VRC01LS / National Institutes of Health, Xencor - LARVOL DELTA

Proviral genotype and phenotype as predictors of broadly neutralizing antibody susceptibility (IAS-HIV 2025) - "The utility of PT and GT testing in the Tatelo Study was bNAb dependent. PT susceptibility testing was associated with treatment outcome for 10-1074, and GT testing aligned with the PT results. Neither PT nor GT testing proved useful for VRC01LS, but only few specimens showed preexisting susceptibility."

Human Immunodeficiency Virus • Infectious Disease

Pharmacokinetics Analysis of Serum and Rectal Tissue Concentrations of a Pair of Anti-HIV Monoclonal Antibodies, VRC01 and VRC01LS, in Adults without HIV. (PubMed, J Clin Pharmacol) - "Median elimination half-life estimates were 20 days for VRC01 and 63 days for VRC01LS in serum and rectal tissues. These data support lower dosage and/or less frequent dosing of LS monoclonal antibodies providing potentially more immediate protection against HIV exposure in the rectum."

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

Predictive markers for sustained viral suppression on dual bNAbs during ART interruption in children. (PubMed, J Acquir Immune Defic Syndr) - "At the start of bNAb-only treatment, negative qualitative DNA, and especially negative/negative DNA and EIA, have potential to predict maintenance of viral suppression among children on dual bNAbs. HIV RNA target detection below the assay limit did not prove to be a clinically useful biomarker in the visits preceding failure."

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

Immune Correlates of Viral Rebound During Broadly Neutralizing Antibody Treatment in Children (CROI 2025) - "Results Of 25 participants aged 2-5 years who received VRC01LS plus 10-1074 dual-bNAb treatment, 11 maintained viral suppression (controllers) and 14 rebounded (rebounders). Conclusions Specific NK cell responses at the beginning of bNAb-only treatment were associated with viral rebound, the kinetics of rebound, and the intact viral reservoir size. HIV-1 specific T cell responses were low in this group of early-treated children and differences could not be identified between controllers and rebounders."

Clinical • Human Immunodeficiency Virus • Infectious Disease • HLA-C • KIR2DL1 • KLRC1

Use of broadly neutralizing antibodies in pediatric HIV for treatment and remission. (PubMed, Curr Opin HIV AIDS) - "This review synthesizes data for ongoing and planned pediatric bNAb treatment studies, focusing on available trial results that underscore the ability of newer and more potent long-acting bNAbs to sustain viral suppression. We discuss the potential impact of bNAbs to reduce the latent viral reservoir and their use as a strategy to achieve viral remission in children with HIV."

Journal • Human Immunodeficiency Virus • Infectious Disease • Pediatrics

Virologic effects of broadly neutralizing antibodies VRC01LS and VRC07-523LS on chronic HIV-1 infection. (PubMed, JCI Insight) - P1 | "In contrast, VRC01LS administration resulted in a smaller average decline (0.8 ± 0.8 log10 copies/mL), and 3 out of 7 participants showedno change in VL. Postinfusion maximum decline in VL correlated with post hoc baseline in vitro viral susceptibility results for both bNAbs.CONCLUSIONThe results of this trial support inclusion of potent CD4bs-specific bNAbs, such as VRC07-523LS, into next-generation treatment regimens for HIV-1.TRIAL REGISTRATIONClinicalTrials.gov NCT02840474.FUNDINGNational Institute of Allergy and Infectious Diseases (NIAID)/NIH (grants UM1 AI068634, UM1 AI068636, UM1 AI106701, UM1AI069424, UM1AI069501, UM1AI69415, UM1AI069534, UM1AI69494); the Intramural Research Program of the NIAID/NIH; National Center for Advancing Translational Sciences/NIH (grants UM1TR004548, UL1TR001881, and UL1TR001878); and the National Cancer Institute/NIH (contract 75N91019D00024)."

Journal • Allergy • Human Immunodeficiency Virus • Immunology • Infectious Disease • Oncology • CD4

Enhanced and sustained biodistribution of HIV-1 neutralizing antibody VRC01LS in human genital and rectal mucosa. (PubMed, Nat Commun) - "Elimination half-lives in mucosal tissues are 20-28 days for VRC01 and 51-68 days for VRC01LS. Thus, VRC01LS infusion achieves higher, sustained concentrations in human mucosal tissues than VRC01, supporting the future investigation of potent, long-acting LS-modified antibodies to prevent HIV-1."

Journal • Human Immunodeficiency Virus • Infectious Disease

Improved growth during bNAb-only treatment among early-treated suppressed children with HIV (AIDS 2024) - "We evaluated anthropometrics over time among children in Botswana who underwent up to 6 months of ART interruption while receiving dual-bNAbs (VRC01LS and 10-1074) alone. The Tatelo Study included 25 early-treated children with HIV who paused lopinavir/ritonavir-based triple ART and received dual bNAbs for up to 24 weeks. Children who maintained virologic suppression during dual bNAb-only treatment had significant improvement in WAZ that was not sustained following ART restart. These results suggest improved WAZ during bNAb treatment and ART pause, though further studies are needed to assess the impact on growth with different ART regimens and longer ART pauses."

