- |||||||||| Zolinza (vorinostat) / Merck (MSD), Selzentry (maraviroc) / ViiV Healthcare, VRC01 / Acuitas Therap
[VIRTUAL] Impact of baseline variables on time to viral rebound after treatment interruption in acutely treated HIV-1 infected participants () - Feb 7, 2021 - Abstract #HIVR4P2021HIVR4P_354;
Viral load specific variables at baseline (higher VL peak and AUC, longer time to viral suppression,) were associated with a shorter time to rebound, providing evidence that greater initial seeding of the HIV latent reservoir prior to ART initiation leads to faster rebound viremia post-ATI. Quantification of the latent viral reservoir will be critical to identifying biomarkers that can predict time to rebound for individuals prior to ATI initiation.
- |||||||||| VRC01 / Acuitas Therap
[VIRTUAL] Improved potency, breadth, and pharmacokinetics of VRC01-class antibodies for HIV-1 prevention and treatment () - Feb 7, 2021 - Abstract #HIVR4P2021HIVR4P_179;
Another variant, VRC07-523-F54-LS.v3, exhibited even greater potency and breadth, with a geometric mean IC80 of 0.072 mg/ml and a breadth of 97%. Thus, a matrix-based approach combined with autoreactivity measurements and with serum half-life assessment in human neonatal Fc receptor mice enabled the engineering of VRC01-class variants with improved potency, breadth, and pharmacokinetics.
- |||||||||| VRC01 / Acuitas Therap
[VIRTUAL] Precursor frequencies of naïve B cells targeting HIV candidate immunogens () - Feb 7, 2021 - Abstract #HIVR4P2021HIVR4P_173;
Studying the interaction of the NB repertoire with lineage-based vaccine candidates is paramount to understanding if germline targeting potential of immunogens is physiologically relevant. This reveals how frequent precursors to bNAb lineages are in the NB repertoire and aids iterative immunogen design for better vaccine trial outcomes.
- |||||||||| VRC01 / Acuitas Therap
[VIRTUAL] 35O22 and VRC44 define a new highly glycan-dependent multidonor class of HIV-1 gp120:gp41 interface-directed bnAbs () - Feb 7, 2021 - Abstract #HIVR4P2021HIVR4P_172;
Moreover, this class exhibits extensive glycan dependence, with approximately 70% of the binding epitope composed of glycans. These findings highlight the potential interest for the 35O22 epitope as a template for vaccine design, as it is targeted reproducibly by multiple HIV-1-infected individuals, and that priming immunogens with oligomannose glycans may be a potential strategy for eliciting such lineages.
- |||||||||| VRC01 / Acuitas Therap
[VIRTUAL] Structure of a CD4 binding site directed antibody in a donor with broadly neutralizing antibodies () - Feb 7, 2021 - Abstract #HIVR4P2021HIVR4P_165;
Sequencing and structural analysis of a novel CD4bs antibody lineage suggests that a CDRL3 insertion contributes substantially to the binding and neutralization breadth of mAb CAP314_52. The characterization of novel neutralizing antibodies targeting the CD4bs may provide insights into the diverse pathways used by antibodies to target this site.
- |||||||||| VRC01 / Acuitas Therap
[VIRTUAL] Development of a novel VRC01-class germline targeting immunogen derived from anti-idiotypic antibodies (Live channel 3) - Feb 7, 2021 - Abstract #HIVR4P2021HIVR4P_39;
The characterization of novel neutralizing antibodies targeting the CD4bs may provide insights into the diverse pathways used by antibodies to target this site. Our results are relevant not only to the development of an HIV-1 vaccine aimed at eliciting VRC01-class antibodies, but to general effort to activate specific B cell lineages that produce protective antibodies, and further suggest that ai-mAbs-derived immunogens may have general utility as germline targeting immunogens against diverse B cell targets.
