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Optimal Combinations of Broadly Neutralizing Antibodies for Prevention and Treatment of HIV-1 Clade C Infection.

Wagh K, Bhattacharya T, Williamson C, Robles A, Bayne M, Garrity J, Rist M, Rademeyer C, Yoon H, Lapedes A, Gao H, Greene K, Louder MK, Kong R, Karim SA, Burton DR, Barouch DH, Nussenzweig MC, Mascola JR, Morris L, Montefiori DC, Korber B, Seaman MS - PLoS Pathog. (2016)

Bottom Line: While combinations of bnAbs targeting distinct epitopes on the viral envelope (Env) will likely be required to overcome the extraordinary diversity of HIV-1, a key outstanding question is which bnAbs, and how many, will be needed to achieve optimal clinical benefit.Using this model, we performed a comprehensive and systematic comparison of the predicted neutralizing activity of over 1,600 possible double, triple, and quadruple bnAb combinations.By this set of criteria, triple and quadruple combinations of bnAbs were identified that were significantly more effective than the best double combinations, and further improved the probability of having multiple bnAbs simultaneously active against a given virus, a requirement that may be critical for countering escape in vivo.

View Article: PubMed Central - PubMed

Affiliation: Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.

ABSTRACT
The identification of a new generation of potent broadly neutralizing HIV-1 antibodies (bnAbs) has generated substantial interest in their potential use for the prevention and/or treatment of HIV-1 infection. While combinations of bnAbs targeting distinct epitopes on the viral envelope (Env) will likely be required to overcome the extraordinary diversity of HIV-1, a key outstanding question is which bnAbs, and how many, will be needed to achieve optimal clinical benefit. We assessed the neutralizing activity of 15 bnAbs targeting four distinct epitopes of Env, including the CD4-binding site (CD4bs), the V1/V2-glycan region, the V3-glycan region, and the gp41 membrane proximal external region (MPER), against a panel of 200 acute/early clade C HIV-1 Env pseudoviruses. A mathematical model was developed that predicted neutralization by a subset of experimentally evaluated bnAb combinations with high accuracy. Using this model, we performed a comprehensive and systematic comparison of the predicted neutralizing activity of over 1,600 possible double, triple, and quadruple bnAb combinations. The most promising bnAb combinations were identified based not only on breadth and potency of neutralization, but also other relevant measures, such as the extent of complete neutralization and instantaneous inhibitory potential (IIP). By this set of criteria, triple and quadruple combinations of bnAbs were identified that were significantly more effective than the best double combinations, and further improved the probability of having multiple bnAbs simultaneously active against a given virus, a requirement that may be critical for countering escape in vivo. These results provide a rationale for advancing bnAb combinations with the best in vitro predictors of success into clinical trials for both the prevention and treatment of HIV-1 infection.

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IIP for bnAbs and bnAb combinations.IIP values (log10 reduction) are shown for the best-in-class single bnAbs and their combinations at 1 μg/ml (A), 10 μg/ml (B) and 100 μg/ml (C). In each panel, numbers in the top row show median IIP values and in the bottom row show the percentage of viruses with IIP > 5. The dotted horizontal lines are at IIP = 5.
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ppat.1005520.g007: IIP for bnAbs and bnAb combinations.IIP values (log10 reduction) are shown for the best-in-class single bnAbs and their combinations at 1 μg/ml (A), 10 μg/ml (B) and 100 μg/ml (C). In each panel, numbers in the top row show median IIP values and in the bottom row show the percentage of viruses with IIP > 5. The dotted horizontal lines are at IIP = 5.

Mentions: IIP values for single bnAbs were calculated using either the best-fit Hill curves of experimental neutralization data for the best-in-class bnAbs (Fig 7, S1 Text), or estimated Hill curves using IC50 and IC80 values (Fig P in S1 Text) (with the former expected to yield more accurate predictions since IIP values are critically sensitive to neutralization close to 100%). Using BH model, we calculated the IIP values (Methods) for 2, 3 and 4 bnAb combinations of the best-in-class bnAbs (Fig 7). Since IIP values depend on bnAb concentration, and precise doses and pharmacokinetics of bnAbs are still being established, we analyzed IIP at bnAb concentrations of 1, 10 and 100 μg/ml. The 1 and 10 μg/ml concentrations are within the experimental assay range, whereas results for the 100 μg/ml dose are estimates obtained by extrapolation.


