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Multimechanistic Monoclonal Antibodies (MAbs) Targeting Staphylococcus aureus Alpha-Toxin and Clumping Factor A: Activity and Efficacy Comparisons of a MAb Combination and an Engineered Bispecific Antibody Approach

Secreted alpha-toxin and surface-localized clumping factor A (ClfA) are key virulence determinants in Staphylococcus aureus bloodstream infections. We previously demonstrated that prophylaxis with a multimechanistic monoclonal antibody (MAb) combination against alpha-toxin (MEDI4893*) and ClfA (11H1...

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Autores principales: Tkaczyk, C., Kasturirangan, S., Minola, A., Jones-Nelson, O., Gunter, V., Shi, Y. Y., Rosenthal, K., Aleti, V., Semenova, E., Warrener, P., Tabor, D., Stover, C. K., Corti, D., Rainey, G., Sellman, B. R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5527613/
https://www.ncbi.nlm.nih.gov/pubmed/28584141
http://dx.doi.org/10.1128/AAC.00629-17
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author Tkaczyk, C.
Kasturirangan, S.
Minola, A.
Jones-Nelson, O.
Gunter, V.
Shi, Y. Y.
Rosenthal, K.
Aleti, V.
Semenova, E.
Warrener, P.
Tabor, D.
Stover, C. K.
Corti, D.
Rainey, G.
Sellman, B. R.
author_facet Tkaczyk, C.
Kasturirangan, S.
Minola, A.
Jones-Nelson, O.
Gunter, V.
Shi, Y. Y.
Rosenthal, K.
Aleti, V.
Semenova, E.
Warrener, P.
Tabor, D.
Stover, C. K.
Corti, D.
Rainey, G.
Sellman, B. R.
author_sort Tkaczyk, C.
collection PubMed
description Secreted alpha-toxin and surface-localized clumping factor A (ClfA) are key virulence determinants in Staphylococcus aureus bloodstream infections. We previously demonstrated that prophylaxis with a multimechanistic monoclonal antibody (MAb) combination against alpha-toxin (MEDI4893*) and ClfA (11H10) provided greater strain coverage and improved efficacy in an S. aureus lethal bacteremia model. Subsequently, 11H10 was found to exhibit reduced affinity and impaired inhibition of fibrinogen binding to ClfA002 expressed by members of a predominant hospital-associated methicillin-resistant S. aureus (MRSA) clone, ST5. Consequently, we identified another anti-ClfA MAb (SAR114) from human tonsillar B cells with >100-fold increased affinity for three prominent ClfA variants, including ClfA002, and potent inhibition of bacterial agglutination by 112 diverse clinical isolates. We next constructed bispecific Abs (BiSAbs) comprised of 11H10 or SAR114 as IgG scaffolds and grafted anti-alpha-toxin (MEDI4893*) single-chain variable fragment to the amino or carboxy terminus of the anti-ClfA heavy chains. Although the BiSAbs exhibited in vitro potencies similar to those of the parental MAbs, only 11H10-BiSAb, but not SAR114-BiSAb, showed protective activity in murine infection models comparable to the respective MAb combination. In vivo activity with SAR114-BiSAb was observed in infection models with S. aureus lacking ClfA. Our data suggest that high-affinity binding to ClfA sequesters the SAR114-BiSAb to the bacterial surface, thereby reducing both alpha-toxin neutralization and protection in vivo. These results indicate that a MAb combination targeting ClfA and alpha-toxin is more promising for future development than the corresponding BiSAb.