- |||||||||| VRC01 / Acuitas Therap
[VIRTUAL] Vaccination induces maturation of diverse unmutated VRC01-class precursors to HIV-1 broadly neutralizing antibodies in an Ig-humanized mouse model (Live channel 3) - Feb 7, 2021 - Abstract #HIVR4P2021HIVR4P_36;
Our results are relevant not only to the development of an HIV-1 vaccine aimed at eliciting VRC01-class antibodies, but to general effort to activate specific B cell lineages that produce protective antibodies, and further suggest that ai-mAbs-derived immunogens may have general utility as germline targeting immunogens against diverse B cell targets. Overall, our study provides proof-of-concept for the induction of VRC01-class bnAbs of greater than 50%-neutralization breadth by sequential immunization, succeeds in eliciting antibodies capable of recognizing glycan276-bearing strains, and uses longitudinal analysis to pinpoint the development of specific SHM in response to specific immunogens.
- |||||||||| VRC07-523LS / National Institute of Allergy and Infectious Diseases, IAVI, TaiMed Biologics
[VIRTUAL] Safety and PK of Potent Anti-HIV Monoclonal AB VRC07-523LS in HIV-exposed Infants (Live channel 1) - Feb 7, 2021 - Abstract #HIVR4P2021HIVR4P_12;
Week 12 is an appropriate time for a second dose in infants with ongoing breastmilk exposure. VRC07-523LS, with its enhanced potency and extended half-life, could achieve target levels for the duration of breastfeeding with dosing every 3 months.
- |||||||||| VRC07-523LS / National Institute of Allergy and Infectious Diseases, IAVI, TaiMed Biologics
[VIRTUAL] Safety and single-dose pharmacokinetics of VRC07-523LS administered via different routes and doses (Live channel 1) - Feb 7, 2021 - Abstract #HIVR4P2021HIVR4P_11;
In the only bnAb HIV prevention efficacy studies, the AMP studies, another CD4-binding site targeting bnAb, VRC01, was administered intravenously (IV). VRC07-523LS appears to be safe and well-tolerated across a range of doses and routes and is a promising bnAb for inclusion in HIV-1 prevention regimens.
- |||||||||| PGT121 / Theraclone Sciences, Gilead, VRC01 / Acuitas Therap
[VIRTUAL] Serum IgA inhibits HIV-specific broadly neutralising antibody Fc functions (Live channel 1) - Feb 7, 2021 - Abstract #HIVR4P2021HIVR4P_4;
HIV-negative serum IgA, and to a lesser extent HIV-positive IgA, reduced the functional capacity of HIVIG and BnAbs, suggesting IgA may inhibit through two mechanisms: epitope competition and IgA-FcaR mediated inhibitory mechanisms. Understanding the mechanisms behind why IgA inhibits Fc responses could lead to improved future HIV vaccine design and educate passive transfer monoclonal antibody therapies.
- |||||||||| VRC01 / Acuitas Therap
Journal: Neutralizing antibody VRC01 failed to select for HIV-1 mutations upon viral rebound. (Pubmed Central) - Feb 3, 2021
Across the cohort, participant derived Env showed different sensitivity to VRC01 neutralization (including two resistant viruses), yet neutralization sensitivity was similar at diagnosis and post-rebound, indicating the lack of selection for VRC01-resistance during treatment interruption.Our results showed that viremia rebounded despite the absence of HIV-1 adaptation to VRC01 and an average VRC01 trough of 221µg/mL. While VRC01 levels were insufficient to prevent a resurgent infection, knowledge that they did not mediate Env mutations in acute-like viruses is relevant for antibody-based strategies in acute infection.
- |||||||||| VRC01 / Acuitas Therap
Journal: A facile method of mapping HIV-1 neutralizing epitopes using chemically masked cysteines and deep sequencing. (Pubmed Central) - Jan 12, 2021
Env gene sequencing from NAb-resistant viruses was used to accurately delineate epitopes for the NAbs VRC01, PGT128, and PGT151...We therefore extended our methodology to map multiple specificities of epitopes targeted in polyclonal sera, elicited in immunized animals as well as in an HIV-1-infected elite neutralizer capable of neutralizing tier 3 pseudoviruses with high titers. The method can be readily extended to other viruses for which convenient reverse genetics or lentiviral surface display systems are available.
