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...
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| creator | Mausser, Emilie Nador, Ellena Politch, Joseph A Pauly, Michael R Marathe, Jai G Moench, Thomas R Zeitlin, Larry Whaley, Kevin J Anderson, Deborah J |
| 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. |
| doi_str_mv | 10.1371/journal.pone.0282147 |
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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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0282147</identifier><identifier>PMID: 36996137</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adaptive immunity ; Agglutination ; Antibodies ; Antibodies, Monoclonal ; Antibody-Dependent Cell Cytotoxicity ; Antigen presentation ; Antigens ; Assaying ; Biology and Life Sciences ; Birth control ; Cervix ; Clinical trials ; Contraception ; Contraceptive Agents ; Contraceptives ; Cytotoxicity ; Engineering and Technology ; Fab ; FDA approval ; Female ; Health aspects ; Herpes viruses ; HIV ; Human immunodeficiency virus ; Humans ; Immobilization ; Infertility ; Inflammation ; Male ; Medicine and Health Sciences ; Monoclonal antibodies ; Motility ; Mucus ; Mutation ; Ovulation ; Pathogens ; Phagocytosis ; Pregnancy ; Reproductive system ; Semen ; Sperm ; Sperm Agglutination - genetics ; Toxicity ; Trapping ; Vagina ; Womens health</subject><ispartof>PloS one, 2023-03, Vol.18 (3), p.e0282147-e0282147</ispartof><rights>Copyright: © 2023 Mausser et al. 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This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c594t-b9f047a79aac698783ce5762ec7b2edf6f2be9661c1a2f87d3d44f7b734ece1b3</citedby><cites>FETCH-LOGICAL-c594t-b9f047a79aac698783ce5762ec7b2edf6f2be9661c1a2f87d3d44f7b734ece1b3</cites><orcidid>0000-0001-5920-8808 ; 0000-0002-7022-0135</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10062632/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10062632/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36996137$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mausser, Emilie</creatorcontrib><creatorcontrib>Nador, Ellena</creatorcontrib><creatorcontrib>Politch, Joseph A</creatorcontrib><creatorcontrib>Pauly, Michael R</creatorcontrib><creatorcontrib>Marathe, Jai G</creatorcontrib><creatorcontrib>Moench, Thomas R</creatorcontrib><creatorcontrib>Zeitlin, Larry</creatorcontrib><creatorcontrib>Whaley, Kevin J</creatorcontrib><creatorcontrib>Anderson, Deborah J</creatorcontrib><title>LALAPG variant of the Human Contraception Antibody (HCA) reduces Fc-mediated effector functions while maintaining sperm agglutination activity</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>High rates of unintended pregnancies worldwide indicate a need for more accessible and acceptable methods of contraception. 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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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>36996137</pmid><doi>10.1371/journal.pone.0282147</doi><orcidid>https://orcid.org/0000-0001-5920-8808</orcidid><orcidid>https://orcid.org/0000-0002-7022-0135</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | PloS one, 2023-03, Vol.18 (3), p.e0282147-e0282147 |
| issn | 1932-6203 1932-6203 |
| language | eng |
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| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Adaptive immunity Agglutination Antibodies Antibodies, Monoclonal Antibody-Dependent Cell Cytotoxicity Antigen presentation Antigens Assaying Biology and Life Sciences Birth control Cervix Clinical trials Contraception Contraceptive Agents Contraceptives Cytotoxicity Engineering and Technology Fab FDA approval Female Health aspects Herpes viruses HIV Human immunodeficiency virus Humans Immobilization Infertility Inflammation Male Medicine and Health Sciences Monoclonal antibodies Motility Mucus Mutation Ovulation Pathogens Phagocytosis Pregnancy Reproductive system Semen Sperm Sperm Agglutination - genetics Toxicity Trapping Vagina Womens health |
| title | LALAPG variant of the Human Contraception Antibody (HCA) reduces Fc-mediated effector functions while maintaining sperm agglutination activity |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-06T20%3A00%3A27IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=LALAPG%20variant%20of%20the%20Human%20Contraception%20Antibody%20(HCA)%20reduces%20Fc-mediated%20effector%20functions%20while%20maintaining%20sperm%20agglutination%20activity&rft.jtitle=PloS%20one&rft.au=Mausser,%20Emilie&rft.date=2023-03-30&rft.volume=18&rft.issue=3&rft.spage=e0282147&rft.epage=e0282147&rft.pages=e0282147-e0282147&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0282147&rft_dat=%3Cgale_plos_%3EA743645954%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2792881983&rft_id=info:pmid/36996137&rft_galeid=A743645954&rft_doaj_id=oai_doaj_org_article_5a9999709243450cb529b912f0f767f4&rfr_iscdi=true |