PGDM1400 / National Institute of Allergy and Infectious Diseases, IAVI - LARVOL DELTA

Triple rAAV9 Vector Combinations Encoding Broadly Neutralizing Antibodies Effectively Suppress HIV-1 Infection in Humanized Mice. (PubMed, Int J Mol Sci) - "We demonstrated that mice preventively treated with CombiMab-1 or CombiMab-2 did not develop viremia and maintained human CD4+ T-lymphocyte counts following viral challenge, in contrast to control animals. These results demonstrate the significant protective capacity of CombiMab-1 and CombiMab-2 against HIV-1 challenge."

Journal • Preclinical • Human Immunodeficiency Virus • Infectious Disease • CD4

Distinct neutralization sensitivity between adult and infant transmitted/founder HIV-1 subtype C viruses to broadly neutralizing monoclonal antibodies. (PubMed, PLoS Pathog) - "The bnAbs VRC07-523LS, CAP256-VRC26.25, PGDM1400, 10E8 and PGT151 displayed higher neutralization breadth and potency than other bnAbs against FRESH TF viruses (>70% coverage, starting concentration of 10 μg/ml). Moreover, high transmission of escape variants in both vertical and heterosexual transmissions is of concern. This information may be important in the selection of bnAbs that will undergo clinical testing in subtype C settings."

Journal • Human Immunodeficiency Virus • Infectious Disease • Pediatrics

Safety, pharmacokinetics, and neutralisation activity of PGDM1400LS, a V2 specific HIV-1 broadly neutralising antibody, infused intravenously or subcutaneously in people without HIV-1 in the USA (HVTN 140/HPTN 101 part A): a first-in-human, phase 1 randomised trial. (PubMed, Lancet HIV) - P1 | "PGDM1400LS is a promising candidate for combination monoclonal antibody efficacy trials going forward."

Clinical • Journal • P1 data • PK/PD data • Allergy • Human Immunodeficiency Virus • Immunology • Infectious Disease

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

Resistance of Inducible, Infectious HIV-1 to Autologous Neutralizing IgG After Long-Term ART (CROI 2025) - "Neutralization assays tested either contemporaneous aNAbs or one of three broadly neutralizing antibodies (bNAbs; VRC01, 10-1074, PGDM1400). Conclusions Our findings demonstrated increased resistance of outgrowth viruses to aNAbs over long-term ART, which was not fully explained by a decline in neutralizing antibody concentrations. This increased resistance may be driven partially by ADCC-mediated elimination of infected cells carrying aNAb-sensitive viruses, leaving only aNAb-resistant viruses which can contribute to viral rebound."

Human Immunodeficiency Virus • Infectious Disease • CD4

Maximizing Benefits to Participants in Analytic Treatment Interruption With Antibody Infusions (CROI 2025) - "Neutralization data from 116 participants showed 54 (46.5%) sensitive to PGDM1400LS, 55 (46.7%) sensitive to VRC07-523LS, and 25 (21.5%) sensitive to both. We also modeled the Instantaneous Inhibitory Potential (IIP) values; at week 20 post ATI, 75 participants had clones with IIP (PGDM1400 + VRC07)>3.5, allowing prioritization of participants for study enrolment...Our approach benefitted from the fact that participants initiated ART in acute infection and therefore had a typically homogeneous viral reservoir recapitulated by the limited number of distinct env sequences we sampled. While the benefits of this approach will only be ascertained after the ATI is conducted, these data provide the largest description of sensitivity to two potent bnAbs across CRF01_AE viruses."

Human Immunodeficiency Virus • Infectious Disease

Cytoplasmic Tail Engineering of Stabilized mRNA Env Immunogens Enhances Neutralizing Response (CROI 2025) - "Cell surface protein expression from mRNA was assessed following transfection of 293F cells and staining with conformationally-dependent antibodies (e.g., PGDM1400, 17b) using flow cytometry...Conclusions Engineering of the mRNA-encoded Env CT increases cell surface expression and, in combination with trimer stabilization, confers enhanced immunogenicity in mice. This strategy may be applied to generate mRNA vaccines from genetically diverse Env strains for preventative and therapeutic vaccine applications."

Human Immunodeficiency Virus • Infectious Disease

Sensitivity of HIV-1 CRF01_AE Envelopes to Broadly Neutralizing Antibodies VRC07-523 and PGDM1400 (CROI 2025) - "Background Understanding the sensitivity of viral envelopes to broadly neutralizing antibodies (bNAbs) encoded within the reservoir is of major importance in evaluating efficacy in analytical treatment interruption (ATI) trials using bNAbs as an intervention in people living with HIV (PLWH). Combining VRC07-523LS and PGDM1400LS bNAbs provided increased coverage across viral Envs. Furthermore, PGDM1400LS demonstrated more potent neutralization across the screened candidates and required lower concentrations to achieve a higher level of viral inhibition in comparison to VRC07-523LS. These data provide evidence that CRF01_AE Envs sequenced from viral Env are sensitive to VRC07-523LS and PGDM1400LS and antibodies may be used as candidate bNAbs in future ATI trials."