- |||||||||| 10-1074 / National Institute of Allergy and Infectious Diseases, Rockefeller University, Gilead, VRC01 / Acuitas Therap
Trial completion, Enrollment change, Trial completion date, Trial primary completion date, Combination therapy: Combination Therapy With VRC01 and 10-1074 in HIV-Infected Individuals Undergoing Sequential Treatment Interruptions (clinicaltrials.gov) - Dec 10, 2020
P1, N=27, Completed,
The method can be readily extended to other viruses for which convenient reverse genetics or lentiviral surface display systems are available. Recruiting --> Completed | N=75 --> 27 | Trial completion date: Mar 2024 --> Dec 2020 | Trial primary completion date: Mar 2023 --> Dec 2020
- |||||||||| VRC01 / Acuitas Therap
Biomarker, Clinical, PK/PD data, Journal: Assessing pharmacokinetic marker correlates of outcome, with application to antibody prevention efficacy trials. (Pubmed Central) - Nov 7, 2020
The trials randomize 4600 HIV-negative volunteers to receive 10 infusions of the monoclonal antibody VRC01 or placebo...We also find that the quality of the infection time estimator majorly impacts method performance, and thus, incorporating details of an optimized estimator is critical. The methods apply more generally for assessing a time-dependent longitudinal marker as a correlate of risk when the marker trajectory is modeled pharmacokinetically.
- |||||||||| Ad26.Mos4.HIV / J&J, VRC01 / Acuitas Therap
Clinical, Review, Journal: Review of preventative HIV vaccine clinical trials in South Africa. (Pubmed Central) - Oct 30, 2020
Finally, passive immunization trials are underway to build on the experience with VRC01, including single and combination antibody trials with an antibody derived from a subtype-C-infected South African donor. Future consideration should be given to the evaluation of novel strategies, for example, inactivated-whole-virus vaccines.
- |||||||||| 3BNC117 / Rockefeller University, Cornell University, Frontier Biotech, Gilead, VRC01 / Acuitas Therap
Clinical, Journal: Predicting Antibody Neutralization Efficacy in Hypermutated Epitopes Using Monte Carlo Simulations. (Pubmed Central) - Oct 23, 2020
Our method consists of simulating the three-dimensional binding process between the gp120 and the antibody by using Protein Energy Landscape Exploration (PELE), a Monte Carlo stochastic approach. Our results clearly indicate that the binding profiles of sensitive and resistant strains to a bNAb behave differently, showing the latter's weaker binding profiles, that can be exploited for predicting antibody neutralization efficacy in hypermutated HIV-1 strains.
- |||||||||| VRC01 / Acuitas Therap
Journal: HIV-1 VRC01 Germline-Targeting Immunogens Select Distinct Epitope-Specific B Cell Receptors. (Pubmed Central) - Oct 21, 2020
VRC01 B cell sub-populations with distinct cross-reactivity properties were activated by each immunogen, and these differences correlated with distinct biophysical and biochemical features of the germline-targeting immunogens. Our study indicates that the design of effective immunogens to activate B cell receptors leading to protective HIV-1 antibodies will require a better understanding of how the biophysical properties of the epitope and its surrounding surface on the germline-targeting immunogen influence its interaction with the available receptor variants in vivo.
- |||||||||| 3BNC117 / Rockefeller University, Cornell University, Frontier Biotech, Gilead, VRC01 / Acuitas Therap
Journal: Antigenicity and immunogenicity of HIV-1 gp140 with different combinations of glycan mutation and V1/V2 region or V3 crown deletion. (Pubmed Central) - Oct 1, 2020
Taken together, our results indicate that removal of glycans at N276/N463 and deletion of the V1/V2 region can expose the CD4-binding site and CD4-induced epitopes, but such exposure alone appears incapable of enhancing the induction of bNAbs in mice, informing that additional modification or/and immunization strategies are needed. In addition, the strategies which we established for producing gp140 proteins and for analyzing the antigenicity and immunogenicity of gp140 provide useful means for further vaccine design and assessment.
- |||||||||| VRC01 / Acuitas Therap
Journal: Prediction of Serum HIV-1 Neutralization Titers After Passive Administration of VRC01. (Pubmed Central) - Sep 13, 2020
VRC01 serum neutralization could be accurately predicted, especially when using pharmacokinetics models. The proposed prediction approaches could potentially save significant resources for the characterization of serum neutralization of VRC01, including for other bnAbs and bnAb combinations.
