Drugs

3BNC117

Other Names: 3BNC117-LS Drug Class: Therapeutic Vaccines (Broadly Neutralizing Antibodies) Registry Number: 1412902-17-0 (CAS) Organization: Rockefeller University Phase of Development: 3BNC117 is in Phase 2 development as a therapeutic HIV vaccine. (3BNC117 is also being developed for HIV prevention.)

(Compound details obtained from ChemIDplus Advanced,1 Current Opinion in Virology article,2 Nature article,3 Treatment Action Group website,4 and ClinicalTrials.gov5)

Pharmacology


Mechanism of Action: Therapeutic vaccine (broadly neutralizing antibody [bNAb]). 3BNC117 is a bNAb-based therapeutic HIV vaccine.2,4 Therapeutic vaccines are being investigated as an immunotherapeutic approach to correcting HIV-associated immune dysfunction, such as impaired dendritic cell (DC) responses to HIV and suboptimal adaptive immune responses (including HIV-specific T cell responses).6-9 A therapeutic vaccine may potentially increase the effectiveness of ART, simplify ART regimens, or allow for periodic structured treatment interruptions. A successful therapeutic vaccine would either completely eradicate the virus or improve an individual’s immune response to the point where it could suppress viral replication without ART. In either case, a therapeutic vaccine would help to circumvent a lifetime of ART.10

While the focus of therapeutic HIV vaccine study has been on the development of vaccines that induce cellular immune responses, researchers are also exploring humoral-based vaccine strategies.11 Since the identification of next-generation bNAbs – naturally occurring antibodies with potent neutralizing activity against a broad array of HIV strains – antibody research has been centered on the utility of bNAbs 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.11-14 Because it is difficult to induce in vivo generation of bNAbs using conventional vaccination techniques, researchers generally believe that bNAbs will need to be given by passive transfer, whereby a bNAb is directly administered to an individual.12,15

3BNC117 is a next-generation bNAb that targets the CD4 binding site on HIV envelope gp160. It is a recombinant human IgG1 kappa monoclonal antibody cloned from an HIV-infected viremic controller. 3BNC117 is being developed for HIV prevention and as a possible component to an HIV cure.3-5 A long-acting version of 3BNC117, called 3BNC117-LS, is also in clinical development.4,16 

Half-life (T½): 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.15 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 3BNC117.3

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).17 

Resistance: HIV has developed resistance to 3BNC117 in both a Phase 1 (NCT02018510) and IIa (NCT02446847) trial of 3BNC117.3,15 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.15

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 10-1074.3


Select Clinical Trials


Study Identifier: NCT02588586
Sponsor: Rockefeller University
Phase: 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 a 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/mm3.18

 

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 a 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.3,19

Selected Study Results:

 

Study Identifiers: ROADMAP; NCT02850016
Sponsor: Rockefeller University
Phase: 2a
Status: This study is ongoing, but not recruiting participants.
Study Purpose: The purpose of this open-label study is 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 a treatment interruption of ART.
Study Population:

  • Participants are adults with HIV who have been on ART for at least 24 months.
  • Participants on a PI- or NNRTI-based ART regimen or on a cobicistat-containing regimen must be willing to switch to an INI-based regimen prior to enrollment.
  • Participants have had HIV RNA <50 copies/mL for at least 18 months and have CD4 counts >500 cells/mm3 at screening.20

 

Study Identifiers: eCLEAR; NCT03041012
Sponsor: Aarhus University Hospital
Phase: 2 
Status: This study is currently 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 limit the size of the latent HIV reservoir.
Study Population:

  • Participants have HIV but have never received ART.
  • Participants have CD4 counts >200 cells/mm3 prior to study entry.21

 

Study Identifiers: TITAN; NCT03837756
Sponsor: University of Aarhus
Phase: 2a
Status: This study is currently 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 re-initiation of ART during a 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 10-1074.22

 

Study Identifier: NCT03719664
Sponsor: Frontier Biotechnologies Inc.
Phase: 2
Status: This study is currently recruiting participants.
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 last 24 weeks prior to screening and at screening and have CD4 counts >300 cells/mm3 at screening.23

 

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

  • NCT02825797: A completed Phase 1b study that assessed the safety, pharmacokinetics, and antiretroviral effects of 3BNC117 plus 10-1074 in adults with HIV.24
  • NCT03526848: A Phase 1 study that will assess whether 3BNC117 and 10-1074 can control viral rebound in adults with HIV during a treatment interruption of ART. This study is currently recruiting participants.25
  • NCT03571204: A Phase 1 study evaluating whether 3BNC117 and 10-1074 can control viral load levels in individuals with HIV who are currently not receiving ART and in individuals with HIV who stop ART during a treatment interruption. This study is currently recruiting participants.26
  • NCT03554408: A Phase 1 study investigating the safety and pharmacokinetics of 10-1074-LS (long-acting form of 10-1074) when given alone and when given in combination with 3BNC117-LS in adults with and without HIV. This study is currently recruiting participants.16
  • BEAT-2 (NCT03588715): A Phase 1 study that will evaluate whether peginterferon alfa-2b plus 3BNC117 and 10-1074 can control viral rebound and reduce the latent HIV reservoir in adults with HIV during a treatment interruption of ART. See the ClinicalTrials.gov record for this study’s status.27