Clinical • 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

Predictive Markers for Sustained Viral Suppression on Dual bNAbs During ART Interruption in Children (CROI 2024) - "We now report findings for additional biomarker combinations, at entry to and during the bNAb-only step of the study.Twenty-five children received up to 24 weeks of bNAb-only treatment (VRC01LS+10-1074) following ART interruption. Negative qualitative DNA, and especially negative/negative DNA and EIA, at start of bNAb-only treatment predicted maintenance of viral suppression among children on dual bNAbs. HIV-1 RNA target detection below the assay limit did not prove to be a predictive biomarker, and no biomarker combination was clinically useful in the visits preceding failure."

Biomarker • Clinical • Human Immunodeficiency Virus • Infectious Disease

Fc-modified HIV-1 broadly neutralizing monoclonal antibody, VRC01LS, shows enhanced biodistribution in human genital and rectal mucosal tissue compared to VRC01 (IAS-HIV 2023) - "These results demonstrate benefits of VRC01LS for durable mAb distribution at HIV-1 exposure sites. Both monoclonals reach the lamina propria where most HIV target cells lie. More potent, LS-modified broadly neutralizing mAbs could be a promising, long-acting component for preventing sexually transmitted HIV-1."

Human Immunodeficiency Virus • Infectious Disease

Broadly neutralizing antibody treatment maintained HIV suppression in children with favorable reservoir characteristics in Botswana. (PubMed, Sci Transl Med) - "We conducted a prospective clinical trial with two HIV-1 bNAbs (VRC01LS and 10-1074) in children (n = 25) who had previously initiated small-molecule ART treatment before 7 days of age and who continued treatment for at least 96 weeks. This proof-of-concept study suggests that bNAbs may represent a promising treatment modality for infants and children living with HIV-1. Future studies using newer bNAb combinations with greater breadth and potency are warranted."

Journal • Human Immunodeficiency Virus • Infectious Disease

Phenotypic analysis of HIV-1 resistance to CD4 binding site broadly-neutralizing antibodies (P455) (IMMUNOLOGY 2023) - "The ex vivo assay used pre-infusion CD4+ T cells from participants enrolled in the VRC 607/ACTG A5378 phase I study of the CD4 binding site (CD4bs) bNAbs’ VRC01LS (n=7) or VRC07-523LS (n=9). From these assays, the escape variant signatures of outgrowth viruses that replicated in presence of CD4bs bNAbs, were identified. We found complementary escape profiles from 3 CD4bs bNAbs (1-18LS, N6LS, and VRC01v23)  with ex vivo and neutralization assays showing suppression by 1 or 2 but not all 3 bNAbs, supporting the potential for combination bNAb therapy. Our data suggest that the simultaneous use of multiple CD4 binding site bNAbs together could aid in limiting viral escape."

IO biomarker • Human Immunodeficiency Virus • Infectious Disease • CD4

CAREGIVERS OF CHILDREN WITH HIV IN BOTSWANA PREFER MONTHLY IV bNAbs TO DAILY ORAL ART (CROI 2023) - " We evaluated monthly infusion of dual bNAbs (VRC01LS and 10-1074) as a treatment alternative to ART among children participating in the Tatelo Study in Botswana. Monthly intravenous bNAb infusions were highly acceptable to caregivers of children with HIV in Botswana and preferred over standard ART by most. Our findings suggest that caregiver acceptability is an unlikely barrier to bNAb uptake and eventual programmatic use for children living with HIV."

Clinical • Human Immunodeficiency Virus • Infectious Disease

EFFICACY AND COMPLEMENTARITY OF HIV-1 SUPPRESSION BY CD4-BINDING bNAbs (CROI 2023) - "In vivo and ex vivo effect of HIV-1 bNAbs comparison suggest that the ex vivo assay shows potential to reliably predict bNAbs antiviral effect in clinical trials and contribute to analysis of resistant strains that could emerge in vivo. Our data indicate that optimal combinations of CD4bs bNAbs can be used to mitigate viral resistance to bNAb-based immunotherapies. Comparative suppression profiles of VRC01LS, VRC07-523LS, VRC01v23, N6LS and 1-18LS treated conditions in ex vivo assay"

Clinical • IO biomarker • Human Immunodeficiency Virus • Infectious Disease • CD4

Safety and Pharmacokinetics of Intravenous 10-1074 and VRC01LS in Young Children. (PubMed, J Acquir Immune Defic Syndr) - "10-1074 and VRC01LS were safe and well-tolerated among children receiving ART. Troughs exceeded minimal targets with every 4-week administration of 10-1074 at 30 mg/kg and VRC01LS at 15 mg/kg."