- |||||||||| VRC01 / Acuitas Therap
[VIRTUAL] At-line nutrient profiling from cell media in 7 minutes with a new integrated analyzer (On Demand Poster) - Aug 20, 2020 - Abstract #ACSFall2020ACS-Fall_2473;
Finally, the analyzer was tested doing spent media analysis of a batch fed process of CHO NIH VRC01 cell line grown under different ammonia stress concentrations on an ambr®250...Other media components either steadily decreased in concentration or were completely depleted by the end of culture. In the future, the rapid analysis capability of the analyzer combined with the low sample volume requirements would allow for more frequent spent media analysis to occur for real-time observation of these process changes and associated control strategies.
- |||||||||| VRC01 / Acuitas Therap
Journal: Engineering the interactions between a plant-produced HIV antibody and human Fc receptors. (Pubmed Central) - Jul 10, 2020
To test the impact of glycosylation in detail, on binding to human Fc receptors, different glycovariants of VRC01, a broadly neutralizing HIV monoclonal antibody, were generated in Nicotiana benthamiana and characterized...However, this was independent of plant glycosylation, but related to the oxidation status of two methionine residues in the Fc region. This points towards a need for process optimisation to control oxidation levels and improve the quality of plant-produced antibodies.
- |||||||||| VRC01 / Acuitas Therap
Journal: Immunogenicity of RNA Replicons Encoding HIV Env Immunogens Designed for Self-Assembly into Nanoparticles. (Pubmed Central) - Jun 28, 2020
Immunization of transgenic mice expressing human inferred-germline VRC01 heavy chain B cell receptors that are the targets of the eOD antigen led to priming of B cells and somatic hypermutation consistent with VRC01-class antibody development. Altogether, these data suggest replicon delivery of Env immunogens may be a promising avenue for HIV vaccine development.
- |||||||||| VRC01 / Acuitas Therap
Journal: Targeting broadly neutralizing antibody precursors: a naïve approach to vaccine design. (Pubmed Central) - Jun 12, 2020
A better understating of how efficiently germline-targeting immunogens can specifically target rare bNAb precursors is emerging. In addition, a more comprehensive structure-based understanding of critical barriers to bNAb elicitation, as well as commonalities between bNAb classes can further inform vaccine design.
- |||||||||| VRC01 / Acuitas Therap
Journal: Coevolution of HIV-1 and broadly neutralizing antibodies. (Pubmed Central) - Jun 12, 2020
In addition, a more comprehensive structure-based understanding of critical barriers to bNAb elicitation, as well as commonalities between bNAb classes can further inform vaccine design. These studies provide templates for immunogen design to elicit bNAbs against a widened set of epitopes, generating new directions in the quest for an HIV vaccine.
- |||||||||| VRC01 / Acuitas Therap
Journal: Anti-idiotypic antibodies elicit anti-HIV-1-specific B cell responses. (Pubmed Central) - Jun 12, 2020
In mice, iv8 induced target cells to expand and mature in the context of a polyclonal immune system and produced serologic responses targeting the CD4bs on Env. In summary, the results demonstrate that an anti-idiotypic antibody can specifically recognize and expand rare B cells that express VRC01-class antibodies against HIV-1.
- |||||||||| VRC01 / Acuitas Therap
Journal: Hinge length contributes to the phagocytic activity of HIV-specific IgG1 and IgG3 antibodies. (Pubmed Central) - May 6, 2020
In the context of the broadly neutralizing CD4 binding site-specific antibody VRC01 and the variable loop (V3) binding antibody 447-52D, hinge truncation and extension had a considerable impact on the magnitude of phagocytic activity of both IgG1 and IgG3 subclasses...In vivo stability testing showed that IgG molecules with altered hinges can exhibit similar biodistribution and pharmacokinetic profiles as IgG1. Overall, these results suggest that when high phagocytic activity is desirable, therapeutic antibodies may benefit from being formatted as human IgG3 or engineered IgG1 forms with elongated hinges.
- |||||||||| VRC01 / Acuitas Therap
Exploration of roles of CD4 T cell help in recruitment of rare B cells to germinal centers (Board Number: P1233) - Apr 25, 2020 - Abstract #IMMUNOLOGY2020IMMUNOLOGY_820;
However, improvements in early GC VRC01gHL cells were not observed for low affinity Env trimer immunogens. We are actively exploring whether slow delivery immunization strategies (Cirelli et al., Cell 2019) enhance the ability of Env-specific CD4 T cells to recruit rare VRC01-class B cells to GCs in mice.
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