Rational Design of Envelope Identifies Broadly Neutralizing Human Monoclonal Antibodies to HIV-1

Wu, Xueling; Yang, Zhi Yong; Li, Yuxing; Hogerkorp, Carl Magnus; Schief, William R.; Seaman, Michael S.; Zhou, Tongqing; Schmidt, Stephen D.; Wu, Lan; Xu, Li; Longo, Nancy S.; McKee, Krisha; O’Dell, Sijy; Louder, Mark K.; Wycuff, Diane; Feng, Yanghe; Nason, Martha; Doria‐Rose, Nicole A.; Connors, Mark; Kwong, Peter D.; Roederer, Mario; Wyatt, Richard T.; Nabel, Gary J.; Mascola, John R.

doi:10.1126/science.1187659

Cited by 1,631 publications

(2,161 citation statements)

References 38 publications

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“…The first CD4‐binding site bnAb isolated, apart from b12,12 was VRC01, which partially mimics the binding of CD4 to its receptor site 74. The RSC3 bait used to capture the VRC01 B‐cell lineage was modified to preferentially bind b12 and a negative bait that could not bind b12 was used for counter selection 39. This strategy was re‐utilized to isolate PGV04 from a separate donor.…”

Section: Specificity Of Hiv Bnabsmentioning

confidence: 99%

Identification and specificity of broadly neutralizing antibodies against HIV

McCoy

Burton

2017

Immunological Reviews

210

193

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SummaryBeginning in 2009, studies of the humoral responses of HIV‐positive individuals have led to the identification of scores, if not hundreds, of antibodies that are both broadly reactive and potently neutralizing. This development has provided renewed impetus toward an HIV vaccine and led directly to the development of novel immunogens. Advances in identification of donors with the most potent and broad anti‐HIV serum neutralizing responses were crucial in this effort. Equally, development of methods for the rapid generation of human antibodies from these donors was pivotal. Primarily these methods comprise single B‐cell culture coupled to high‐throughput neutralization screening and flow cytometry‐based sorting of single B cells using HIV envelope protein baits. In this review, the advantages and disadvantages of these methodologies are discussed in the context of the specificities targeted by individual antibodies and the need for further improvements to evaluate HIV vaccine candidates.

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Section: Specificity Of Hiv Bnabsmentioning

confidence: 99%

Identification and specificity of broadly neutralizing antibodies against HIV

McCoy

Burton

2017

Immunological Reviews

210

193

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“…These estimates indicated several recombinations to occur each day, with the roadblock to broad neutralization being the extraordinary SHM required for function 40. Additional multidonor classes have now been identified including CD4‐binding‐site antibodies from the VH1‐46 germline5, 39 and V1V2‐directed antibodies characterized by a protruding anionic loop formed by recombination 6, 11.…”

Section: Antibodyomics5mentioning

confidence: 99%

“…The effects of antibody interface mutants for three VRC01‐class antibodies [VRC01, VRC03 40, and VRC‐PG04 9] on HIV‐1 gp120 binding were quantified by surface‐plasmon resonance (SPR) measurements. By using FEP simulations, we were able to reproduce the experimental changes in binding affinities for alanine mutants to gp120 (average error less than 1 kcal/mole)—the level of accuracy sufficient to provide meaningful prospective predictions of binding free energies for antibody improvement.…”

Section: Antibodyomics8mentioning

confidence: 99%

Antibodyomics: bioinformatics technologies for understanding B‐cell immunity to HIV‐1

