PGT121 / Theraclone Sciences, Gilead, IAVI - LARVOL DELTA

Direct detection and quantification of HIV particles and their envelope trimers bound by combinations of broadly neutralizing antibodies. (PubMed, iScience) - "Analysis of N49P7, PGT121, and PGDM1400, targeting the CD4-binding site, V3-glycan region, and trimer apex, respectively, revealed subpopulations bound by one, two, or three bnAbs. Across strains, the proportion of virions bound by all three antibodies correlated significantly with neutralization activity. These findings define the distribution of combinatorial bnAb binding across heterogeneous virion populations and support quantitative single-particle fluorescence approaches for evaluating antibody combinations against HIV."

Journal • Human Immunodeficiency Virus • Infectious Disease • CD4

Rapid elicitation of neutralizing N332-glycan independent antibodies to the V3-glycan epitope of HIV-1 Env in nonhuman primates (AIDS 2026) - " WIN332 bound precursors of N332-glycan dependent bNAbs (PGT121, BG18) and the N332-glycan independent bNAb EPTC112... One immunization with WIN332 induced diverse V3-glycan-bNAb-like antibodies and early neutralization activity in NHPs. We identified a new class of V3-glycan antibodies that do not require the N332-glycan for binding. WIN332 is therefore a promising immunogen to advance to clinical testing."

Human Immunodeficiency Virus • Infectious Disease

Redirecting antibody specificity from the gp41 base to the V3-glycan epitope through env-based immunization (AIDS 2026) - " To test this hypothesis, we compared macaque gp41 base–binding Abs with known V3-glycan bNAbs and selected the macaque base-binding Ab1718 for its high sequence similarity to PGT121... These data show that rational vaccine design can redirect off-target antibody lineages toward conserved neutralizing epitopes of Env. We demonstrate that the specificity of a gp41 base–targeting antibody can be switched toward the V3-glycan supersite through vaccination, driven by natural affinity maturation and germinal center selection. Importantly, these findings indicate that some off-target antibody responses are not immunological dead ends, but instead harbor latent features that can be leveraged to expand the pool of broadly neutralizing antibody precursor lineages."

Human Immunodeficiency Virus • Infectious Disease

Proof-of-Concept Development and Preclinical Evaluation of a Microarray Patch Platform for Codelivery of Multiple Broadly Neutralizing Antibodies for HIV Prevention. (PubMed, Mol Pharm) - "Here, we present proof-of-concept data on a minimally invasive microneedle (MN) patch platform codelivering three bnAbs, PGT121, VRC07-523LS, and PGDM1400LS, from separate MN patch units or pixels. These preliminary findings suggest that the MN patch platform may serve as a promising alternative to injectable bnAb formulations for HIV prevention and treatment, particularly in neonates and infants, although further investigation is required to establish its clinical utility. Additionally, the solid-state MN formulation of bnAbs may eliminate the need for cold-chain storage or distribution, making the patch particularly suitable for use in resource-limited settings."

Journal • Preclinical • Human Immunodeficiency Virus • Infectious Disease • Pediatrics

Miniaturized subcutaneous cellular implants for sustained therapeutic protein delivery in resource-limited settings. (PubMed, bioRxiv) - "Clonal mesenchymal stromal cells engineered to produce PGT121, a broadly neutralizing anti-HIV-1 antibody, were encapsulated and inserted subcutaneously, achieving long-term cell survival and sustained serum PGT121 concentrations for up to 36 weeks across multiple murine models...These mini-"cellular factories" represent a translatable strategy for sustained delivery of biologic drugs in resource-limited settings. An insertable and retrievable mini cellular construct enables sustained protein delivery, supporting its potential use in resource-limited settings."

Journal • Human Immunodeficiency Virus • Infectious Disease

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

Safety, Immunogenicity, Efficacy of Ad26.Mos4.HIV, MVA-BN-HIV and PGT121, PGDM1400, and VRC07-523LS in HIV-1-Infected Adults (clinicaltrials.gov) - P1/2 | N=28 | Completed | Sponsor: Boris Juelg, MD PhD | Active, not recruiting ➔ Completed

Trial completion • Human Immunodeficiency Virus • Infectious Disease • Primary Immunodeficiency • CD4

Identification of correlates of HIV-1 Neutralizing Antibodies through a systems serology approach (IMMUNOLOGY 2026) - "These NHPs were further subdivided into groups receiving the monoclonal antibody (mAb) PGT121 or placebo to characterize how exogenous mAbs influence the neutralizing antibody profile. Predicted neutralizing antibodies to HIV-1 Env isolates and clades were quantified through SNAb, and showed heterogeneous neutralization capacities for all treatment arms. Our approach provides a method for dissecting correlates of HIV-1 neutralizing activity that may inform future vaccine and/or mAb therapy design. Future studies understanding how these neutralization signatures relate to latent reservoir expansion/contraction are ongoing."

