3BNC117 / Rockefeller University, Cornell University, Frontier Biotech, Gilead - LARVOL DELTA

Genotypic susceptibility to broadly neutralizing antibodies and fostemsavir of transmitted viruses, and evolution over time in the French acute HIV infection PRIMO cohort (EACS 2025) - "Method : We analyzed 191 sequences from participants in the acute infection French ANRS PRIMO cohort, over 3 decades (1988–2022), using sequence-based algorithms to predict susceptibility to teropavimab (3BNC117), zinlirvimab (10-1074) and entry inhibitors (fostemsavir, maraviroc). Conclusions : These findings underscore the importance of continuous surveillance of transmitted viruses to therapies targeting HIV-1 Env. Integrating phenotypic assessment with genotypic surveillance to refine resistance prediction models will also be important for predicting susceptibility, as well as the correlation with clinical efficacy in ongoing trials."

Human Immunodeficiency Virus • Infectious Disease • CD4

Transient rapamycin treatment avoids unwanted host immune responses toward AAV-delivered anti-HIV antibodies. (PubMed, Nat Commun) - "Long-term delivery of broadly neutralizing antibodies (bnAbs) using adeno-associated virus (AAV) vector is a promising approach for both the prevention and treatment of HIV infection. Use of the agent in monkeys results in 12 of 15 successful deliveries of the bnAbs 3BNC117, 10-1074, and PGT145 following drug cessation across all animals. The results of this 5-monkey trial lend strong support to continuing studies in SHIV-infected monkeys and use of this approach in humans for potential worldwide use."

Journal • Human Immunodeficiency Virus • Infectious Disease

Factors influencing monoclonal antibody pharmacokinetics across varying immune perturbations. (PubMed, J Control Release) - "Here, we investigated the PK profile of the human mAb 3BNC117 after intravenous, subcutaneous, and intraperitoneal injections in four mouse strains: BL6, BCD, RAG2, and NSG mice...The scaled parameters obtained from BCD and RAG2 mice led to reasonably accurate human predicted PK, whereas the parameters obtained from NSG and BL6 mice did not. These results emphasize that the mechanistic differences influencing NSG and BL6 PK must be considered when assessing the translatability of data."

Journal • PK/PD data

Distinct modes of evolution drive HIV escape from two broadly neutralizing antibodies. (PubMed, bioRxiv) - "We characterize viral escape from two such bNAbs, 10-1074 and 3BNC117, using deep, longitudinal sequencing of full length HIV envelope (env) genes from study participants treated with bNAb monotherapy. In contrast, 3BNC117 escape follows background-specific patterns in which specific escape mutations present in one population rarely emerge or spread in other populations, but often still exhibit parallel evolutionary responses within their host. That bNAbs elicit starkly different in vivo escape profiles depending on their Env target exposes the limitations of generalizing escape patterns across therapies and highlights the substantial challenges in predicting a viral population's bNAb susceptibility from genetic diversity alone."

Journal • Human Immunodeficiency Virus • Infectious Disease

HIV-specific T-cell responses in suppressed people with HIV-1 receiving lenacapavir, teropavimab, and zinlirvimab (IAS-HIV 2025) - P1 | "Small increases in these responses were observed when the broadly neutralizing antibodies (bNAbs) 3BNC117 and 10-1074 were dosed during analytical treatment interruption or at ART initiation. Lack of increase from baseline in HIV-specific T-cell response following LEN+TAB+ZAB treatment in VS PWH suggests virologic suppression by LEN+TAB+ZAB did not increase viral antigen expression, which may have limited expansion of HIV-specific T-cells. This has implications for HIV-1 cure studies if greater antigen exposure if required for increased HIV-specific T-cell responses after bNAb administration."

Human Immunodeficiency Virus • Infectious Disease • CD4 • CD8

The Immunogenicity of AAV-Encoded HIV-1 bNAbs in Rhesus Macaques Is Unaffected by a Short Course of the Immunomodulator CTLA4Ig. (PubMed, AIDS Res Hum Retroviruses) - "Six rhesus macaques (RMs) were treated intramuscularly with AAV-1 vectors encoding "rhesusized" (rh) versions of the bNAbs 3BNC117 (IgG1) and 10-1074 (IgG2). In conclusion, a short course rh-CTLA4Ig did not significantly reduce the immunogenicity of AAV-encoded bNAbs in RMs. Although our study was not powered to detect marginal effects, robust improvements in AAV-driven expression of hypermutated HIV-1 bNAbs may require combination approaches, such as multiple co-stimulation blockers, pharmacological immunosuppression, and/or muscle-specific promoters."