Kwong

Chuang

DeKosky

et al. 2017

Immunological Reviews

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SummaryNumerous antibodies have been identified from HIV‐1‐infected donors that neutralize diverse strains of HIV‐1. These antibodies may provide the basis for a B cell‐mediated HIV‐1 vaccine. However, it has been unclear how to elicit similar antibodies by vaccination. To address this issue, we have undertaken an informatics‐based approach to understand the genetic and immunologic processes controlling the development of HIV‐1‐neutralizing antibodies. As DNA sequencing comprises the fastest growing database of biological information, we focused on incorporating next‐generation sequencing of B‐cell transcripts to determine the origin, maturation pathway, and prevalence of broadly neutralizing antibody lineages (Antibodyomics1, 2, 4, and 6). We also incorporated large‐scale robotic analyses of serum neutralization to identify and quantify neutralizing antibodies in donor cohorts (Antibodyomics3). Statistical analyses furnish another layer of insight (Antibodyomics5), with physical characteristics of antibodies and their targets through molecular dynamics simulations (Antibodyomics7) and free energy perturbation analyses (Antibodyomics8) providing information‐rich output. Functional interrogation of individual antibodies (Antibodyomics9) and synthetic antibody libraries (Antibodyomics10) also yields multi‐dimensional data by which to understand and improve antibodies. Antibodyomics, described here, thus comprise resolution‐enhancing tools, which collectively embody an information‐driven discovery engine aimed toward the development of effective B cell‐based vaccines.

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“…Arising from the long history of using passive administration of antibodies to treat and/or prevent disease, 3 passive administration of HIV broadly neutralizing monoclonal antibodies (mAbs) represents a promising new HIV prevention modality. mAbs isolated from chronically infected individuals have shown impressive breadth, inhibiting 80-90% or more of HIV-Env pseudoviruses in in vitro neutralization assays at bnAb concentrations as low as 1 μg/mL 4–6,8–10 …”

Section: Introductionmentioning

confidence: 99%

“…VRC01 targets the conserved CD4 binding site of the HIV envelope 7,8 and has been demonstrated to prevent HIV infection in non-human primate (NHP) challenge studies. 11–13,30 Building on these NHP results, the first efficacy studies of VRC01 – termed the Antibody Mediated Prevention (AMP) trials – for HIV prevention were launched in 2016, with an estimated total study duration of 5 years including enrollment and follow up.…”

Section: Introductionmentioning

confidence: 99%

Modeling cumulative overall prevention efficacy for the VRC01 phase 2b efficacy trials

Huang

Karuna

Carpp

et al. 2018

Human Vaccines & Immunotherapeutics

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The Antibody Mediated Prevention trials are assessing whether intravenously-administered VRC01 (10 mg/kg or 30 mg/kg vs placebo) can prevent HIV infection. In a modeling exercise, we used two models to predict the overall prevention efficacy (PE) of each VRC01 dose in preventing HIV infection. For the first per-exposure PE model, parameters were estimated from studies where nonhuman primates (NHPs) were administered high-dose intra-rectal simian-human immunodeficiency virus challenge two days post-VRC01 infusion at various dosages (“NHP model”). To account for the fact that humans may require greater VRC01 concentration to achieve the same level of protection, we next assumed that a 5-fold greater VRC01 serum concentration would be needed to provide the same level of per-exposure PE as seen in the NHP data (“5-fold model”). For the 10 mg/kg regimen, the 5-fold and NHP models predict an overall PE of 37% and 64%, respectively; for the 30 mg/kg regimen, the two models predict an overall PE of 53% and 82%, respectively. Our results support that VRC01 may plausibly confer positive PE in the AMP trials. Given the lack of available knowledge and data to verify the assumptions undergirding our modeling framework, its quantitative predictions of overall PE are preliminary. Its current main applications are to supplement decisions to advance mAb regimens to efficacy trials, and to enable mAb regimen ranking by their potential for PE in humans.

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Rational Design of Envelope Identifies Broadly Neutralizing Human Monoclonal Antibodies to HIV-1

Cited by 1,631 publications

References 38 publications

Identification and specificity of broadly neutralizing antibodies against HIV

Identification and specificity of broadly neutralizing antibodies against HIV

Antibodyomics: bioinformatics technologies for understanding B‐cell immunity to HIV‐1

Modeling cumulative overall prevention efficacy for the VRC01 phase 2b efficacy trials

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