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

Dual bNAb Treatment in Children (clinicaltrials.gov) - P1/2 | N=30 | Completed | Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) | Active, not recruiting ➔ Completed

Trial completion • Human Immunodeficiency Virus • Infectious Disease

EX VIVO ASSAY PREDICTS HIV-1 SUPPRESSION BY bNAbs INFUSED IN A PHASE I CLINICAL TRIAL (CROI 2022) - "CD4+ T cells were isolated from blood of viremic subjects with HIV enrolled in VRC607/ACGT5378, a phase I study investigating antiviral efficacy of VRC01LS or VRC07-523LS, both targeting the CD4 binding site on the HIV-1 envelope glycoprotein. These data compare the in vivo and ex-vivo effect of HIV-1 bNAbs and suggest that the ex vivo assay has the potential to reliably predict the antiviral effect of bNAbs in clinical trials. Because it is possible to test multiple bNAbs in the assay, it could be an effective tool for pre-clinical testing and selection of the most efficacious bNAb or bNAb combinations to advance to clinical trials."

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

IMPACT OF CD4 BINDING SITE bNAbs ON BARCODED TF-SHIV-D REBOUND IN MACAQUES AT ATI (CROI 2022) - "At ATI #2, all 18 RMs were treated with both 30mg/kg VRC07.523.LS and VRC01.LS. CD4bs bNAb monotherapy in barcoded TF-SHIV-D-infected RMs at ATI recapitulates key components of bNAb monotherapy in humans, including a modest but statistically significant delay in time to viral rebound. Thus, barcoded TF-SHIV-D infection in RMs is a promising predictive model for bNAb therapy and studying the mechanisms of viral escape from bNAb pressure."

Human Immunodeficiency Virus • Infectious Disease • CD4

TREATMENT WITH BROADLY NEUTRALIZING ANTIBODIES IN CHILDREN WITH HIV IN BOTSWANA (CROI 2022) - "Twenty-eight children entered the treatment component of the study while receiving lopinavir/ritonavir-based ART, at a median age of 3.6 (range 2.4, 5.6) years, and median CD4 count 1198 cells/mm3; 25 (89%) went on to the bNAb-only treatment phase (viral rebound occurred in 2 on the day of bNAb initiation and in 1 while on ART and bNAbs). In this proof-of-concept study, dual bNAb treatment with VRC01LS and 10-1074 maintained viral suppression for 24 weeks in the absence of ART in 44% of children, and was well-tolerated. Newer bNAb combinations with greater breadth and potency, used in children with favorable pre-treatment characteristics and possibly with longer bNAb/ART overlap, may improve treatment success for this novel ART-sparing strategy."

Clinical • Hematological Disorders • Human Immunodeficiency Virus • Infectious Disease • Neutropenia • CD4

Evaluating the Safety and Pharmacokinetics of VRC01, VRC01LS, and VRC07-523LS, Potent Anti-HIV Neutralizing Monoclonal Antibodies, in HIV-1-Exposed Infants (clinicaltrials.gov) - P1; N=83; Completed; Sponsor: National Institute of Allergy and Infectious Diseases (NIAID); Active, not recruiting ➔ Completed

Trial completion • Human Immunodeficiency Virus • Infectious Disease

[VIRTUAL] POPULATION PHARMACOKINETICS OF VRC01LS IN TERM INFANTS AND ADULTS (CROI 2021) - "Background: VRC01LS, a long-acting variant of VRC01, is a broadly neutralizing monoclonal antibody (bNAb) with activity against many HIV-1 strains. The PopPK of VRC01LS demonstrates slow elimination in infants and adults allowing every 12 week dosing. VRC01LS has promise in infant HIV prophylaxis and treatment."

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

Evaluating the Safety and Pharmacokinetics of VRC01, VRC01LS, and VRC07-523LS, Potent Anti-HIV Neutralizing Monoclonal Antibodies, in HIV-1-Exposed Infants (clinicaltrials.gov) - P1; N=83; Active, not recruiting; Sponsor: National Institute of Allergy and Infectious Diseases (NIAID); N=158 ➔ 83

Clinical • Enrollment change • Human Immunodeficiency Virus • Infectious Disease

A matrix of structure-based designs yields improved VRC01-class antibodies for HIV-1 therapy and prevention. (PubMed, MAbs) - "On a 208-strain panel, variant VRC01.23LS neutralized 90% of the panel at a geometric mean IC less than 1 μg/ml, and in transgenic mice with human neonatal-Fc receptor, the serum half-life of VRC01.23LS was indistinguishable from that of the parent VRC01LS, which has a half-life of 71 d in humans. Another variant, VRC07-523-F54-LS.v3, neutralized 95% of the 208-isolated panel at a geometric mean IC of less than 1 μg/ml, with a half-life comparable to that of the parental VRC07-523LS. Our matrix-based structural approach thus enables the engineering of VRC01 variants for HIV-1 therapy and prevention with improved potency, breadth, and pharmacokinetics."

Journal • Human Immunodeficiency Virus • Infectious Disease

Safety, Tolerability, and Pharmacokinetics of a Long-Acting Broadly Neutralizing HIV-1 Monoclonal Antibody VRC01LS in HIV-1-Exposed Newborn Infants. (PubMed, J Infect Dis) - "VRC01LS was well tolerated with pharmacokinetics that support further studies of more potent long-acting bNAbs as adjunct treatment with ARVs to prevent infant HIV-1 transmission."

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