Human Immunodeficiency Virus • Infectious Disease

Inhibition of HIV-1 cell-to-cell transmission in-vitro using engineered CAR NK/T cells. (IMMUNOLOGY 2026) - "Here, we studied the effects of immune-based strategies, including ADCC and CAR NK/T cells, on HIV-1 transmission between cells. We developed a highly sensitive assay for precise quantification of cell lysis using luciferase activity and built CAR NK/T based on the VRC01 and PGT121 bnAbs. These results provide proof of concept that targeting HIV-1 C-CT through ADCC and CAR NK/T cell therapies can overcome the limitations of bnAbs. This study offers the first evidence to test these approaches to effectively target HIV-1 C-CT, highlighting their potential in studying HIV-1 treatment strategies."

Preclinical • Human Immunodeficiency Virus • Infectious Disease

Intravaginal delivery of mRNA-encoded antibodies with enhanced breadth and potency for SHIV/HIV protection. (PubMed, Nat Commun) - "Vaginal explants from rhesus macaques, treated with intravaginal aerosolized mRNAs, show robust protection against ex vivo challenges with multiple SHIV strains when PGT121 and VRC07 are co-expressed as IgM-like multimers. Our data present novel drug compositions for intravaginal mRNA delivery to prevent HIV acquisition and advance antibody-design strategies that enhance breadth and potency of existing bnAbs."

Journal • Human Immunodeficiency Virus • Infectious Disease • CD4

Differences in neutralization susceptibility between clade C HIV viruses from breastmilk versus contemporaneous circulating viruses from sexually acquired infections. (PubMed, bioRxiv) - "Breastmilk viruses were more resistant to PGT121 and VRC07.523 (median IC80 >50 compared to 1.16 for PGT121, and 12.75 vs. 0.38 for VRC07.523; p=0.013 and <0.001 respectively), and more breastmilk viruses than adult viruses were resistant to VRC07.523 (94% vs. 43%, p=0.001). Interestingly, the breastmilk viruses most resistant to VRC07.523 had on average one or more glycans in V3 compared to adult transmitted viruses (median 3 vs. 2 glycosylation sites, including flanking position 295; p=0.009), and the number of V3 glycans was negatively correlated with VRC07.523 sensitivity (p=0.007). These findings highlight potential differences in bnAb susceptibility of vertically transmitted viruses and emphasize the need to increase sequencing efforts and screening of infant viruses to better inform the efficacy of candidate bnAbs to prevent vertical transmission of HIV."

Journal • Human Immunodeficiency Virus • Infectious Disease

Decision-making and acceptability of subcutaneously administered broadly neutralising monoclonal antibodies for HIV prevention amongst CAPRISA 012A trial participants in Durban, South Africa. (PubMed, Sci Rep) - "This study explored the acceptability of subcutaneously administered broadly neutralising antibodies, receiving either one or two doses of VRC07-523LS and/or PGT121, from the perspective of women living without HIV in KwaZulu-Natal, South Africa. The findings underscore the importance of integrating clear messaging on product efficacy, linking potential HIV prevention products to broader healthcare services, and supporting different users to make the decision to use this product. This study provides a novel contribution to understanding the complex dynamics of acceptability and behaviour change, essential for successful implementation and uptake of HIV prevention strategies."

Journal • Human Immunodeficiency Virus • Infectious Disease

Next Generation polymer nanoparticles (PNPs) for DNA encoded Biologics (ACS-Fall 2025) - "In this work, we present customized PNPs that deliver plasmid DNA (pDNA) encoding for PGT121, an anti-HIV antibody that is undergoing clinical trials for HIV treatment or cure...Furthermore, the pharmacokinetic profile was tunable by pDNA dose, PNP formulation conditions, and animal re-dosing, enabling machine learning techniques to further optimize delivery performance. Finally, we show that PNPs for DEb delivery is a universal approach to secrete model peptides and small proteins with wide implications in obesity/diabetes, osteomalacia, muscular dystrophy, and liver disease."

