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

Immunological comparison of viral control in the RIO trial versus HIV elite and post-treatment controllers (AIDS 2026) - "The RIO trial tested two LS-bNAbs, 10-1074 and 3BNC117, during analytical treatment interruption (ATI) and found that 25% of participants remained off ART after two years. VECs exhibited stronger baseline CD8+ responses than BCs and demonstrated viral inhibition capacity comparable to ECs. These findings suggest that bNAbs can help harness pre-existing HIV-specific immunity to support viral control."

Human Immunodeficiency Virus • Infectious Disease • CD4 • CD8 • HAVCR2 • LAG3 • TIGIT

Modeling quantifies in vivo neutralization, Fc-mediated killing, and resistance in human clinical trials of five anti-HIV broadly neutralizing antibodies. (PubMed, bioRxiv) - "We therefore performed a mathematical modeling meta-analysis which integrated four clinical trials and reproduced serial bnAb concentrations, viral loads, and bnAb sensitivities (IC50) in 43 viremic trial participants who received an infusion of VRC01, VRC01LS, VRC07-523LS, 3BNC117 or 10-1074. For each bnAb, our best model identified a scaling factor of 36-462 to pro j ect in vivo activity from in vitro IC50, quantified Fc-mediated infected cell killing in humans over time, and pro j ected the timing of bnAb-resistant strain emergence. Using this holistic profile, VRC07-523-LS was generally optimal."

Journal • Preclinical • Human Immunodeficiency Virus • Infectious Disease

Overcoming host immune responses to an AAV-delivered HIV-1 bNAb in rhesus macaques mediated by co-delivery of PD-L1. (PubMed, bioRxiv) - "We have previously shown that PD-L1-mediated immune shielding improves the consistency of AAV-delivered bNAb 3BNC117 expression from muscle tissue in rhesus macaques. Here, we test the breadth of this approach with another bNAb, 10-1074...Histopathological profiling showed that AAV9.PD-L1 co-delivery prevented severe local inflammation and tertiary lymphoid structure formation at the administration site. Thus, immune shielding could serve as a broad strategy to prolong transgene expression from muscle-directed AAV-delivered biologics."

IO biomarker • Journal • Human Immunodeficiency Virus • Infectious Disease • Inflammation • PD-L1

Co-delivered PD-L1 rescues the protective efficacy mediated by an AAV-expressed HIV-1 bNAb. (PubMed, bioRxiv) - "AAV9.PD-L1 co-delivery with AAV9.3BNC117 reduced the occurrence of ADA and T cell responses and improved the durability of 3BNC117 expression for one year post administration...Histopathological and spatial transcriptomic profiling showed that AAV9.PD-L1 co-delivery prevented severe local inflammation, muscle injury, and tertiary lymphoid structure formation at the administration site. Thus, immune shielding could serve as a strategy to prolong transgene expression from muscle-directed AAV-delivered biologics."

IO biomarker • Journal • Human Immunodeficiency Virus • Infectious Disease • Inflammation • PD-L1

Once yearly cell-based therapy for sustained and dose tunable delivery of monoclonal antibodies. (PubMed, bioRxiv) - "Screening chemically modified alginate biomaterials in immunocompetent mice identified a lead immunomodulatory alginate formulation that sustains stable serum titers of the HIV-neutralizing mAb 3BNC117 for one year...The platform's versatility was demonstrated by production of thirteen diverse mAbs from an allogeneic cell chassis, with sustained in vivo delivery of a subset including ipilimumab, pembrolizumab, adalimumab, and PGT121...In a non-human primates, subcutaneous implantation maintained stable ipilimumab titers for over six months with no detectable toxicity, anti-drug antibodies, or adverse events, and dose-dependent exposure was confirmed across a three-dose escalation. These results demonstrate a clinically translatable platform offering a practical strategy to replace frequent injections with single-administration therapy."

Journal • Fibrosis • Human Immunodeficiency Virus • Immunology • Infectious Disease

Therapeutic efficacy of AAV-delivered HIV-1 bNAbs to prevent SHIV rebound in rhesus macaques (ASGCT 2026) - "Macaques in the treatment group received AAV9 vectors encoding 10-1074 and 3BNC117 co-delivered with AAV9 vectors encoding PD-L1. Our ongoing study reveals that the co-delivery 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."

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

Tertiary lymphoid structures undermine muscle-targeted AAV delivery of biologics (ASGCT 2026) - "Methods Five groups of rhesus macaques (n=6 per group) received 2.5×10¹² vg kg⁻¹ of each of the following vectors: 1) AAV9.PD-L1; 2) AAV9.10-1074; 3) AAV9.10-1074 and AAV9.PD-L1; 4) AAV9.3BNC117 and 5) AAV9.3BNC117 and AAV9.PD-L1. The formation and persistence of TLSs at the administration site may be a previously unrecognized mechanism by which ADA persists. Thus, PD-L1-mediated immune shielding may be a strategy to prolong transgene expression of AAV-delivered biologics and preserve the health of the muscle."

IO biomarker • Fibrosis • Human Immunodeficiency Virus • Immunology • Infectious Disease • Inflammation • PD-L1

Broadly neutralizing antibody-secreting HIV-specific duoCAR-T cells potently suppress HIV-1 infection in humanized mice (ASGCT 2026) - "T cells were transduced with lentiviral vectors (LV) encoding 3BNC117 bNAb (3BNC) and the duoCAR to generate T cells expressing the two anti-HIV-1 duoCARs and/or secreting 3BNC...DuoCAR-T cells secreting bNAbs display robust anti-HIV-1 activity both in vitro and in humanized mice. This novel therapeutic approach combining a duoCAR-T cell with anti-HIV bNAb secretion offers a promising strategy for a functional cure of HIV-1 infection."

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

Diverse paths to broadly neutralizing antibody escape among HIV-1 strains. (PubMed, Nat Microbiol) - "Here we developed a medium-to-high throughput approach to determine the mutations that confer resistance to neutralization by the bnAbs 3BNC117 and 10-1074 currently in clinical development. Some 3BNC117 resistance mutations conferred resistance to additional bnAbs targeting the same or different epitopes, and unconventional escape mechanisms were occasionally encountered. These data provide a rationale for selecting bnAb combinations that are most likely to achieve treatment success."

Journal • Human Immunodeficiency Virus • Infectious Disease

Recurrent mutations drive rapid HIV escape from two broadly neutralizing antibodies in vivo. (PubMed, Proc Natl Acad Sci U S A) - "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. Despite this, 3BNC117 escape mutations can still emerge recurrently within their host. Our findings map longitudinal in vivo antibody escape across 20 diverse clade B HIV intrahost populations and reveal clinically relevant resistance dynamics that highlight how combination bNAb therapies will need to contend with extensively recurring escape mutations and dependence on genetic background."

Journal • Preclinical • Human Immunodeficiency Virus • Infectious Disease

Albuvirtide plus 3BNC117 provides a promising combination strategy for multidrug-resistant HIV-1 infection: a prospective, open-label, multicenter phase 2 trial. (PubMed, BMC Infect Dis) - P2 | "In patients with MDR HIV-1 infection who have limited treatment therapeutic options, the combination of ABT+3BNC117 plus an OBR was observed to have significant antiviral activity during a 34-week study period."

Journal • P2 data • Human Immunodeficiency Virus • Infectious Disease • CD4

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