Optimal combinations of broadly neutralizing antibodies for prevention and treatments of HIV-1 clade C infection

Wagh, Kshitij; Bhattacharya, Tanmoy; Williamson, Carolyn; Robles, Alex; Bayne, Madeleine; Garrity, Jetta; Rist, Michael; Rademeyer, Cecilia; Yoon, Hyejin; Lapedes, Alan Scott; Gao, Hongmei; Greene, Kelli; Louder, Mark K.; Kong, Rui; Karim, Salim Abdool; Burton, Dennis R.; Barouch, Dan H.; Nussenzweig, Michael C.; Mascola, John R.; Morris, Lynn; Montefiori, David; Korber, Bette Tina; Seamon, Michael S.

doi:10.1371/journal.ppat.1005520

Title: Optimal combinations of broadly neutralizing antibodies for prevention and treatments of HIV-1 clade C infection

Journal Article · Wed Mar 30 00:00:00 EDT 2016 · PLoS Pathogens

DOI:https://doi.org/10.1371/journal.ppat.1005520· OSTI ID:1291229

Wagh, Kshitij ^[1]; Bhattacharya, Tanmoy ^[2]; Williamson, Carolyn ^[3]; Robles, Alex ^[4]; Bayne, Madeleine ^[4]; Garrity, Jetta ^[4]; Rist, Michael ^[4]; Rademeyer, Cecilia ^[3]; Yoon, Hyejin ^[1]; Lapedes, Alan Scott ^[1]; Gao, Hongmei ^[5]; Greene, Kelli ^[5]; Louder, Mark K. ^[6]; Kong, Rui ^[6]; Karim, Salim Abdool ^[7]; Burton, Dennis R. ^[8]; Barouch, Dan H. ^[4]; Nussenzweig, Michael C. ^[9]; Mascola, John R. ^[6]; Morris, Lynn ^[10] more »

Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Santa Fe Institute, Santa Fe, NM (United States)
Univ. of Cape Town and NHLS, Cape Town (South Africa)
Beth Israel Deaconess Medical Center, Boston, MA (United States)
Duke Univ. Medical Center, Durham, NC (United States)
NIAID, NIH, Bethesda, MD (United States)
Univ. of KwaZulu-Natal, Durban (South Africa)
The Scripps Research Institute, La Jolla, CA (United States)
The Rockefeller Univ., New York, NY (United States)
Univ. of KwaZulu-Natal, Durban (South Africa); Univ. of the Witwatersrand, Johannesburg (South Africa)

In this study, 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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Research Organization:: Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)

Sponsoring Organization:: USDOE

Grant/Contract Number:: AC52-06NA25396

OSTI ID:: 1291229

Report Number(s):: LA-UR-16-20914

Journal Information:: PLoS Pathogens, Vol. 12, Issue 3; ISSN 1553-7374

Publisher:: Public Library of ScienceCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 127 works