Diabetes • Genetic Disorders • Hepatology • Human Immunodeficiency Virus • Immunology • Infectious Disease • Metabolic Disorders • Muscular Dystrophy • Obesity

In Vitro Selection of Cyclized, Glycosylated Peptide Antigens That Tightly Bind HIV High Mannose Patch Antibodies. (PubMed, ACS Cent Sci) - "From selection, we obtained binders to HIV bnAbs PGT128, PGT122, and gl-PGT121, a germline precursor of PGT122, and chemically synthesized numerous glycopeptide hits. Several glycopeptides bound very tightly to their target HIV bnAb, e.g., with a K D as low as 0.5 nM for PGT128. These glycopeptides are of interest as immunogens and tools for HIV vaccine design."

Journal • Preclinical • Human Immunodeficiency Virus • Infectious Disease

Broadly-neutralizing Anti-HIV Antibody Production in Rhesus Macaques Transplanted with B Cells Engineered at the IgH Locus. (ASGCT 2025) - "B cells were engineered to express anti-HIV HCAbs based on either a humanized J3 VHH domain or an optimized scFv derived from the well-characterized bnAb, PGT121...However, the lack of response to antigen suggests the need to further optimize ex vivo selection and culture conditions to better support B cell subtypes that can give rise to long-lived antibody-secreting cells and memory phenotypes in vivo. Disease Focus of Abstract:HIV"

Human Immunodeficiency Virus • Infectious Disease • Transplantation • IGH

High Level Persistent In Vivo Production of an anti-HIV Antibody via the Delivery of Plasmid DNA by a Polymer Nanoparticle (ASGCT 2025) - "In this work, we demonstrate our ability to design PNPs that can deliver pDNA encoding for PGT121, a broadly neutralizing anti-HIV antibody that targets a V3 glycan-dependent epitope site on the HIV-1 envelope glycoprotein...Finally, we emphasize that this strategy of delivering a DNA-encoded secreted proteins via a safe and effective PNP in vivo could be applicable to a wide range of other disease modalities. Disease Focus of Abstract:None"

Preclinical • Human Immunodeficiency Virus • Infectious Disease

In vitro selection of cyclized, glycosylated peptide antigens that tightly bind HIV high mannose patch antibodies. (PubMed, bioRxiv) - "We performed selections to obtain binders of HIV bnAbs PGT128, PGT122, and gl-PGT121, a germline precursor of PGT122, and prepared numerous glycopeptide hits by chemical synthesis. Selected glycopeptides in some cases bound very tightly to their target HIV bnAb, e.g., with a K D as low as 0.5 nM for PGT128. These glycopeptides are of interest as immunogens and tools for HIV vaccine design."

Journal • Preclinical • Human Immunodeficiency Virus • Infectious Disease

Fc Functions and Anti-HIV Neutralizing Antibodies: A Perspective. (PubMed, Curr HIV Res) - "Nay-sayers point to the primary role of neutralization in the control of HIV, the general failure of vaccine trials in-cluding antibodies with Fc functions, and the lack of additional benefit with newer broadly neu-tralizing monoclonal antibodies, such as PGT121...In general, however, the additional benefit of Fc function over and above robust anti-HIV neutralizing anti-bodies may be modest. The intense primary research focus on delivering and inducing potent and broadly neutralizing antibodies, regardless of their Fc function potential, is justified."

Journal • Human Immunodeficiency Virus • Infectious Disease

Bispecific Antibody VRC07/PGT121 Protects Against High-Dose Intravenous SHIV-BG505 Challenge (CROI 2025) - "We have yet to observe evidence of viral replication in animals pre-treated with VRC07/PGT121 before SHIV-BG505 exposure, including during the post-CD8 depletion period (animals are currently between one- and five-weeks post-depletion). Conclusions Bispecific anti-HIV-1 bNAbs are potentially valuable biomedical interventions for ongoing efforts to achieve HIV-1 immunoprophylaxis, as evidenced in this very stringent IV challenge model."

