Los Alamos National Lab. (LANL), Los Alamos, NM (United States). Theoretical Biology & Biophysics; New Mexico Consortium, Los Alamos, NM (United States); DOE/OSTI
Beth Israel Deaconness Medical Center, Boston, MA (United States). Center for Virology & Vaccine Research
The Scripps Research Inst., La Jolla, CA (United States). Dept. of Immunology and Microbiology
National Inst. of Health (NIH), Bethesda, MD (United States). National Inst. of allergy and Infectious Diseases. Lab. of Immunoregulation
Rockefeller Univ., New York, NY (United States). Aaron Diamond AIDS Research Center
National Inst. of Health (NIH), Bethesda, MD (United States). National Inst. of Allergy and Infectious Diseases. Vaccine Research Center
Rockefeller Univ., New York, NY (United States). Lab. of
Molecular Immunology
Rockefeller Univ., New York, NY (United States). Lab. of
Molecular Genetics and Immunology
National Inst. of Health (NIH), Bethesda, MD (United States). National Inst. of Allergy and Infectious Diseases. Lab. of Molecular Microbiology
Duke Univ., Durham, NC (United States). Medical Center. Dept. of Surgery
Los Alamos National Lab. (LANL), Los Alamos, NM (United States). Theoretical Biology & Biophysics; New Mexico Consortium, Los Alamos, NM (United States)
There is great interest in passive transfer of broadly neutralizing antibodies (bnAbs) and engineered bispecific antibodies (Abs) for prevention of HIV-1 infections due to their in vitro neutralization breadth and potency against global isolates and long in vivo half-lives. We compared the potential of eight bnAbs and two bispecific Abs currently under clinical development, and their 2 Ab combinations, to prevent infection by dominant HIV-1 subtypes in sub-Saharan Africa. Using in vitro neutralization data for Abs against 25 subtype A, 100 C, and 20 D pseudoviruses, we modeled neutralization by single Abs and 2 Ab combinations assuming realistic target concentrations of 10μg/ml total for bnAbs and combinations, and 5μg/ml for bispecifics. We used IC80 breadth-potency, completeness of neutralization, and simultaneous coverage by both Abs in the combination as metrics to characterize prevention potential. Additionally, we predicted in vivo protection by Abs and combinations by modeling protection as a function of in vitro neutralization based on data from a macaque simian-human immunodeficiency virus (SHIV) challenge study. Our model suggests that nearly complete neutralization of a given virus is needed for in vivo protection (~98% neutralization for 50% relative protection). Using the above metrics, we found that bnAb combinations should outperform single bnAbs, as expected; however, different combinations are optimal for different subtypes. Remarkably, a single bispecific 10E8-iMAb, which targets HIV Env and host-cell CD4, outperformed all combinations of two conventional bnAbs, with 95–97% predicted relative protection across subtypes. Combinations that included 10E8-iMAb substantially improved protection over use of 10E8-iMAb alone. Our results highlight the promise of 10E8-iMAb and its combinations to prevent HIV-1 infections in sub-Saharan Africa.
Wagh, Kshitij, et al. "Potential of conventional & bispecific broadly neutralizing antibodies for prevention of HIV-1 subtype A, C & D infections." PLoS Pathogens, vol. 14, no. 3, Mar. 2018. https://doi.org/10.1371/journal.ppat.1006860
Wagh, Kshitij, Seaman, Michael S., Zingg, Marshall, Fitzsimons, Tomas, Barouch, Dan H., Burton, Dennis R., Connors, Mark, Ho, David D., Mascola, John R., Nussenzweig, Michel C., Ravetch, Jeffrey, Gautam, Rajeev, Martin, Malcolm A., Montefiori, David C., & Korber, Bette (2018). Potential of conventional & bispecific broadly neutralizing antibodies for prevention of HIV-1 subtype A, C & D infections. PLoS Pathogens, 14(3). https://doi.org/10.1371/journal.ppat.1006860
Wagh, Kshitij, Seaman, Michael S., Zingg, Marshall, et al., "Potential of conventional & bispecific broadly neutralizing antibodies for prevention of HIV-1 subtype A, C & D infections," PLoS Pathogens 14, no. 3 (2018), https://doi.org/10.1371/journal.ppat.1006860
@article{osti_1627916,
author = {Wagh, Kshitij and Seaman, Michael S. and Zingg, Marshall and Fitzsimons, Tomas and Barouch, Dan H. and Burton, Dennis R. and Connors, Mark and Ho, David D. and Mascola, John R. and Nussenzweig, Michel C. and others},
title = {Potential of conventional & bispecific broadly neutralizing antibodies for prevention of HIV-1 subtype A, C & D infections},
annote = {There is great interest in passive transfer of broadly neutralizing antibodies (bnAbs) and engineered bispecific antibodies (Abs) for prevention of HIV-1 infections due to their in vitro neutralization breadth and potency against global isolates and long in vivo half-lives. We compared the potential of eight bnAbs and two bispecific Abs currently under clinical development, and their 2 Ab combinations, to prevent infection by dominant HIV-1 subtypes in sub-Saharan Africa. Using in vitro neutralization data for Abs against 25 subtype A, 100 C, and 20 D pseudoviruses, we modeled neutralization by single Abs and 2 Ab combinations assuming realistic target concentrations of 10μg/ml total for bnAbs and combinations, and 5μg/ml for bispecifics. We used IC80 breadth-potency, completeness of neutralization, and simultaneous coverage by both Abs in the combination as metrics to characterize prevention potential. Additionally, we predicted in vivo protection by Abs and combinations by modeling protection as a function of in vitro neutralization based on data from a macaque simian-human immunodeficiency virus (SHIV) challenge study. Our model suggests that nearly complete neutralization of a given virus is needed for in vivo protection (~98% neutralization for 50% relative protection). Using the above metrics, we found that bnAb combinations should outperform single bnAbs, as expected; however, different combinations are optimal for different subtypes. Remarkably, a single bispecific 10E8-iMAb, which targets HIV Env and host-cell CD4, outperformed all combinations of two conventional bnAbs, with 95–97% predicted relative protection across subtypes. Combinations that included 10E8-iMAb substantially improved protection over use of 10E8-iMAb alone. Our results highlight the promise of 10E8-iMAb and its combinations to prevent HIV-1 infections in sub-Saharan Africa.},
doi = {10.1371/journal.ppat.1006860},
url = {https://www.osti.gov/biblio/1627916},
journal = {PLoS Pathogens},
issn = {ISSN 1553-7374},
number = {3},
volume = {14},
place = {United States},
publisher = {Public Library of Science},
year = {2018},
month = {03}}