Human Immunodeficiency Virus • Infectious Disease • CD4

Structural development of the HIV-1 apex-directed PGT145-PGDM1400 antibody lineage. (PubMed, Cell Rep) - "Despite similar breadth and potency, the two antibodies differ in their residue-level interactions with important apex features, including N160 glycans and apex cavity, with residue 100i of PGT145 (sulfated tyrosine) penetrating ∼7 Å farther than residue 100i of PGDM1400 (aspartic acid). While apex-directed bNAbs from other donors use maturation pathways that often converge on analogous residue-level recognition, our results demonstrate that divergent residue-level recognition can occur within the same lineage, thereby enabling improved coverage of escape variants."

Journal • Human Immunodeficiency Virus • Infectious Disease

A novel HIV triple broadly neutralizing antibody (bNAb) combination-based passive immunization of infant rhesus macaques achieves durable protective plasma neutralization levels and mediates anti-viral effector functions. (PubMed, PLoS One) - "Our group previously identified a triple broadly neutralizing antibody (bNAb) combination comprising of 3BNC117, PGDM1400 and PGT151 that mediates robust in vitro neutralization and non-neutralizing effector functions against a cross-clade panel of simian human immunodeficiency viruses (SHIVs). Finally, using the predicted serum neutralization 80% inhibitory dilution titer (PT80) biomarker threshold of >200, which was recently identified as a surrogate endpoint for evaluation of the preventative efficacy of bNAbs against mucosal viral acquisition in human clinical trials, we demonstrated that our regimen has PT80>200 against a large panel of plasma and breast milk-derived HIV strains and cross-clade SHIV variants. This data will guide the development of combination bNAbs for eliminating vertical HIV transmission and for achieving ART-free viral suppression among children living with HIV."

Journal • Human Immunodeficiency Virus • Infectious Disease • Pediatrics

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

Cryo-EM characterization of diverse antibody interactions with HIV envelope to facilitate vaccine and therapeutic antibody development (HIVR4P 2024) - "Third, we determined cryo-EM structures of PGDM1400 (currently in clinical trials for the treatment of HIV-1) and an improved variant of the clonal relative PGT145 bound to BG505 envelope trimers; these structures revealed how different clades of a single antibody lineage can adopt different strategies for broad recognition at the V2 apex-site of vulnerability. Collectively, these vignettes demonstrate how structural biology will continue to accelerate the development of vaccines and therapeutics against HIV-1."

Human Immunodeficiency Virus • Infectious Disease

Acceptability of intravenous (IV) and subcutaneous (SC) infusion administration of monoclonal antibody (mAb) combinations: VRC07-523LS with PGT121, PGDM1400, PGT121.414.LS and PGDM1400LS in phase 1 anti-HIV mAb trials (HIVR4P 2024) - "Participants consistently chose the route of administration that was used during study participation (IV or SC) or IM injection as their method of HIV prevention. Additionally, opinions of infusion visit time and recommendation of their route of administration was not different after the first and last administrations. These data support consideration for multiple routes of mAb administration appropriate for the volumes and doses needed for HIV prevention."

Late-breaking abstract • P1 data • Human Immunodeficiency Virus • Infectious Disease

Pharmacokinetic interaction assessment of the HIV broadly neutralizing monoclonal antibody VRC07-523LS: a cross-protocol analysis of three phase 1 HIV prevention trials HVTN127/HPTN087, HVTN130/HPTN089 and HVTN136/HPTN092 (HIVR4P 2024) - "We included participants receiving intravenous or subcutaneous VRC07-523LS alone (HVTN127/HPTN087, n=100), combined with PGT121, PGDM1400 or 10-1074 (HVTN130/HPTN089, n=26), or combined with PGT121.414.LS (HVTN136/HPTN092, n=20). Biodistribution of VRC07-523LS differed when administered combined with other mAbs versus alone, but overall concentration-over-time was not impacted. This is important for planning future trials of VRC07-523LS with new mAb formulations."

Clinical • P1 data • PK/PD data • Human Immunodeficiency Virus • Infectious Disease

Contemporary HIV-1 subtype C from India shows resistance to env V1/V2 loop directed broadly neutralizing antibodies (HIVR4P 2024) - "Further, some of the viruses (12.5%) were resistant to both CAP256 and PGDM1400 and some (15.9%) were resistant to all of the studied V1V2 bnAbs (CAP256-VRC26.25, PGDM1400, PG9 and PGT145)... Our study showed emergence of bnAb resistant HIV-1 amongst Indian population. This emphasizes the importance of continued virus surveillance towards bnAb sensitivity of circulating HIV-1 from India for appropriate preventive measures."

