Drug information

Audio
Pronounce:
Other Names
GS-2872, 10-1074-LS and 10-1074-LS-J (long-acting forms of 10-1074)
Drug Class
Broadly Neutralizing Antibodies
Organization
Universidad Rockefeller, Gilead Sciences
Phase of Development

10-1074 is in Phase 2 development as a broadly neutralizing antibody for HIV treatment. (10-1074 is also being developed for HIV prevention).

(Compound details obtained from Treatment Action Group website,1 Treatment Action Group Pipeline Report 2021,2 and Gilead Sciences press release3)

Pharmacology

Pharmacology

Mechanism of Action: Broadly neutralizing antibody (bNAb). 10-1074 is a recombinant human IgG1 lambda monoclonal antibody. It is a next-generation bNAb that targets the base of the V3 loop and surrounding glycans on the HIV envelope spike protein.4,5

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

10-1074 and long-acting versions of 10-1074 (known as 10-1074-LS and 10-1074-LS-J) are being developed for HIV prevention and/or as a possible component to HIV treatment or cure.1,2

Half-life (T½): In a Phase 1 trial (NCT02511990) where 10-1074 was administered as a single intravenous (IV) infusion (3, 10, or 30 mg/kg) to adults with and without HIV, the estimated serum half-life of 10-1074 was found to be 12.8 days in participants with HIV and 24 days in participants without HIV.5

The half-life of modified long-acting 10-1074-LS was estimated in a preclinical study in uninfected macaques. Following a single IV infusion of 10-1074 LS (20 mg/kg), the median half-life was 3.8 weeks, representing a 3.8-fold increase compared to the half-life of unmodified 10-1074 administered in macaques.11

Resistance: Treatment-emergent resistance to 10-1074 has been observed in clinical trials. In a Phase 1 dose-escalation study (NCT02511990), multiple 10-1074-resistant HIV variants were detected in participants following a single infusion of 10-1074. Resistance to 10-1074 arose from pre-existing virus and/or selection of new variants within weeks after 10-1074 infusion. Escape variants, however, were found to retain sensitivity to bNAbs that target non-overlapping sites on HIV-1 Env (3BNC117, VRC01, and PGDM1400).5

In a Phase 1b trial (NCT02825797) that evaluated 3BNC117 administered in combination with 10-1074, resistance to 10-1074 emerged as serum levels of 3BNC117 decreased (essentially resulting in 10-1074 monotherapy). Notably, however, no participants developed resistance to both antibodies during the trial.12,13

Select Clinical Trials

Select Clinical Trials

Study Identifiers: Tatelo Study; NCT03707977
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Phase: 1/2
Status: This study is ongoing, but not recruiting participants.
Study Purpose: The purpose of this open-label study is to evaluate the efficacy of the investigational bNAbs VRC01LS and 10-1074 in maintaining HIV suppression in a cohort of children who had received early ART treatment.
Study Population:

  • Participants are children who had received ART from less than 7 days through at least 96 weeks of life.
  • Participants have HIV RNA <40 copies/mL for at least 24 weeks before study entry.14,15

Selected Study Results:


Study Identifiers: HIVACAR; NCT03619278
Sponsor: David Garcia Cinca
Phase: 1/2a
Status: See the ClinicalTrials.gov record for this study’s status.
Study Purpose: The purpose of this study is to evaluate the safety and efficacy of combinations of therapeutic HIV vaccines (HIVARNA01.3, MVA-vectored vaccine, and HIVACAR01) with 10-1074 and the latency-reversing agent romidepsin in controlling viral load levels during a treatment interruption of ART.
Study Population:

  • Participants are adults with HIV who have been on a stable ART regimen for at least 18 months.
  • Participants have had HIV RNA <50 copies/mL for the past 12 months and have CD4 counts ≥450 cells/mm3. Participants’ nadir CD4 counts are ≥350 cells/mm3.16


Study Identifiers: NCT04357821
Sponsor: University of California, San Francisco
Phase: 1/2
Status: This study is currently recruiting participants.
Study Purpose: The purpose of this open-label study is to evaluate whether a combination regimen can control viral load levels during a treatment interruption of ART. The combination regimen includes therapeutic HIV vaccines (IL-12 adjuvanted p24CE, IL-12 adjuvanted p24CE plus p55gag, and MVA62B), bNAbs (VRC07-523LS and 10-1074), and the TLR9 agonist lefitolimod.
Study Population:

  • Participants are adults with HIV who have been on a continuous ART regimen for at least 12 months. For at least 4 weeks before study entry, participants have been on a stable ART regimen that does not include an NNRTI.
  • Participants have had undetectable HIV RNA in the past 24 months and have CD4 counts ≥500 cells/mm3.17


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 10-1074.18


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 after a 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 and are on an INSTI- or boosted PI-based regimen at the time of randomization.
  • Participants have had undetectable HIV RNA for at least 1 year and have CD4 counts >500 cells/mm3. Participants’ nadir CD4 counts are >350 cells/mm3.
  • Participants show no evidence of viral insensitivity to either 10-1074 or 3BNC117.19


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

  • NCT03526848: A Phase 1 study that is evaluating whether 3BNC117 and 10-1074 can control viral load levels in adults with HIV during a treatment interruption of ART. This study is ongoing, but not recruiting participants.20
  • NCT04250636: A Phase 1 study that will evaluate the safety, pharmacokinetics, and antiviral activity of single infusions of both 3BNC117-LS and 10-1074-LS in adults with HIV who are off ART. This study is currently recruiting participants.21
  • NCT04811040: A Phase 1b study evaluating the safety and efficacy of 3BNC117-LS (GS-5423) and 10-1074-LS (GS-2872) in combination with the investigational capsid inhibitor lenacapavir in controlling viral load levels in virologically suppressed adults with HIV. This study is currently recruiting participants.22
  • NCT03831945: A Phase 1 trial that assessed whether the combination of VRC01 plus 10-1074 could control viral load levels in virologically suppressed adults undergoing treatment interruptions of ART. This study has been completed.23
  • 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. This study is ongoing, but not recruiting participants.24
  • 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.25

Adverse Events

Adverse Events

Tatelo Study (NCT03707977):

In this Phase 1/2 trial, the safety and pharmacokinetics of VRC01LS and 10-1074 were assessed when the bNAbs were administered separately (Phase A) and in combination (Phase B) in children with HIV who were on suppressive ART. In Phase A, 12 children received infusions of either VRC01LS or 10-1074 every 28 days over 12 weeks. During Phase B, six children received monthly infusions of both VRC01LS and 10-1074 over 8 weeks, and safety was evaluated through 32 weeks. No participants experienced infusion reactions or Grade 3 or 4 adverse events (AEs) related to single or dual bNAb administration, and no expedited AEs occurred with dual bNAb treatment.14,26,27

Drug Interactions

Drug Interactions

Drug-drug interactions associated with 10-1074 are currently unknown.