Journal • Human Immunodeficiency Virus • Infectious Disease • CD28 • CD4 • CD80 • CD86

Determinants of successful AAV-vectored delivery of HIV-1 bNAbs in early life. (PubMed, Nature) - "Here, using infant rhesus macaques (Macaca mulatta) as a model, we show that a one-time administration of an AAV vector encoding bNAb 3BNC117 at birth led to sustained bNAb expression for more than three years without redosing...Thus, our results suggest that neonatal and fetal immunological tolerance can be leveraged to improve postnatal AAV delivery of HIV-1 bNAbs in primates. Since years-long HIV-1 immunity can be generated in rhesus macaques from a one-time AAV vector administration at birth, future studies should evaluate the ability of this strategy to prevent perinatal and adolescent HIV-1 infections in humans."

Journal • Human Immunodeficiency Virus • Infectious Disease • ACACA

CAR-T cell-secreted bNAbs mediate Fc-effector functions and reduce viral load in humanized mouse model of HIV infection (IAS-HIV 2025) - "The Hybrid CAR-T cells are engineered to secrete bNAbs with an Fc-IgG1 domain, which trigger secondary immune effector functions such as Antibody-Dependent Cellular Cytotoxicity (ADCC) and Phagocytosis (ADCP) on top of cell-free HIV neutralization. We engineered a bicistronic lentiviral vector encoding a 3rd generation CD4-based CAR and the 3BNC117 bNAb... We successfully engineered Hybrid CAR-T cells that secrete bNAbs, exert cytotoxic killing against HIV-infected cells, neutralize cell-free HIV and mediate Fc-dependent functions in vitro. The anti-HIV activity of Hybrid CAR-T cells was confirmed in vivo. Combining CAR-T cells and bNAbs, the Hybrid CAR concept harnesses multiple arms of the immune system and therefore holds a strong potential for a functional HIV cure."

CAR T-Cell Therapy • Preclinical • Gene Therapies • Human Immunodeficiency Virus • Infectious Disease • CD4 • CD8

HIV-1 envelopes from virions that persist in plasma on antiretroviral therapy show reduced susceptibility to autologous immunoglobulins and variable sensitivity to broadly neutralizing monoclonal antibodies. (PubMed, bioRxiv) - "Two Env protein variants from one donor, R-09_A8 and R-09_C2, were less sensitive to VRC01 likely due to an additional N-glycan site at a VRC01 contact site and longer V5 regions...The CD4 binding site mAb 3BNC117 and the Gp41-specific mAb 10E8 neutralized pseudoviruses from all donors, indicating the potential for clearance of persistent viremia in these individuals studied...The results revealed that these pseudovirus were not neutralized by their autologous Igs and exhibited complex pseudovirus-specific susceptibility profiles for the monoclonal antibodies they were tested against. Collectively, our findings suggest that despite resistance to autologous Ig, likely combinations of monoclonal antibodies will be needed to clear this persistent viremia."

Journal • Human Immunodeficiency Virus • Infectious Disease • CD4

Synergizing Broadly Neutralizing Antibody-Secreting T Cells and CAR-T Cells Against HIV-1 Infection (ASGCT 2025) - "As a proof-of-concept, we engineered a lentiviral vector (LV) encoding 3BNC117 bNAb (3BNC) to transduce T cells... We successfully engineered T cells that secrete bNAb, and exhibit in vitro anti-HIV function and sustained in vivo bNAb production. BNAb-secreting T cells can synergize with CAR-T cells both in vitro and in mice to enhance HIV-1 killing as compared to CAR-T cells alone. This novel therapy combining cellular and humoral anti-HIV approach provides a new strategy to generate more potent immunotherapeutics, which may contribute to a functional cure of HIV-1 infection."

CAR T-Cell Therapy • Human Immunodeficiency Virus • Infectious Disease

AAV-vectored PD-L1 Co-Expression as a Strategy to Enhance AAV-Delivered bNAb Efficacy (ASGCT 2025) - " Five groups of six rhesus macaques each received the following vectors: 1) AAV9.PD-L1; 2) AAV9.10-1074; 3) AAV9.PD-L1 and AAV9.10-1074; 4) AAV9.3BNC117; and 5) AAV9.PD-L1 and AAV9.3BNC117. These studies suggest that co-expression of PD-L1 at the site of administration reduces the host immune response to an AAV-expressed transgene in rhesus macaques. We propose that our vectored PD-L1 co-expression strategy can facilitate the sustained expression of other viral-vectored transgenes. Disease Focus of Abstract:HIV"

Clinical • IO biomarker • Human Immunodeficiency Virus • Infectious Disease • PD-1 • PD-L1

