phase 2a, randomized study of romidepsin with or without 3BNC117 to evaluate the effects on the HIV-1 reservoir (ROADMAP). In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on July 26, 2016. NLM Identifier: NCT02850016. Accessed March 20, 2023
15. Gruell H, Gunst JD, Cohen YZ, et al. Effect of 3BNC117 and romidepsin on the HIV-1 reservoir in people taking suppressive antiretroviral therapy (ROADMAP): a randomised, open-label, phase 2A trial. Lancet Microbe. 2022;3(3):e203-e214. doi:10.1016/S2666-5247(21)00239-1. Accessed March 20, 2023
16. Aarhus University Hospital. Early administration of latency reversing therapy and broadly neutralizing antibodies to limit the establishment of the HIV-1 reservoir during initiation of antiretroviral treatment - a randomized controlled trial. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on January 20, 2017. NLM Identifier: NCT03041012. Accessed March 20, 2023
17. Gunst JD, Pahus MH, Rosás-Umbert M, et al. The impact of 3BNC117 and romidepsin treatment at ART initiation on HIV-1 persistence. Webcast presented at: Conference on Retroviruses and Opportunistic Infections (CROI); February 12-16, 2022; Virtual. Accessed March 20, 2023
18. University of Aarhus. Combining a TLR9 agonist with broadly neutralizing antibodies for reservoir reduction and immunological control of HIV infection: an investigator-initiated randomized, placebo-controlled, Phase IIa trial. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on February 7, 2019. NLM Identifier: NCT03837756. Accessed March 20, 2023
19. Gunst JD, Reikvam DH, McMahon JH, et al. The impact of 3BNC117, 10-1074, and lefitolimod on HIV-1 persistence: the TITAN trial. Abstract presented at: Conference on Retroviruses and Opportunistic Infections (CROI); February 19-22, 2023; Seattle, WA. Abstract 136. Accessed March 20, 2023
20. Frontier Biotechnologies Inc. A Phase 2, multicenter, three-part study to establish the dosage, safety and antiviral activity of combination therapy with albuvirtide and 3BNC117 as long-acting maintenance therapy in virologically suppressed subjects with HIV-1 infection. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on October 22, 2018. NLM Identifier: NCT03719664. Accessed March 20, 2023
21. Imperial College London. A randomised placebo controlled trial of ART plus dual long-acting HIV-specific broadly neutralising antibodies (bNAbs) vs ART plus placebo in treated primary HIV infection on viral control off ART. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 2, 2020. NLM Identifier: NCT04319367. Accessed March 20, 2023
22. Frontier Biotechnologies Inc. The Phase 2, two arms, one site, safety and antiviral activity of combination therapy with albuvirtide and 3BNC117 in virologically suppressed subjects with HIV-1 infection after analytical treatment interruption. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 22, 2021. NLM Identifier: NCT04819347. Accessed March 20, 2023
23. Frontier Biotechnologies Inc. A multicenter, two-arm, 24-week study of albuvirtide in combination with 3BNC117 in patients with multi-drug resistant (MDR) HIV-1 infection. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on September 17, 2020. NLM Identifier: NCT04560569. Accessed March 20, 2023
24. ANRS, Emerging Infectious Diseases. A randomised Phase II placebo-controlled trial of antiretroviral therapy (ART) plus dual long-acting HIV-specific broadly neutralising antibodies (bNAbs) vs ART plus placebo during primary HIV-1 infection to study the impact on post-treatment HIV control. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on January 3, 2022. NLM Identifier: NCT05300035. Accessed March 20, 2023
25. Rockefeller University. An open label, randomized study of the safety and antiretroviral activity of 3BNC117 and 10-1074 in HIV-infected individuals on combination antiretroviral therapy and during analytical treatment interruption. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on May 3, 2018. NLM Identifier: NCT03526848. Accessed March 20, 2023
26. Gaebler C, Nogueira L, Stoffel E, et al. Prolonged viral suppression with anti-HIV-1 antibody therapy. Nature. 2022;606(7913):368-374. doi:10.1038/s41586-022-04597-1. Accessed March 20, 2023
27. National Institute of Allergy and Infectious Diseases (NIAID). An exploratory study of combination therapy with 3BNC117 and 10-1074 in HIV-infected individuals. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US).  Registered on June 22, 2018. NLM Identifier: NCT03571204. Accessed March 20, 2023 
28. Sneller MC, Blazkova J, Justement JS, et al. Combination anti-HIV antibodies provide sustained virological suppression. Nature. 2022;606(7913):375-381. doi:10.1038/s41586-022-04797-9. Accessed March 20, 2023
29. Luis Montaner. Pilot study on innate activation and viral control in HIV-infected adults undergoing an analytical treatment interruption after administration of pegylated interferon alpha 2b with broadly HIV-1 neutralizing antibodies (3BNC117, 10-1074). In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on April 30, 2018. NLM Identifier: NCT03588715. Accessed March 20, 2023 
30. Gilead Sciences. A Phase 1b randomized, blinded, proof-of-concept study to evaluate the safety and efficacy of broadly neutralizing antibodies (bNAbs) GS-5423 and GS-2872 in combination with capsid inhibitor lenacapavir (GS-6207) in virologically suppressed adults with HIV-1 infection. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 19, 2021. NLM Identifier: NCT04811040. Accessed March 20, 2023
31. National Institute of Allergy and Infectious Diseases (NIAID). A Phase I, open-label study of the safety and ability of broadly neutralizing antibodies 3BNC117-LS and 10-1074-LS in combination to durably prevent viral relapse during a monitored analytical treatment interruption. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on September 2, 2021. NLM Identifier: NCT050709451. Accessed March 20, 2023
32. Rockefeller University. An open label, single arm study of the safety and antiretroviral activity of two long-acting broadly neutralizing antibodies plus an IL-15 superagonist in ART-treated adults living with HIV during analytical treatment interruption. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on February 8, 2022. NLM Identifier: NCT05245292. Accessed March 20, 2023

  

Last Reviewed: March 20, 2023