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Rational design of a trispecific antibody targeting the HIV-1 Env with elevated anti-viral activity Steinhardt, James J.; Guenaga, Javier; Turner, Hannah L. Nature Communications, Vol. 9, Issue 1 https://doi.org/10.1038/s41467-018-03335-4	journal	February 2018
Pharmaceutical Approaches to HIV Treatment and Prevention Yavuz, Burcin; Morgan, Jessica L.; Showalter, Laura Advanced Therapeutics, Vol. 1, Issue 6 https://doi.org/10.1002/adtp.201800054	journal	July 2018
A Bispecific Antibody That Simultaneously Recognizes the V2- and V3-Glycan Epitopes of the HIV-1 Envelope Glycoprotein Is Broader and More Potent than Its Parental Antibodies Davis-Gardner, Meredith E.; Alfant, Barnett; Weber, Jesse A. mBio, Vol. 11, Issue 1 https://doi.org/10.1128/mbio.03080-19	journal	January 2020
Prediction of HIV-1 sensitivity to broadly neutralizing antibodies shows a trend towards resistance over time Hake, Anna; Pfeifer, Nico PLOS Computational Biology, Vol. 13, Issue 10 https://doi.org/10.1371/journal.pcbi.1005789	journal	October 2017
Landscape review of current HIV ‘kick and kill’ cure research - some kicking, not enough killing Thorlund, Kristian; Horwitz, Marc S.; Fife, Brian T. BMC Infectious Diseases, Vol. 17, Issue 1 https://doi.org/10.1186/s12879-017-2683-3	journal	August 2017
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Predicting the broadly neutralizing antibody susceptibility of the HIV reservoir Yu, Wen-Han; Su, David; Torabi, Julia JCI Insight, Vol. 4, Issue 17 https://doi.org/10.1172/jci.insight.130153	journal	September 2019
When two are better than one: Modeling the mechanisms of antibody mixtures Einav, Tal; Bloom, Jesse D. PLOS Computational Biology https://doi.org/10.1101/808394	journal	February 2020
Adeno-associated virus gene delivery of broadly neutralizing antibodies as prevention and therapy against HIV-1 Lin, Allen; Balazs, Alejandro B. Retrovirology, Vol. 15, Issue 1 https://doi.org/10.1186/s12977-018-0449-7	journal	October 2018
Sensitivity to Broadly Neutralizing Antibodies of Recently Transmitted HIV-1 Clade CRF02_AG Viruses with a Focus on Evolution over Time Stefic, Karl; Bouvin-Pley, Mélanie; Essat, Asma Journal of Virology, Vol. 93, Issue 2 https://doi.org/10.1128/jvi.01492-18	journal	November 2018
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Increasing the Clinical Potential and Applications of Anti-HIV Antibodies Hua, Casey K.; Ackerman, Margaret E. Frontiers in Immunology, Vol. 8 https://doi.org/10.3389/fimmu.2017.01655	journal	November 2017
Features of Recently Transmitted HIV-1 Clade C Viruses that Impact Antibody Recognition: Implications for Active and Passive Immunization Rademeyer, Cecilia; Korber, Bette; Seaman, Michael S. PLOS Pathogens, Vol. 12, Issue 7 https://doi.org/10.1371/journal.ppat.1005742	journal	July 2016
Antibody-virus co-evolution in HIV infection: paths for HIV vaccine development Bonsignori, Mattia; Liao, Hua-Xin; Gao, Feng Immunological Reviews, Vol. 275, Issue 1 https://doi.org/10.1111/imr.12509	journal	January 2017
Modeling cumulative overall prevention efficacy for the VRC01 phase 2b efficacy trials Huang, Yunda; Karuna, Shelly; Carpp, Lindsay N. Human Vaccines & Immunotherapeutics, Vol. 14, Issue 9 https://doi.org/10.1080/21645515.2018.1462640	journal	May 2018
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Antibody-Mediated Therapy against HIV/AIDS: Where Are We Standing Now? Awi, Noel Jacques; Teow, Sin-Yeang Journal of Pathogens, Vol. 2018 https://doi.org/10.1155/2018/8724549	journal	June 2018
Mapping Polyclonal HIV-1 Antibody Responses via Next-Generation Neutralization Fingerprinting Doria-Rose, Nicole A.; Altae-Tran, Han R.; Roark, Ryan S. PLOS Pathogens, Vol. 13, Issue 1 https://doi.org/10.1371/journal.ppat.1006148	journal	January 2017
Landscape review of current HIV ‘kick and kill’ cure research - some kicking, not enough killing Thorlund, Kristian; Horwitz, Marc S.; Fife, Brian T. BioMed Central https://doi.org/10.14288/1.0355234	text	January 2017
Staged induction of HIV-1 glycan–dependent broadly neutralizing antibodies Todd, Bradley,; Baptiste, Aussedat,; Amit, Kumar, The University of North Carolina at Chapel Hill University Libraries https://doi.org/10.17615/a0m6-td59	text	January 2017
Mapping Polyclonal HIV-1 Antibody Responses via Next-Generation Neutralization Fingerprinting Doria-Rose, Nicole A.; Altae-Tran, Han R.; Roark, Ryan S. Columbia University https://doi.org/10.7916/d8zw1rks	text	January 2017