Therapeutic efficacy of AAV-delivered HIV-1 bNAbs to prevent SHIV rebound in rhesus macaques (ASGCT 2025) - "Macaques in the treatment group received AAV9 vectors encoding 10-1074 and 3BNC117 co-delivered with AAV9 vectors encoding PD-L1 administered intramuscularly at 36 weeks post-infection. Our ongoing study reveals that the co-expression of PD-L1 is sufficient to achieve therapeutic concentrations of bNAb expression in rhesus macaques that can suppress a SHIV infection without ART. Additionally, these results suggest AAV-delivered bNAbs are a possible alternative to ART therapy in SHIV-infected macaques. Disease Focus of Abstract:HIV"

Clinical • IO biomarker • Human Immunodeficiency Virus • Infectious Disease • PD-L1

Distinct region-specific neutralization profiles of contemporary HIV-1 clade C against best-in-class broadly neutralizing antibodies. (PubMed, J Virol) - "Env-pseudotyped viruses encoding HIV-1 India clade C env were found to be best neutralized by the V3 glycan-directed bnAbs (10-1074 and BG18) and select CD4 binding site (CD4bs)-directed bnAbs (VRC07, N6, and 1-18); however, they demonstrated significant resistance to V1/V2 apex-directed bnAbs...Notably, the second generation CD4bs bnAbs (VRC07, N6, 1-18) showed neutralization of VRC01- and 3BNC117-resistant viruses but with two- to sevenfold reduced potency compared to the VRC01-sensitive counterparts, likely due to the enrichment of resistance-associated residues observed in loop D. Predictive analysis indicated that the combination of BG18, N6, and PGDM1400 can provide over 95% neutralization coverage of contemporary India clade C at 1 µg/mL (IC80), an observation distinct from that observed with Africa clade C. Our study clearly highlights that both the complementarity of bnAb classes and the regionally relevant HIV-1 forms are important in achieving clinical..."

Journal • Human Immunodeficiency Virus • Infectious Disease • CD4

Comprehensive maps of escape mutations from antibodies 10-1074 and 3BNC117 for Envs from two divergent HIV strains. (PubMed, J Virol) - "This study uses pseudoviruses to map all escape mutations for antibodies 10-1074 and 3BNC117 for the Envelope proteins from two different HIV strains. These maps can inform analyses of viral mutations observed in clinical trials and help understand how the escape mutations from these antibodies differ across HIV strains."

Journal • Human Immunodeficiency Virus • Infectious Disease • CD4

eCLEAR: Early Administration of Romidepsin and 3BNC117 in Treatment-naïve HIV Patients Starting ART (clinicaltrials.gov) - P2 | N=60 | Completed | Sponsor: Aarhus University Hospital | Active, not recruiting ➔ Completed

Trial completion • Human Immunodeficiency Virus • Infectious Disease • CD4

Clinical trials of broadly neutralizing monoclonal antibodies in people living with HIV - a review. (PubMed, AIDS Res Ther) - "More recent trials that paired bNAbs with latency-reversing agents or combined multiple bNAbs demonstrated promising results, including delayed viral rebound and enhanced CD8 + T-cell responses. While bNAbs show potential as an adjunct or alternative to ART, obstacles such as viral resistance, high production costs, and scalability must be addressed. Continued research is crucial to developing more potent, durable, and affordable bNAbs for sustainable HIV treatment and potential remission."

Journal • Review • Human Immunodeficiency Virus • Infectious Disease • CD8

Factors influencing virologic control during analytical treatment interruptions in HIV cure trials - a pooled analysis of individual level data. (PubMed, J Infect Dis) - "Our findings highlight the positive impact of early ART and low HIV reservoirs on time to rebound among people undergoing ATI and provides new insight into therapeutic interventions aimed at achieving virologic control."

Journal • Retrospective data • Human Immunodeficiency Virus • Infectious Disease • CD4

Autologous IgGs Mediate Log Reductions in HIV Infection in a PTC, Contributing to ART-Free Remission (CROI 2025) - "Study participant ID107 enrolled in the eCLEAR trial received broadly neutralizing antibody 3BNC117 and latency reversing agent romidepsin shortly after ART initiation, which was 2 months after HIV acquisition. Conclusions This participant has maintained ART-free remission for >6 years despite a reservoir size in the normal range. The aNAb responses that developed may contribute to the prolonged ART-free remission of study participant ID107."