Optimal Combinations of Broadly Neutralizing Antibodies for Prevention and Treatment of HIV-1 Clade C Infection.

Wagh K, Bhattacharya T, Williamson C, Robles A, Bayne M, Garrity J, Rist M, Rademeyer C, Yoon H, Lapedes A, Gao H, Greene K, Louder MK, Kong R, Karim SA, Burton DR, Barouch DH, Nussenzweig MC, Mascola JR, Morris L, Montefiori DC, Korber B, Seaman MS - PLoS Pathog. (2016)

IIP for bnAbs and bnAb combinations.IIP values (log10 reduction) are shown for the best-in-class single bnAbs and their combinations at 1 μg/ml (A), 10 μg/ml (B) and 100 μg/ml (C). In each panel, numbers in the top row show median IIP values and in the bottom row show the percentage of viruses with IIP > 5. The dotted horizontal lines are at IIP = 5.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4814126&req=5

ppat.1005520.g007: IIP for bnAbs and bnAb combinations.IIP values (log10 reduction) are shown for the best-in-class single bnAbs and their combinations at 1 μg/ml (A), 10 μg/ml (B) and 100 μg/ml (C). In each panel, numbers in the top row show median IIP values and in the bottom row show the percentage of viruses with IIP > 5. The dotted horizontal lines are at IIP = 5.
Mentions: IIP values for single bnAbs were calculated using either the best-fit Hill curves of experimental neutralization data for the best-in-class bnAbs (Fig 7, S1 Text), or estimated Hill curves using IC50 and IC80 values (Fig P in S1 Text) (with the former expected to yield more accurate predictions since IIP values are critically sensitive to neutralization close to 100%). Using BH model, we calculated the IIP values (Methods) for 2, 3 and 4 bnAb combinations of the best-in-class bnAbs (Fig 7). Since IIP values depend on bnAb concentration, and precise doses and pharmacokinetics of bnAbs are still being established, we analyzed IIP at bnAb concentrations of 1, 10 and 100 μg/ml. The 1 and 10 μg/ml concentrations are within the experimental assay range, whereas results for the 100 μg/ml dose are estimates obtained by extrapolation.

Bottom Line: While combinations of bnAbs targeting distinct epitopes on the viral envelope (Env) will likely be required to overcome the extraordinary diversity of HIV-1, a key outstanding question is which bnAbs, and how many, will be needed to achieve optimal clinical benefit.Using this model, we performed a comprehensive and systematic comparison of the predicted neutralizing activity of over 1,600 possible double, triple, and quadruple bnAb combinations.By this set of criteria, triple and quadruple combinations of bnAbs were identified that were significantly more effective than the best double combinations, and further improved the probability of having multiple bnAbs simultaneously active against a given virus, a requirement that may be critical for countering escape in vivo.

View Article: PubMed Central - PubMed

Affiliation: Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.

ABSTRACT
The identification of a new generation of potent broadly neutralizing HIV-1 antibodies (bnAbs) has generated substantial interest in their potential use for the prevention and/or treatment of HIV-1 infection. While combinations of bnAbs targeting distinct epitopes on the viral envelope (Env) will likely be required to overcome the extraordinary diversity of HIV-1, a key outstanding question is which bnAbs, and how many, will be needed to achieve optimal clinical benefit. We assessed the neutralizing activity of 15 bnAbs targeting four distinct epitopes of Env, including the CD4-binding site (CD4bs), the V1/V2-glycan region, the V3-glycan region, and the gp41 membrane proximal external region (MPER), against a panel of 200 acute/early clade C HIV-1 Env pseudoviruses. A mathematical model was developed that predicted neutralization by a subset of experimentally evaluated bnAb combinations with high accuracy. Using this model, we performed a comprehensive and systematic comparison of the predicted neutralizing activity of over 1,600 possible double, triple, and quadruple bnAb combinations. The most promising bnAb combinations were identified based not only on breadth and potency of neutralization, but also other relevant measures, such as the extent of complete neutralization and instantaneous inhibitory potential (IIP). By this set of criteria, triple and quadruple combinations of bnAbs were identified that were significantly more effective than the best double combinations, and further improved the probability of having multiple bnAbs simultaneously active against a given virus, a requirement that may be critical for countering escape in vivo. These results provide a rationale for advancing bnAb combinations with the best in vitro predictors of success into clinical trials for both the prevention and treatment of HIV-1 infection.

Show MeSH
Related in: MedlinePlus