Human Immunodeficiency Virus • Infectious Disease • CD8

Investigating the Effects of ADCC and CAR NK/T Cells on HIV-1 Cell-to-Cell Transmission (CROI 2025) - "Methods Methods We developed a highly sensitive assay for precise quantification of cell lysis using luciferase activity and built CAR-PBMCs based on the VRC01 and PGT121 bnAbs. Conclusions Conclusions These results provide proof of the principle that targeting HIV-1 cell-to-cell transmission through ADCC and CAR NK/T cell therapies can overcome the limitations of bnAbs. This study offers the first evidence to test these approaches to effectively target HIV-1 C-CT, highlighting their potential in studying HIV-1 treatment strategies."

Human Immunodeficiency Virus • Infectious Disease

Investigating the Interaction between Excipients and Monoclonal Antibodies PGT121 and N49P9.6-FR-LS: A Comprehensive Analysis. (PubMed, Mol Pharm) - "Debye-Hückel-Henry charge calculations further indicated that neutral excipients like sucrose and trehalose could alter mAb charges by affecting buffer binding, influencing aggregation propensity. These findings offer valuable insights for optimizing antibody formulations, ensuring enhanced product stability and therapeutic efficacy for HIV treatment."

Journal • Human Immunodeficiency Virus • Infectious Disease

Passive infusion of an S2-Stem broadly neutralizing antibody protects against SARS-CoV-2 infection and lower airway inflammation in rhesus macaques. (PubMed, PLoS Pathog) - "CC40.8 mAb was intravenously infused at 10mg/kg, 1mg/kg, or 0.1 mg/kg into groups (n = 6) of RM, alongside one group that received a control antibody (PGT121)...Viral genome sequencing demonstrated a lack of escape mutations in the CC40.8 epitope. Collectively, these data demonstrate the protective efficiency of broadly neutralizing S2-targeting antibodies against SARS-CoV-2 infection within the lower airway while providing critical preclinical work necessary for the development of pan-β-CoV vaccines."

Journal • Infectious Disease • Inflammation • Novel Coronavirus Disease • Respiratory Diseases

Mechanisms of sterilizing immunity provided by an HIV-1 neutralizing antibody against mucosal infection. (PubMed, PLoS Pathog) - "Therefore, additional challenge viruses were produced that contain SIV Env and graded doses of a fusion-defective trimer of HIV-1 Env, to which the bnAb, PGT121 can bind without interfering with the SIV Env-based cell entry...The results indicate that the sparsity of bnAb binding-sites on HIV-1 virions limits the contribution of Fc-effector functions to provide sterilizing immunity against mucosal viral infection. Hence, harnessing Fc-effector functions for sterilizing immunity against mucosal HIV-1 infection may require strategies to increase the degree of antibody opsonization."

Journal • Human Immunodeficiency Virus • Infectious Disease

Safety, Immunogenicity, Efficacy of Ad26.Mos4.HIV, MVA-BN-HIV and PGT121, PGDM1400, and VRC07-523LS in HIV-1-Infected Adults (clinicaltrials.gov) - P1/2 | N=36 | Active, not recruiting | Sponsor: Boris Juelg, MD PhD | Recruiting ➔ Active, not recruiting

Enrollment closed • Human Immunodeficiency Virus • Infectious Disease • Primary Immunodeficiency • CD4

In vitro characterisation of mRNA-mediated delivery of multispecific bNAbs for HIV-1 immunoprophylaxis (HIVR4P 2024) - "Here we describe the development of in vitro transcribed (IVT)-mRNA delivery of multispecific antibodies as a potential cost-effective, passive immunisation strategy for prevention of HIV-1 acquisition. Previously described tandem single chain variable fragment (scFv) bispecifics (Bi-scFv and Bi-NAb) and heterologous heavy chain (knob-into-hole mutations) assembled tri-specific (Tri-NAb) antibodies combining VRC01/PGT121 and VRC01/PGT121/10e08 paratopes, respectively (>95% neutralisation coverage in vitro (208 pseudovirus panel), with geometric mean IC50 titres <0.4 µg/mL), were selected for development. These data support the preclinical advancement of IVT-mRNA encoding multispecific antibodies as a possible passive immunisation strategy against HIV-1 acquisition and require empirical determination of whether therapeutic titres are attainable in vivo."

Preclinical • Human Immunodeficiency Virus • Infectious Disease