Pharmacokinetics and predicted neutralisation coverage of VRC01 in HIV-uninfected participants of the Antibody Mediated Prevention (AMP) trials

Huang, Yunda; Naidoo, Logashvari; Zhang, Lily; Carpp, Lindsay N.; Rudnicki, Erika; Randhawa, April; Gonzáles, Pedro; McDermott, Adrian B.; Ledgerwood, Julie E.; Lorenzo, Margarita M. Gomez; Burns, David; deCamp, Allan C.; Juraska, Michal; Mascola, John R.; Edupuganti, Srilatha; Mgodi, Nyaradzo; Cohen, Myron S.; Corey, Lawrence; Andrew, P.; Karuna, Shelly; Gilbert, Peter B.; Mngadi, Kathryn; Lazarus, Erica

doi:10.1016/j.ebiom.2020.103203

Cited by 17 publications

(32 citation statements)

References 40 publications

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“…, Eq 1 a relationship that has been empirically confirmed for single bNAbs 19,20 . As a potency measure, titer expresses the fold-relationship between concentration and viral IC50 as a measure of 'protection' against that virus.…”

Section: Fig 1 Pkpd Model Schematic For Optimizing Combination Treatment Against a Genetically Diversementioning

confidence: 76%

“…We previously integrated pharmacokinetic (PK) and multi-strain pharmacodynamic (PD) models to determine longitudinally varying potency of VRC01, a broadly neutralizing antibody (bNAb), to simulate prevention trials and predict strain coverage 18,19 . Because of HIV genetic diversity, it is essential to consider the distribution of potencies against the diverse population of viral strains.…”

Section: Fig 1 Pkpd Model Schematic For Optimizing Combination Treatment Against a Genetically Diversementioning

confidence: 99%

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Optimizing clinical dosing of combination broadly neutralizing antibodies for HIV prevention

Mayer

deCamp

Huang

et al. 2021

Preprint

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Broadly neutralizing antibodies are promising agents to prevent HIV infection and achieve HIV remission without antiretroviral therapy (ART). As learned from effective ART, HIV viral diversity necessitates combination antibody cocktails. Here, we demonstrate how to optimally choose the ratio within combinations based on the constraint of a total dose size. Optimization in terms of prevention efficacy outcome requires a model that synthesizes 1) antibody pharmacokinetics (PK), 2) a mapping between concentration and neutralization against a genetically diverse pathogen (e.g., distributions of viral IC50 or IC80), 3) a protection correlate to translate in vitro potency to clinical protection, and 4) an in vivo interaction model for how drugs work together. We find that there is not a general solution, and the optimal dose ratio likely will be different if antibodies cooperate versus if both products must be simultaneously present. Optimization requires trade-offs between potency and longevity; using an in silico case-study, we show a cocktail can outperform a bi-specific antibody (a single drug with 2 merged antibodies) with superior potency but worse longevity. In another practical case study, we perform a triple antibody optimization of VRC07, 3BNC117, and 10-1074 bNAb variants using empirical PK and a pre-clinical correlate of protection derived from animal challenge studies. Here, a 2:1:1 dose emphasizing VRC07 would optimally balance protection while achieving practical dosing and given conservative judgements about prior data. Our approach can be immediately applied to optimize the next generation of combination antibody prevention and cure studies.

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Section: Fig 1 Pkpd Model Schematic For Optimizing Combination Treatment Against a Genetically Diversementioning

confidence: 76%

Section: Fig 1 Pkpd Model Schematic For Optimizing Combination Treatment Against a Genetically Diversementioning

confidence: 99%

Optimizing clinical dosing of combination broadly neutralizing antibodies for HIV prevention

Mayer

deCamp

Huang

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…A key secondary endpoint was to determine if an association existed between serum neutralization activity and the ID 50 or ID 80 titers required for protection as had been shown in NHP/ SHIV models (41,110). Based on the NHP models, it was estimated that protection would be achieved at serum antibody concentrations 50-100-fold higher than the measured IC 50 of the challenge (infecting) virus (32).…”

Section: Amp Efficacy Trialsmentioning

confidence: 99%

“…The underlying hypothesis of the coordinated AMP trials was that passive transfer of an HIV-1 bnAb would be efficacious at preventing sexual transmission of HIV-1 in exposed individuals. A key secondary endpoint was to determine if an association existed between serum neutralization activity and the ID 50 or ID 80 titers required for protection as had been shown in NHP/SHIV models ( 41 , 110 ). Based on the NHP models, it was estimated that protection would be achieved at serum antibody concentrations 50-100-fold higher than the measured IC 50 of the challenge (infecting) virus ( 32 ).…”

Section: Clinical Evaluation Of Bnabsmentioning

confidence: 99%

Broadly Neutralizing Antibodies for HIV-1 Prevention

Walsh

Seaman

2021

Front. Immunol.