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.3


Drug Interactions


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


References


  1.  United States National Library of Medicine. ChemIDplus Advanced: 3BNC117. https://chem.nlm.nih.gov/chemidplus/rn/1412902-17-0. Accessed May 30, 2019.
  2. Gray GE, Laher F, Lazarus E, Ensoli B, Corey L. Approaches to preventative and therapeutic HIV vaccines. Curr Opin Virol. 2016;17:104-109.
  3. 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.
  4. Treatment Action Group website. Research toward a cure trials. http://www.treatmentactiongroup.org/cure/trials. Accessed May 30, 2019.
  5. Rockefeller University. A Phase 1 study of the safety and pharmacokinetics of the combination of 3BNC117 and 10-1074 in HIV-uninfected adults: In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on June 28, 2016. NLM Identifier: NCT02824536. https://clinicaltrials.gov/ct2/show/NCT02824536. Accessed May 30, 2019.
  6. Lederman M, Rodriguez B, Sieg S. Immunopathogenesis of HIV Infection. In: Coffey S, Volberding P, eds. HIV InSite Knowledge Base. University of California San Francisco; 2004. http://hivinsite.ucsf.edu/InSite?page=kb-00&doc=kb-02-01-04. Accessed May 30, 2019.
  7. Miller E, Bhardwaj N. Advances in dendritic cell immunotherapies for HIV-1 infection. Expert Opin Biol Ther. 2014;14(11):1545-1549.
  8. Smith PL, Tanner H, Dalgleish A. Developments in HIV-1 immunotherapy and therapeutic vaccination. F1000Prime Rep. 2014;6(43). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4047951/. Accessed May 30, 2019.
  9. Routy J-P, Boulassel M-R, Yassine-Diab B, et al. Immunologic activity and safety of autologous HIV RNA–electroporated dendritic cells in HIV-1 infected patients receiving antiretroviral therapy. Clin Immunol. 2010;134(2):140-147.
  10. Graziani GM, Angel JB. Evaluating the efficacy of therapeutic HIV vaccines through analytical treatment interruptions. J Int AIDS Soc. 2015;18(1):20497.
  11. 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. http://www.avac.org/sites/default/files/u16/Theraeutic_Vaccine_Module_June.pptx. Accessed May 30, 2019.
  12. Halper-Stromberg A, Nussenzweig MC. Towards HIV-1 remission: potential roles for broadly neutralizing antibodies. J Clin Invest. 126(2):415-423.
  13. Bruel T, Guivel-Benhassine F, Amraoui S, et al. Elimination of HIV-1-infected cells by broadly neutralizing antibodies. Nat Commun. 2016;7:10844.
  14. Stephenson KE, Barouch DH. Broadly neutralizing antibodies for HIV eradication. Curr HIV/AIDS Rep. 2016;13:31-37.
  15. 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.
  16. Rockefeller University. A Phase 1, dose escalation, first-in-human study of the safety and pharmacokinetics of the subcutaneous and intravenous administration of 10-1074-LS alone and in combination with 3BNC117-LS in HIV-infected and HIV-uninfected individuals. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on July 26, 2016. NLM Identifier: NCT03554408. https://clinicaltrials.gov/ct2/show/NCT03554408. Accessed May 30, 2019.
  17. 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.
  18. 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. https://clinicaltrials.gov/ct2/show/NCT02588586. Accessed May 30, 2019.
  19. 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. https://clinicaltrials.gov/ct2/show/NCT02446847. Accessed May 30, 2019.
  20. 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. https://clinicaltrials.gov/ct2/show/NCT02850016. Accessed May 30, 2019.
  21. 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. https://clinicaltrials.gov/ct2/show/NCT03041012. Accessed May 30, 2019.
  22. 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. https://clinicaltrials.gov/ct2/show/NCT03837756. Accessed May 30, 2019.
  23. 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. https://clinicaltrials.gov/ct2/show/NCT03719664. Accessed May 30, 2019.
  24. Rockefeller University. An Phase 1b study of the safety, pharmacokinetics and antiretroviral activity of the combination of 3BNC117 and 10-1074 in HIV-infected individuals. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on June 28, 2016. NLM Identifier: NCT02825797. https://clinicaltrials.gov/ct2/show/NCT02825797. Accessed May 30, 2019.
  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. https://clinicaltrials.gov/ct2/show/NCT03526848. Accessed May 30, 2019.
  26. 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. https://clinicaltrials.gov/ct2/show/NCT03571204. Accessed May 30, 2019.
  27. 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 July 17, 20185. NLM Identifier: NCT03588715. https://clinicaltrials.gov/ct2/show/NCT03588715. Accessed May 30, 2019.


Last Reviewed: May 30, 2019