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spelling pubmed-55276132017-08-08 Multimechanistic Monoclonal Antibodies (MAbs) Targeting Staphylococcus aureus Alpha-Toxin and Clumping Factor A: Activity and Efficacy Comparisons of a MAb Combination and an Engineered Bispecific Antibody Approach Tkaczyk, C. Kasturirangan, S. Minola, A. Jones-Nelson, O. Gunter, V. Shi, Y. Y. Rosenthal, K. Aleti, V. Semenova, E. Warrener, P. Tabor, D. Stover, C. K. Corti, D. Rainey, G. Sellman, B. R. Antimicrob Agents Chemother Experimental Therapeutics Secreted alpha-toxin and surface-localized clumping factor A (ClfA) are key virulence determinants in Staphylococcus aureus bloodstream infections. We previously demonstrated that prophylaxis with a multimechanistic monoclonal antibody (MAb) combination against alpha-toxin (MEDI4893*) and ClfA (11H10) provided greater strain coverage and improved efficacy in an S. aureus lethal bacteremia model. Subsequently, 11H10 was found to exhibit reduced affinity and impaired inhibition of fibrinogen binding to ClfA002 expressed by members of a predominant hospital-associated methicillin-resistant S. aureus (MRSA) clone, ST5. Consequently, we identified another anti-ClfA MAb (SAR114) from human tonsillar B cells with >100-fold increased affinity for three prominent ClfA variants, including ClfA002, and potent inhibition of bacterial agglutination by 112 diverse clinical isolates. We next constructed bispecific Abs (BiSAbs) comprised of 11H10 or SAR114 as IgG scaffolds and grafted anti-alpha-toxin (MEDI4893*) single-chain variable fragment to the amino or carboxy terminus of the anti-ClfA heavy chains. Although the BiSAbs exhibited in vitro potencies similar to those of the parental MAbs, only 11H10-BiSAb, but not SAR114-BiSAb, showed protective activity in murine infection models comparable to the respective MAb combination. In vivo activity with SAR114-BiSAb was observed in infection models with S. aureus lacking ClfA. Our data suggest that high-affinity binding to ClfA sequesters the SAR114-BiSAb to the bacterial surface, thereby reducing both alpha-toxin neutralization and protection in vivo. These results indicate that a MAb combination targeting ClfA and alpha-toxin is more promising for future development than the corresponding BiSAb. American Society for Microbiology 2017-07-25 /pmc/articles/PMC5527613/ /pubmed/28584141 http://dx.doi.org/10.1128/AAC.00629-17 Text en Copyright © 2017 Tkaczyk et al. https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Experimental Therapeutics
Tkaczyk, C.
Kasturirangan, S.
Minola, A.
Jones-Nelson, O.
Gunter, V.
Shi, Y. Y.
Rosenthal, K.
Aleti, V.
Semenova, E.
Warrener, P.
Tabor, D.
Stover, C. K.
Corti, D.
Rainey, G.
Sellman, B. R.
Multimechanistic Monoclonal Antibodies (MAbs) Targeting Staphylococcus aureus Alpha-Toxin and Clumping Factor A: Activity and Efficacy Comparisons of a MAb Combination and an Engineered Bispecific Antibody Approach
title Multimechanistic Monoclonal Antibodies (MAbs) Targeting Staphylococcus aureus Alpha-Toxin and Clumping Factor A: Activity and Efficacy Comparisons of a MAb Combination and an Engineered Bispecific Antibody Approach
title_full Multimechanistic Monoclonal Antibodies (MAbs) Targeting Staphylococcus aureus Alpha-Toxin and Clumping Factor A: Activity and Efficacy Comparisons of a MAb Combination and an Engineered Bispecific Antibody Approach
title_fullStr Multimechanistic Monoclonal Antibodies (MAbs) Targeting Staphylococcus aureus Alpha-Toxin and Clumping Factor A: Activity and Efficacy Comparisons of a MAb Combination and an Engineered Bispecific Antibody Approach
title_full_unstemmed Multimechanistic Monoclonal Antibodies (MAbs) Targeting Staphylococcus aureus Alpha-Toxin and Clumping Factor A: Activity and Efficacy Comparisons of a MAb Combination and an Engineered Bispecific Antibody Approach
title_short Multimechanistic Monoclonal Antibodies (MAbs) Targeting Staphylococcus aureus Alpha-Toxin and Clumping Factor A: Activity and Efficacy Comparisons of a MAb Combination and an Engineered Bispecific Antibody Approach
title_sort multimechanistic monoclonal antibodies (mabs) targeting staphylococcus aureus alpha-toxin and clumping factor a: activity and efficacy comparisons of a mab combination and an engineered bispecific antibody approach
topic Experimental Therapeutics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5527613/
https://www.ncbi.nlm.nih.gov/pubmed/28584141
http://dx.doi.org/10.1128/AAC.00629-17
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