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Given the absence of an effective vaccine for protection against HIV-1 infection, passive immunization strategies that utilize potent broadly neutralizing antibodies (bnAbs) to block acquisition of HIV-1 are being rigorously pursued in the clinical setting. bnAbs have demonstrated robust protection in preclinical animal models, and several leading bnAb candidates have shown favorable safety and pharmacokinetic profiles when tested individually or in combinations in early phase human clinical trials. Furthermore, passive administration of bnAbs in HIV-1 infected individuals has resulted in prolonged suppression of viral rebound following interruption of combination antiretroviral therapy, and robust antiviral activity when administered to viremic individuals. Recent results from the first efficacy trials testing repeated intravenous administrations of the anti-CD4 binding site bnAb VRC01 have demonstrated positive proof of concept that bnAb passive immunization can confer protection against HIV-1 infection in humans, but have also highlighted the considerable barriers that remain for such strategies to effectively contribute to control of the epidemic. In this review, we discuss the current status of clinical studies evaluating bnAbs for HIV-1 prevention, highlight lessons learned from the recent Antibody Mediated Prevention (AMP) efficacy trials, and provide an overview of strategies being employed to improve the breadth, potency, and durability of antiviral protection.

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“…The results of the first efficacy trials of an antibody for HIV prevention tested in Africa and the Americas have recently been published (14)(15)(16)(17). These two Antibody-Mediated Prevention (AMP www.ampstudy.org.za) trials showed that VRC01 had 75% prevention efficacy in high-risk men and women if the infecting virus was sensitive to the antibody at <1mg/ml (IC 80 ).…”

Section: Introductionmentioning

confidence: 99%

Combinations of Single Chain Variable Fragments From HIV Broadly Neutralizing Antibodies Demonstrate High Potency and Breadth

et al. 2021

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Broadly neutralizing antibodies (bNAbs) are currently being assessed in clinical trials for their ability to prevent HIV infection. Single chain variable fragments (scFv) of bNAbs have advantages over full antibodies as their smaller size permits improved diffusion into mucosal tissues and facilitates vector-driven gene expression. We have previously shown that scFv of bNAbs individually retain significant breadth and potency. Here we tested combinations of five scFv derived from bNAbs CAP256-VRC26.25 (V2-apex), PGT121 (N332-supersite), 3BNC117 (CD4bs), 8ANC195 (gp120-gp41 interface) and 10E8v4 (MPER). Either two or three scFv were combined in equimolar amounts and tested in the TZM-bl neutralization assay against a multiclade panel of 17 viruses. Experimental IC50 and IC80 data were compared to predicted neutralization titers based on single scFv titers using the Loewe additive and the Bliss-Hill model. Like full-sized antibodies, combinations of scFv showed significantly improved potency and breadth compared to single scFv. Combinations of two or three scFv generally followed an independent action model for breadth and potency with no significant synergy or antagonism observed overall although some exceptions were noted. The Loewe model underestimated potency for some dual and triple combinations while the Bliss-Hill model was better at predicting IC80 titers of triple combinations. Given this, we used the Bliss-Hill model to predict the coverage of scFv against a 45-virus panel at concentrations that correlated with protection in the AMP trials. Using IC80 titers and concentrations of 1μg/mL, there was 93% coverage for one dual scFv combination (3BNC117+10E8v4), and 96% coverage for two of the triple combinations (CAP256.25+3BNC117+10E8v4 and PGT121+3BNC117+10E8v4). Combinations of scFv, therefore, show significantly improved breadth and potency over individual scFv and given their size advantage, have potential for use in passive immunization.

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Pharmacokinetics and predicted neutralisation coverage of VRC01 in HIV-uninfected participants of the Antibody Mediated Prevention (AMP) trials

Cited by 17 publications

References 40 publications

Optimizing clinical dosing of combination broadly neutralizing antibodies for HIV prevention

Optimizing clinical dosing of combination broadly neutralizing antibodies for HIV prevention

Broadly Neutralizing Antibodies for HIV-1 Prevention

Combinations of Single Chain Variable Fragments From HIV Broadly Neutralizing Antibodies Demonstrate High Potency and Breadth

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