Potential of conventional & bispecific broadly neutralizing antibodies for prevention of HIV-1 subtype A, C & D infections

Autor: 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
Jazyk: angličtina
Rok vydání: 2018
Předmět:
RNA viruses
Physiology
HIV Infections
Monkeys
HIV Antibodies
Pathology and Laboratory Medicine
Protein Engineering
Biochemistry
Geographical Locations
Antibody Engineering
Immunodeficiency Viruses
Immune Physiology
Antibodies
Bispecific
Medicine and Health Sciences
Macromolecular Engineering
lcsh:QH301-705.5
Mammals
Immune System Proteins
env Gene Products
Human Immunodeficiency Virus
Eukaryota
Medical Microbiology
Viral Pathogens
Vertebrates
Viruses
Engineering and Technology
Synthetic Biology
Pathogens
Macaque
Research Article
Biotechnology
lcsh:Immunologic diseases. Allergy
Primates
Immunology
Bioengineering
Microbiology
Antibodies
Neutralization Tests
Virology
Old World monkeys
Retroviruses
Animals
Humans
Microbial Pathogens
Lentivirus
Organisms
Biology and Life Sciences
Proteins
HIV
Antibodies
Neutralizing
lcsh:Biology (General)
Synthetic Bioengineering
Amniotes
People and Places
Africa
HIV-1
lcsh:RC581-607
Viral Transmission and Infection
Zdroj: PLoS Pathogens
PLoS Pathogens, Vol 14, Iss 3, p e1006860 (2018)
ISSN: 1553-7374
1553-7366
Popis: 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.
Author summary In the absence of effective vaccines, the use of passive transfer of conventional and engineered antibodies to prevent HIV-1 infection is being considered. This approach is promising because of broad efficacy and long in vivo lifetimes of antibodies. We analyzed the potential of leading antibody candidates, and combinations of two antibodies, to prevent HIV-1 infections in sub-Saharan Africa, the hardest-hit region in the world. We used in vitro antibody neutralization data to predict neutralization metrics that might be relevant for in vivo success, and modeled antibody-based in vivo protection as a function of in vitro neutralization using data from a macaque study. By systematic comparison, we found, as expected, that combinations of two conventional antibodies significantly outperformed individual conventional antibodies, even with same total concentration. However, different antibody combinations were optimal for the different HIV-1 subtypes analyzed. The engineered bispecific 10E8-iMAb, which targets epitopes on HIV Env and host-cell CD4, was predicted to reduce infection probability by 20–30 fold, and outperformed all individual antibodies and combinations of two conventional antibodies. This performance was further improved by combining 10E8-iMAb with other antibodies. Thus, our results suggest that passive transfer of current antibody candidates, especially 10E8-iMAb and its combinations, might be successful in prevention of HIV-1 infections in sub-Saharan Africa.
Databáze: OpenAIRE
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