Human Immunodeficiency Virus • Infectious Disease

Assessment of infusion-related reactions after intravenous administration of HIV monoclonal antibodies PGT121.414.LS, PGDM1400.LS or VRC07-523LS (alone or in combination with PGT121, PGDM1400, 10-1074, PGT121.414.LS, PGDM1400.LS), in five phase 1 studies (HIVR4P 2024) - "IRRs after IV administration of anti-HIV mAbs in these trials were uncommon, mild to moderate, and most were self-limited. These findings support the safe administration of these mAbs combinations by IV infusions in future HIV prevention clinical trials."

Combination therapy • Late-breaking abstract • P1 data • Fatigue • Human Immunodeficiency Virus • Infectious Disease • Musculoskeletal Pain • Pain

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

Triple Combinations of AAV9-Vectors Encoding Anti-HIV bNAbs Provide Long-Term In Vivo Expression of Human IgG Effectively Neutralizing Pseudoviruses from HIV-1 Global Panel. (PubMed, Viruses) - "In this study, we investigated two sets of triple combinations of AAV9-vectors encoding different bNAbs: N6, 10E8, 10-1074 (CombiMab1), and VRC07-523, PGDM1400, 10-1074 (CombiMab2). Although CombiMab2 treatment elicited a higher IgG titer than CombiMab1, both combinations resulted in neutralization of all the viral strains from the global HIV-1 panel. Our data highlight the potential of AAV vectors as a long-term option for HIV-1 therapy."

Journal • Preclinical • Gene Therapies • Human Immunodeficiency Virus • Infectious Disease

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

First-in-human evaluation of the safety, pharmacokinetics, and neutralization activity of PGDM1400-LS, a V2 glycan-specific HIV-1 broadly neutralizing antibody, infused intravenously or subcutaneously in people without HIV-1 (HVTN140/HPTN101 Part A) (AIDS 2024) - "Intravenously-administered PGDM1400-LS exhibits favorable pharmacokinetics in vivo and is a promising candidate for future efficacy trials."

Clinical • P1 data • PK/PD data • Human Immunodeficiency Virus • Infectious Disease

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

Ex vivo sensitivity to broadly neutralizing antibodies and anti-CD4 antibody UB-421 of infectious viral isolates from people living with multidrug-resistant HIV. (PubMed, EBioMedicine) - "Our data suggest that combination therapy with HIV-specific bNAbs and/or UB-421 in the presence of optimized background therapy could potentially provide sustained virologic suppression in PLWH with MDR HIV. However, this therapeutic strategy needs to be evaluated in human clinical trials."

IO biomarker • Journal • Preclinical • Allergy • Human Immunodeficiency Virus • Immunology • Infectious Disease • CD8 • PD-1 • TIGIT

A First-in-Human Study of the Trispecific HIV-1 Broadly Neutralizing Antibody, SAR441236 (CROI 2024) - "Background: The trispecific broadly neutralizing antibody (bNAb) SAR441236 combines the HIV-1 specificities of VRC01 (CD4 binding site), PGDM1400 (V1/V2 glycan binding), and 10E8v4 (membrane proximal external region) into one molecule with amino acid modifications (LS) in the Fc-region for half-life extension. SAR441236 administration was safe and well tolerated. The PK of SAR441236 was similar to traditional HIV-1 IgG antibodies with half-life extension modifications, such as VRC07-523LS. The favorable PK and convenience of administering a single biologic with three binding specificities support the evaluation of novel trispecific or multispecific bnAbs for HIV-1 treatment or prevention."

P1 data • Trispecific • Human Immunodeficiency Virus • Infectious Disease • CD4

Long Half-Life Broadly Neutralizing Killer Bispecifics Against HIV-1: Harnessing the Immune System (CROI 2024) - "In-vivo pharmacokinetics were evaluated by inoculating the DNA launched LHL-BnKs in BALB/c mice.DNA launched PGDM1400, 3BNC117 and PGT121 LHL-BnKs respectively were designed and optimized for expression both in-vitro and in-vivo...Combination therapy of 10-1074 and 3BNC117 did significantly reduce viral rebound in clinical trials where the groups received up to 8 infusions of 3BNC117 during the 24-week period. Our data highlights the design and characterization of novel DNA launched immunotherapeutic against HIV-1, which possess significant characteristics of a promising immunotherapy having broad neutralization capacities of a Tier 2/3 global virus panel, specific engagement of effector cells and killing of the infected target cells and longer serum half-life in comparison to conventional bispecific T cell engaging molecules. Delivery of LHL-BnKs as combination therapy"

IO biomarker • Human Immunodeficiency Virus • Infectious Disease

Combination CAR T-Cell Therapy Restricts HIV Escape and Durably Suppresses HIV Replication In Vivo (CROI 2024) - "Distinct in vitro assays identified bNAb CARs with superior potency (PGT128, PGDM1400). HIV escape from individual bNAb CARs can be restricted when CARs associated with orthogonal escape pathways are combined, and restriction of HIV escape leads to durable suppression of HIV replication in vivo."

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