References

References

  1. Treatment Action Group website. Research toward a cure trials. http://www.treatmentactiongroup.org/cure/trials. Accessed August 22, 2021
  2. Jefferys R. HIV vaccines & passive immunization. Treatment Action Group Pipeline Report 2021. https://www.treatmentactiongroup.org/wp-content/uploads/2021/07/pipeline_2021_HIV_vaccine_final.pdf. Accessed August 22, 2021
  3. Gilead Sciences: press release, dated January 9, 2020. Gilead Sciences licenses portfolio of HIV antibodies from The Rockefeller University. https://www.gilead.com/news-and-press/press-room/press-releases/2020/1/gilead-sciences-licenses-portfolio-of-hiv-antibodies-from-the-rockefeller-university. Accessed August 22, 2021
  4. Sharma VK, Misra B, McManus KT, et al. Characterization of co-formulated high-concentration broadly neutralizing anti-HIV-1 monoclonal antibodies for subcutaneous administration. Antibodies (Basel). 2020;9(3):36. doi:10.3390/antib9030036
  5. Caskey M, Schoofs T, Gruell H, et al. Antibody 10-1074 suppresses viremia in HIV-1-infected individuals. Nat Med. 2017;23(2):185-191. doi:10.1038/nm.4268
  6. Halper-Stromberg A, Nussenzweig MC. Towards HIV-1 remission: potential roles for broadly neutralizing antibodies. J Clin Invest. 126(2):415-423.
  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. http://www.avac.org/sites/default/files/u16/Theraeutic_Vaccine_Module_June.pptx. Accessed August 22, 2021
  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.
  9. Stephenson KE, Barouch DH. Broadly neutralizing antibodies for HIV eradication. Curr HIV/AIDS Rep. 2016;13:31-37.
  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.
  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. doi:10.1038/s41591-018-0001-2
  12. Bar-On Y, Gruell H, Schoofs T, et al. Safety and anti-viral activity of combination HIV-1 broadly neutralizing antibodies in viremic individuals. Nat Med. 2018;24(11):1701-1707. doi:10.1038/s41591-018-0186-4
  13. Mendoza P, Gruell H, Nogueira L, et al. Combination therapy with anti-HIV-1 antibodies maintains viral suppression. Nature. 2018;561(7724):479-484. doi:10.1038/s41586-018-0531-2
  14. National Institute of Allergy and Infectious Diseases (NIAID). A clinical trial to evaluate the impact of broadly neutralizing antibodies VRC01LS and 10-1074 on maintenance of HIV suppression in a cohort of early-treated children in Botswana (dual bNAb treatment in children). In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). October 12, 2018. NLM Identifier: NCT03707977. https://clinicaltrials.gov/ct2/show/NCT03707977. Accessed August 22, 2021
  15. Capparelli EV, Ajibola G, Maswabi K, et al. Safety and pharmacokinetics of VRC01LS and 10-1074 among children in Botswana. Webcast presented at: Conference on Retroviruses and Opportunistic Infections (CROI); March 6-10, 2021; Virtual. http://www.croiwebcasts.org/console/player/47673?mediaType=slideVideo&. Accessed August 22, 2021
  16. David Garcia Cinca. A Phase I/IIa, randomised study to evaluate the safety and the effectiveness of a combination of therapeutic vaccine, broadly neutralising antibody (10-1074), and the latency reversing agent romidepsin to achieve a remission of HIV infection in chronically HIV-infected participants under stable combined antiretroviral therapy. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 14, 2018. NLM Identifier: NCT03619278. https://clinicaltrials.gov/ct2/show/NCT03619278. Accessed August 22, 2021
  17. 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. https://clinicaltrials.gov/ct2/show/NCT04357821. Accessed August 22, 2021
  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. https://clinicaltrials.gov/ct2/show/NCT03837756. Accessed August 22, 2021
  19. 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. https://clinicaltrials.gov/ct2/show/NCT04319367. Accessed August 22, 2021
  20. 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 August 22, 2021
  21. Rockefeller University. An open label, single arm study of the safety, pharmacokinetics and antiretroviral activity of the combination of 3BNC117-LS and 10-1074-LS in viremic HIV-infected individuals. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on January 30, 2020. NLM Identifier: NCT04250636. https://clinicaltrials.gov/ct2/show/NCT04250636. Accessed August 22, 2021
  22. 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. https://clinicaltrials.gov/ct2/show/NCT04811040. Accessed August 22, 2021
  23. National Institute of Allergy and Infectious Diseases (NIAID). An exploratory study of combination therapy with VRC-HIVMAB060-00-AB (VRC01) and 10-1074 in HIVinfected individuals undergoing sequential treatment interruptions. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on February 5, 2019. NLM Identifier: NCT03831945. https://clinicaltrials.gov/ct2/show/NCT03831945. Accessed August 22, 2021
  24. 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, 2018. NLM Identifier: NCT03588715. https://clinicaltrials.gov/ct2/show/NCT03588715. Accessed August 22, 2021
  25. 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. https://clinicaltrials.gov/ct2/show/NCT04340596. Accessed August 22, 2021
  26. Capparelli EV, Ajibola G, Maswabi K, et al. Safety and pharmacokinetics of intravenous VRC01LS and 10-1074 in young children. Abstract presented at: Conference on Retroviruses and Opportunistic Infections (CROI); March 8-11, 2020; Virtual. Abstract 465. https://www.croiconference.org/abstract/safety-and-pharmacokinetics-of-intravenous-vrc01ls-and-10-1074-in-young-children/. Accessed August 22, 2021
  27. Capparelli EV, Ajibola G, Maswabi K, et al. Safety and pharmacokinetics of VRC01LS and 10-1074 among children in Botswana. Abstract presented at: Conference on Retroviruses and Opportunistic Infections (CROI); March 6-10, 2021; Virtual. Abstract 609. https://www.croiconference.org/abstract/safety-and-pharmacokinetics-of-vrc01ls-and-10-1074-among-children-in-botswana/. Accessed August 22, 2021

Last Reviewed: August 22, 2021