PGT121 / Theraclone Sciences, Gilead, IAVI - LARVOL DELTA

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

Short-term combination immunotherapy with broadly neutralizing antibodies and CCR5 blockade mediates ART-free viral control in infant rhesus macaques (HIVR4P 2024) - "Here we evaluated whether a triple combination of early ART initiation with HIV broadly neutralizing antibodies (bNAbs) and the CCR5-blocking mAb Leronlimab could mediate virus clearance in simian-HIV (SHIV)-infected infant rhesus macaques. A total of 16 four-week-old infant rhesus macaques were orally infected with SHIV-SF162P3 and placed into the following treatment groups, with all treatments beginning at 72 hours after infection: 1) ART + bolus doses of the bNAbs PGT121-LS and VRC07-523-LS (n=2), 2) ART + Leronlimab for 8 weeks (n=6), or 3) ART + bolus doses of the bNAbs PGT121-LS and VRC07-523-LS + Leronlimab for 8 weeks (n=8). Finding a treatment that can prevent reservoir establishment and spread after the first 48 hours has been elusive. The results of this study suggest that the combination of ART, bNAbs, and CCR5 blockade via Leronlimab synergize in an undefined mechanism to prevent further seeding of of the reservoir early after infection, and may even..."

Human Immunodeficiency Virus • Infectious Disease

WIN332, a novel immunogen to elicit a new class of V3-glycan bNAbs (HIVR4P 2024) - "In summary, we present WIN332, a first-in-class Env immunogen that elicits human V3-glycan bNAb-like antibodies with a novel N332-glycan independent mechanism of binding."

Human Immunodeficiency Virus • Infectious Disease

A redesigned HIV-1 Env V1 hypervariable loop renders CRF01_AE Env sensitive to 10-1074 (HIVR4P 2024) - "Structural examination shows that other PGT121/10-1074-family antibodies recognize the same hydrophobic sites, while PGT128, which can neutralize half of CRF01_AE viruses, does not recognize this hydrophobic pocket. Our results show that the frequent resistance to 10-1074 among CRF01_AE viruses depends on a conserved V1 loop motif. With the motif removed, CRF01_AE Env can be sensitive to 10-1074 in the absence of the 332 glycan. These results highlight that AI-models are valuable tools for vaccine design and that redesigned hypervariable loops can optimize bnAb epitope accessibility on HIV-1 Env antigens."

Human Immunodeficiency Virus • Infectious Disease

A higher proportion of recent compared to historic HIV viruses are resistant to antibody dependent cellular cytotoxicity mediated by monoclonal antibodies (HIVR4P 2024) - "ADCC susceptibility was tested against 16 neutralizing and non-neutralizing mAbs targeting V2 apex, V3 glycan, CD4 binding site, MPER, fusion peptide, and CD4-induced epitopes. Overall, only PGT121 had significantly less ADCC activity against recent viruses compared to historic ones (p=0.004, FDR q=0.06)... These data suggest that HIV is evolving to become more resistant to ADCC. Consequently, careful selection of mAb combinations and vaccine immunogens will be needed to successfully prevent and treat HIV-1 acquisition."

Human Immunodeficiency Virus • Infectious Disease • CD4

Topical vectored broadly neutralizing antibodies prevent ex vivo HIV-1 infection of human cervicovaginal tissue (HIVR4P 2024) - "We show proof-of-concept that AAV vectorized bnAbs can transduce, replicate, and induce sustainable and sufficient production of HIV-specific Abs in human CV tissues to prevent ex vivo HIV-1 infection and potentially serve as a long-acting topical immunoprophylactic tool for HIV prevention in women."

Preclinical • Human Immunodeficiency Virus • Infectious Disease

Safety and antiviral effect of a triple combination of HIV-1 broadly neutralizing antibodies: a phase 1/2a trial. (PubMed, Nat Med) - P1/2 | "Here we performed an open-label, two-part study evaluating a single intravenous dose of HIV-1 bNAbs, PGT121, PGDM1400 and VRC07-523LS, in six adults without HIV in part 1 and a multicenter trial of up to six monthly infusions of these three bNAbs in 12 people living with HIV with an antiretroviral therapy (ART) interruption in part 2. Our data show the potential of a triple bNAb cocktail to suppress HIV-1 in the absence of ART. ClinicalTrials.gov registration: NCT03721510 ."

Journal • P1/2 data • Human Immunodeficiency Virus • Infectious Disease • CD4

Afucosylated broadly neutralizing antibodies enhance clearance of HIV-1 infected cells through cell-mediated killing. (PubMed, Commun Biol) - "Killing of HIV-1 infected cells is most effective with afucosylated bNAbs 2G12, N6, PGT151 and PGDM1400, whereas afucosylated PGT121 and non-neutralizing antibody A32 only induce minor NK cell-mediated killing. These data indicate that the approach angle and affinity of Abs influence the capacity to induce antibody-dependent cellular cytotoxicity. Thus, afucosylated bNAbs have the capacity to induce NK cell-mediated killing of infected cells, which warrants further investigation of afucosylated bNAb administration in vivo, aiming for reduction of the viral reservoir and ART free durable control."

IO biomarker • Journal • Human Immunodeficiency Virus • Infectious Disease • FCGR3A • PD-1 • TIGIT

Passive infusion of an S2-Stem broadly neutralizing antibody protects against SARS-CoV-2 infection and lower airway inflammation in rhesus macaques. (PubMed, bioRxiv) - "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-beta-CoV vaccines."

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

Impact of LS Mutation on Pharmacokinetics of Preventive HIV Broadly Neutralizing Monoclonal Antibodies: A Cross-Protocol Analysis of 16 Clinical Trials in People without HIV. (PubMed, Pharmaceutics) - "To characterize the LS mutation for monoclonal antibodies targeting HIV, we compared pharmacokinetic parameters between parental versus LS variants for five pairs of anti-HIV immunoglobin G1 monoclonal antibodies (VRC01/LS/VRC07-523LS, 3BNC117/LS, PGDM1400/LS PGT121/LS, 10-1074/LS), analyzing data from 16 clinical trials of 583 participants without HIV. Results suggest a favorable pharmacokinetic profile of LS variants regardless of HIV epitope specificity. Insights support lower dosages and/or less frequent dosing of LS variants to achieve similar levels of antibody exposure in future clinical applications."

Journal • PK/PD data • Human Immunodeficiency Virus • Infectious Disease