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LALAPG variant of the Human Contraception Antibody (HCA) reduces Fc-mediated effector functions while maintaining sperm agglutination activity

High rates of unintended pregnancies worldwide indicate a need for more accessible and acceptable methods of contraception. We have developed a monoclonal antibody, the Human Contraception Antibody (HCA), for use by women in vaginal films and rings for contraception. The divalent F(ab’)2 region of H...

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Autores principales: Mausser, Emilie, Nador, Ellena, Politch, Joseph A., Pauly, Michael R., Marathe, Jai G., Moench, Thomas R., Zeitlin, Larry, Whaley, Kevin J., Anderson, Deborah J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10062632/
https://www.ncbi.nlm.nih.gov/pubmed/36996137
http://dx.doi.org/10.1371/journal.pone.0282147
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author Mausser, Emilie
Nador, Ellena
Politch, Joseph A.
Pauly, Michael R.
Marathe, Jai G.
Moench, Thomas R.
Zeitlin, Larry
Whaley, Kevin J.
Anderson, Deborah J.
author_facet Mausser, Emilie
Nador, Ellena
Politch, Joseph A.
Pauly, Michael R.
Marathe, Jai G.
Moench, Thomas R.
Zeitlin, Larry
Whaley, Kevin J.
Anderson, Deborah J.
author_sort Mausser, Emilie
collection PubMed
description High rates of unintended pregnancies worldwide indicate a need for more accessible and acceptable methods of contraception. We have developed a monoclonal antibody, the Human Contraception Antibody (HCA), for use by women in vaginal films and rings for contraception. The divalent F(ab’)2 region of HCA binds to an abundant male reproductive tract-specific antigen, CD52g, and potently agglutinates sperm. Certain other antibody activities mediated by the Fc region such as mucus trapping, complement-dependent cytotoxicity (CDC) and antibody-dependent cellular phagocytosis (ADCP) could have beneficial or negative effects. The purpose of this study was to document HCA Fc effector functions and determine whether an engineered variant of HCA with a modified Fc region, HCA-LALAPG, retains desirable contraceptive activity while minimizing Fc-mediated effects. Fab and Fc functions were compared between HCA and HCA-LALAPG. Fab activity was assessed using sperm agglutination and modified swim-up ("sperm escape”) assays. Fc functions were assessed by CDC (sperm immobilization), ADCP, and cervical mucus penetration assays. HCA and HCA-LALAPG showed equivalent activity in assays of Fab function. In the assays of Fc function, HCA supported strong CDC, ADCP, and sperm trapping in cervical mucus whereas HCA-LALAPG demonstrated little to no activity. HCA and the HCA-LALAPG variant were both highly effective in the sperm agglutination assays but differed in Fc mediated functions. Use of the HCA-LALAPG variant for contraception in women could reduce antibody-mediated inflammation and antigen presentation but may have reduced contraceptive efficacy due to much weaker sperm trapping in mucus and complement-dependent sperm immobilization activity.
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spelling pubmed-100626322023-03-31 LALAPG variant of the Human Contraception Antibody (HCA) reduces Fc-mediated effector functions while maintaining sperm agglutination activity Mausser, Emilie Nador, Ellena Politch, Joseph A. Pauly, Michael R. Marathe, Jai G. Moench, Thomas R. Zeitlin, Larry Whaley, Kevin J. Anderson, Deborah J. PLoS One Research Article High rates of unintended pregnancies worldwide indicate a need for more accessible and acceptable methods of contraception. We have developed a monoclonal antibody, the Human Contraception Antibody (HCA), for use by women in vaginal films and rings for contraception. The divalent F(ab’)2 region of HCA binds to an abundant male reproductive tract-specific antigen, CD52g, and potently agglutinates sperm. Certain other antibody activities mediated by the Fc region such as mucus trapping, complement-dependent cytotoxicity (CDC) and antibody-dependent cellular phagocytosis (ADCP) could have beneficial or negative effects. The purpose of this study was to document HCA Fc effector functions and determine whether an engineered variant of HCA with a modified Fc region, HCA-LALAPG, retains desirable contraceptive activity while minimizing Fc-mediated effects. Fab and Fc functions were compared between HCA and HCA-LALAPG. Fab activity was assessed using sperm agglutination and modified swim-up ("sperm escape”) assays. Fc functions were assessed by CDC (sperm immobilization), ADCP, and cervical mucus penetration assays. HCA and HCA-LALAPG showed equivalent activity in assays of Fab function. In the assays of Fc function, HCA supported strong CDC, ADCP, and sperm trapping in cervical mucus whereas HCA-LALAPG demonstrated little to no activity. HCA and the HCA-LALAPG variant were both highly effective in the sperm agglutination assays but differed in Fc mediated functions. Use of the HCA-LALAPG variant for contraception in women could reduce antibody-mediated inflammation and antigen presentation but may have reduced contraceptive efficacy due to much weaker sperm trapping in mucus and complement-dependent sperm immobilization activity. Public Library of Science 2023-03-30 /pmc/articles/PMC10062632/ /pubmed/36996137 http://dx.doi.org/10.1371/journal.pone.0282147 Text en © 2023 Mausser et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Mausser, Emilie
Nador, Ellena
Politch, Joseph A.
Pauly, Michael R.
Marathe, Jai G.
Moench, Thomas R.
Zeitlin, Larry
Whaley, Kevin J.
Anderson, Deborah J.
LALAPG variant of the Human Contraception Antibody (HCA) reduces Fc-mediated effector functions while maintaining sperm agglutination activity
title LALAPG variant of the Human Contraception Antibody (HCA) reduces Fc-mediated effector functions while maintaining sperm agglutination activity
title_full LALAPG variant of the Human Contraception Antibody (HCA) reduces Fc-mediated effector functions while maintaining sperm agglutination activity
title_fullStr LALAPG variant of the Human Contraception Antibody (HCA) reduces Fc-mediated effector functions while maintaining sperm agglutination activity
title_full_unstemmed LALAPG variant of the Human Contraception Antibody (HCA) reduces Fc-mediated effector functions while maintaining sperm agglutination activity
title_short LALAPG variant of the Human Contraception Antibody (HCA) reduces Fc-mediated effector functions while maintaining sperm agglutination activity
title_sort lalapg variant of the human contraception antibody (hca) reduces fc-mediated effector functions while maintaining sperm agglutination activity
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10062632/
https://www.ncbi.nlm.nih.gov/pubmed/36996137
http://dx.doi.org/10.1371/journal.pone.0282147
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