When two are better than one: Modeling the mechanisms of antibody mixtures Einav, Tal; Bloom, Jesse D. PLOS Computational Biology, Vol. 16, Issue 5 https://doi.org/10.1371/journal.pcbi.1007830	journal	May 2020
Features of Recently Transmitted HIV-1 Clade C Viruses that Impact Antibody Recognition: Implications for Active and Passive Immunization E., Giorgi, Elena; S., Seaman, Michael; C., Montefiori, David The University of North Carolina at Chapel Hill University Libraries https://doi.org/10.17615/2f0r-b813	text	January 2016
Safety, pharmacokinetics, and immunological activities of multiple intravenous or subcutaneous doses of an anti-HIV monoclonal antibody, VRC01, administered to HIV-uninfected adults: Results of a phase 1 randomized trial Mayer, Kenneth H.; Seaton, Kelly E.; Huang, Yunda Columbia University https://doi.org/10.7916/d8pv7xs0	text	January 2017
Broadly Neutralizing Antibodies as Treatment: Effects on Virus and Immune System Bhiman, Jinal N.; Lynch, Rebecca M. Current HIV/AIDS Reports, Vol. 14, Issue 2 https://doi.org/10.1007/s11904-017-0352-1	journal	March 2017
Surface-Matrix Screening Identifies Semi-specific Interactions that Improve Potency of a Near Pan-reactive HIV-1-Neutralizing Antibody Kwon, Young D.; Chuang, Gwo-Yu; Zhang, Baoshan Cell Reports, Vol. 22, Issue 7 https://doi.org/10.1016/j.celrep.2018.01.023	journal	February 2018
HIV-1 Neutralizing Antibody Signatures and Application to Epitope-Targeted Vaccine Design Bricault, Christine A.; Yusim, Karina; Seaman, Michael S. Cell Host & Microbe, Vol. 26, Issue 2 https://doi.org/10.1016/j.chom.2019.07.016	journal	August 2019
Structural Basis for Broad HIV-1 Neutralization by the MPER-Specific Human Broadly Neutralizing Antibody LN01 Pinto, Dora; Fenwick, Craig; Caillat, Christophe Cell Host & Microbe, Vol. 26, Issue 5 https://doi.org/10.1016/j.chom.2019.09.016	journal	November 2019
AAV-Mediated Expression of Broadly Neutralizing and Vaccine-like Antibodies Targeting the HIV-1 Envelope V2 Region van den Berg, Fiona T.; Makoah, Nigel A.; Ali, Stuart A. Molecular Therapy - Methods & Clinical Development, Vol. 14 https://doi.org/10.1016/j.omtm.2019.06.002	journal	September 2019
Adeno-associated virus vectored immunoprophylaxis to prevent HIV in healthy adults: a phase 1 randomised controlled trial Priddy, Frances H.; Lewis, David J. M.; Gelderblom, Huub C. The Lancet HIV, Vol. 6, Issue 4 https://doi.org/10.1016/s2352-3018(19)30003-7	journal	April 2019
Promise and problems associated with the use of recombinant AAV for the delivery of anti-HIV antibodies Fuchs, Sebastian P.; Desrosiers, Ronald C. Molecular Therapy - Methods & Clinical Development, Vol. 3 https://doi.org/10.1038/mtm.2016.68	journal	January 2016
Broad and potent cross clade neutralizing antibodies with multiple specificities in the plasma of HIV-1 subtype C infected individuals Cheedarla, Narayanaiah; Precilla, K. Lucia; Babu, Hemalatha Scientific Reports, Vol. 7, Issue 1 https://doi.org/10.1038/srep46557	journal	April 2017
Engineering antibody-like inhibitors to prevent and treat HIV-1 infection Gardner, Matthew R.; Farzan, Michael Current Opinion in HIV and AIDS, Vol. 12, Issue 3 https://doi.org/10.1097/coh.0000000000000367	journal	May 2017
Polyvalent vaccine approaches to combat HIV-1 diversity Korber, Bette; Hraber, Peter; Wagh, Kshitij Immunological Reviews, Vol. 275, Issue 1 https://doi.org/10.1111/imr.12516	journal	January 2017
Engineering multi-specific antibodies against HIV-1 Padte, Neal N.; Yu, Jian; Huang, Yaoxing Retrovirology, Vol. 15, Issue 1 https://doi.org/10.1186/s12977-018-0439-9	journal	August 2018
Mathematical modeling to reveal breakthrough mechanisms in the HIV Antibody Mediated Prevention (AMP) trials Reeves, Daniel B.; Huang, Yunda; Duke, Elizabeth R. PLOS Computational Biology, Vol. 16, Issue 2 https://doi.org/10.1371/journal.pcbi.1007626	journal	February 2020
Prospects for passive immunity to prevent HIV infection Morris, Lynn; Mkhize, Nonhlanhla N. PLOS Medicine, Vol. 14, Issue 11 https://doi.org/10.1371/journal.pmed.1002436	journal	November 2017
Neutralizing Monoclonal Antibodies to Fight HIV-1: On the Threshold of Success Jaworski, Juan Pablo; Vendrell, Alejandrina; Chiavenna, Sebastián Matias Frontiers in Immunology, Vol. 7 https://doi.org/10.3389/fimmu.2016.00661	journal	January 2017
Long-Acting HIV Treatment and Prevention: Closer to the Threshold Barnhart, Matthew Global Health: Science and Practice, Vol. 5, Issue 2 https://doi.org/10.9745/ghsp-d-17-00206	journal	June 2017

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