Clinical • Human Immunodeficiency Virus • Infectious Disease • CD4

A Strategy for Durable AAV-Vectored bNAb Expression in Adult Rhesus Macaques (CROI 2025) - "Methods Five groups of six rhesus macaques each received the following vectors: 1) AAV9.PD-L1; 2) AAV9.10-1074; 3) AAV9.PD-L1 and AAV9.10-1074; 4) AAV9.3BNC117; and 5) AAV9.PD-L1 and AAV9.3BNC117. Conclusions We have developed a strategy for sustained bNAb expression in NHPs. This will allow the prophylactic and therapeutic efficacy of AAV-delivered bNAbs to be studied in preclinical NHP models."

Clinical • IO biomarker • Human Immunodeficiency Virus • Infectious Disease

A Multicenter Study of Albuvirtide Combined With 3BNC117 in Multidrug-Resistant HIV-1 Infection (CROI 2025) - "In the eight-week analysis after ABT+3BNC117 cessation in 14 participants, 92.8% had a viral load below 50 RNA copies/mL. Conclusions In patients with MDR HIV-1 infection who have advanced disease and limited treatment therapeutic options, the combination of ABT+3BNC117 had significant antiviral activity during a 34-week study period."

Clinical • Human Immunodeficiency Virus • Infectious Disease

The Barrier to Escape From Broadly Neutralizing Antibodies Varies Between Different HIV-1 Isolates (CROI 2025) - "Conclusions This study demonstrates that various pathways exist for escape from a CD4 binding site bNAb 3BNC117 among divergent HIV-1 isolates. Understanding the pathways enabling escape from bNAb neutralization as well as the frequency at which they are maintained in the population will help to tailor these antibody-based therapies and inform the design of vaccines that aim to elicit bNAb-like antibodies."

Human Immunodeficiency Virus • Infectious Disease • CD4

HIV-Specific CD8+ T Cell Stemness Predicts Postintervention Control of Viremia (CROI 2025) - "Methods We obtained longitudinal peripheral blood before and 6-12 weeks following ATI, prior to viral rebound, from post-intervention controllers (PICs, n=7) and non-controllers (PINCs, n=5) from the MCA-906, MCA-965, TITAN, and eCLEAR trials, in which participants received infusions of bNAbs 3BNC117 and/or 10-1074 and underwent ATI. Although PIC was not associated with the emergence of new responses or the in vivo activation or expansion of memory responses, modest increases in proliferative capacity and TSCM frequency after bNAb therapy were consistent with a potential vaccinal effect. These results identify functional determinants of PIC that may guide the development of effective immunotherapies to elicit durable ART-free control of viremia in a larger proportion of PWH."

IO biomarker • Late-breaking abstract • Human Immunodeficiency Virus • Infectious Disease • CD8 • IFNG

Sustained T Cell-Mediated Immunity After LS-bNAbs in the RIO Trial: A Vaccinal Effect (CROI 2025) - "The RIO trial facilitated analysis of participants receiving two LS-bNAbs (10-1074 & 3BNC117) followed by analytical treatment interruption (ATI). At time of submission, there was evidence for an association between baseline CD8+ T cell proliferation to Gag and viral control (HR 1.92; P=0.097), most marked in participants who remained suppressed >15 weeks after bNAb dosing (HR 3.72; P=0.004). Conclusions In RIO, after dosing with two LS-bNAbs and an ATI, there was increased Gag-specific T cell immunity in aviraemic participants which was associated with viral control."

IO biomarker • Late-breaking abstract • Human Immunodeficiency Virus • Infectious Disease • CD38 • CD4 • CD69 • CD8 • IL2RA • ISG20

Viral Genetic Traits of Durable Control in Dual Immunotherapy-Treated SHIV-Infected Rhesus Macaques (CROI 2025) - "Background A recent study demonstrated that combined administration of N-803 (IL15 agonist) and the 10-1074 and 3BNC117 broadly neutralizing antibodies (bNAbs) results in durable virologic remission following ART cessation in SHIV-infected, ART-suppressed rhesus macaques (RM). Observed mutational patterns and glycosylation site disruption likely reflect evolutionary responses to pressure from neutralizing antibodies. Phenotypic characterization of the induced SHIV Env mutants will inform the development of HIV cure approaches."

IO biomarker • Human Immunodeficiency Virus • Infectious Disease • IL15

Time-to-Rebound Measurements in ATI Trials With bNAb Intervention Are Confounded by Autologous NAbs (CROI 2025) - P1 | "Participants in the NCT03588715 (BEAT2) clinical trial received six infusions of the bNAbs 3BNC117 and 10-1074, and thirty doses of IFNa2b...Higher proportions of replication-competent outgrowth viruses neutralized by aNAbs was associated with a more delayed time-to-rebound following cessation of all immunotherapies. ATI studies must consider the role of pre-existing aNAbs in potentially confounding time-to-rebound measurements."

IO biomarker • Human Immunodeficiency Virus • Infectious Disease • CD4