{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T15:24:28Z","timestamp":1792250668260,"version":"4.4.0"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,6,24]],"date-time":"2021-06-24T00:00:00Z","timestamp":1624492800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Cervical cancer caused by human papillomavirus (HPV) infections is the fourth most common cancer in women worldwide. Current prophylactic HPV vaccines have achieved promising success in preventing HPV infection. However, still 570,000 new cases were reported in 2018. The current primary treatment for the patient with cervical cancer is either surgery or chemoradiotherapy. Cervical cancer still lacks standard medical therapy. HPV18 induced cervical cancer has the worst prognosis and high mortality compared to other HPV infections. The development of HPV18 related with cervical malignancy requires the persistent infection of cervical\u2013vaginal epithelium by HPV18 subtype, which can take years to transform the epithelium. This period of repeated infection provides a window for therapeutic intervention. Neutralizing antibodies formulated as topical agents that inhibit HPV18 infection should reduce the chance of cervical malignancy. We previously demonstrated that potent neutralizing anti-sera against HPV18 infection were induced by HPV18 viral like particle (VLP) generated in mammalian cells. We, therefore, isolated two potent neutralizing antibodies, 2A12 and 8H4, from over 3,810 hybridomas prepared from mice immunized with HPV18 VLP. 2A12 and 8H4 exhibited excellent potency, with 50% virus-inhibitory concentrations (IC<jats:sub>50<\/jats:sub>) of 0.4 and 0.9 ng\/ml, respectively. Furthermore, 2A12 and 8H4 recognized distinct and non-overlapping quaternary epitopes and bound specifically with HPV18. Humanized 2A12 (Hu2A12) retained comparable neutralizing activity against HPV18 infection in various acidic pH settings and in hydrogel formulation with IC<jats:sub>50<\/jats:sub> values of 0.04 to 0.77 ng\/ml, indicating that Hu2A12 will be a promising candidate for clinical development as a topical vaginal biopharmaceutical agent against HPV18 infection.<\/jats:p>","DOI":"10.3389\/fimmu.2021.678318","type":"journal-article","created":{"date-parts":[[2021,6,24]],"date-time":"2021-06-24T06:35:29Z","timestamp":1624516529000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Potent Neutralizing Humanized Antibody With Topical Therapeutic Potential Against HPV18-Related Cervical Cancer"],"prefix":"10.3389","volume":"12","author":[{"given":"Bilian","family":"Huang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linjing","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongxia","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haixia","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Doudou","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huanyun","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linlin","family":"Luan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shijie","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Waqas","family":"Nawaz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Hong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xilin","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiwei","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,6,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.30667","article-title":"Cervical Cancer: A Global Health Crisis","volume":"123","author":"Small","year":"2017","journal-title":"Cancer"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2012.06.083","article-title":"The Biology and Life-Cycle of Human Papillomaviruses","volume":"30","author":"Doorbar","year":"2012","journal-title":"Vaccine"},{"key":"B3","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1038\/nrc2050","article-title":"The Natural History of Cervical HPV Infection: Unresolved Issues","volume":"7","author":"Woodman","year":"2007","journal-title":"Nat Rev Cancer"},{"key":"B4","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1016\/j.ygyno.2017.04.004","article-title":"HPV Vaccines -\u00a0A Review of the First Decade","volume":"146","author":"Harper","year":"2017","journal-title":"Gynecologic Oncol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1017\/S0950268815002198","article-title":"Prophylactic HPV Vaccination: Past, Present, and Future","volume":"144","author":"Castle","year":"2016","journal-title":"Epidemiol Infect"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/S2214-109X(19)30482-6","article-title":"Estimates of Incidence and Mortality of Cervical Cancer in 2018: A Worldwide Analysis","volume":"8","author":"Arbyn","year":"2020","journal-title":"Lancet Glob Health"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.02478","article-title":"Advances in Designing and Developing Vaccines, Drugs and Therapeutic Approaches to Counter Human Papilloma Virus","volume":"9","author":"Dadar","year":"2018","journal-title":"Front Immunol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1097\/AOG.0b013e31825bc6e8","article-title":"Treatment of Cervical Intraepithelial Neoplasia With Topical Imiquimod a Randomized Controlled Trial","volume":"120","author":"Grimm","year":"2012","journal-title":"Obstet Gynecol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/S0029-7844(99)00407-X","article-title":"Vaginal 5-Fluorouracil for High-Grade Cervical Dysplasia in Human Immunodeficiency Virus Infection: A Randomized Trial","volume":"94","author":"Maiman","year":"1999","journal-title":"Obstet Gynecol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-9071(200002)60:2<205::AID-JMV16>3.0.CO;2-8","article-title":"Cidofovir, a New Approach for the Treatment of Cervix Intraepithelial Neoplasia Grade III (CIN III)","volume":"60","author":"Snoeck","year":"2000","journal-title":"J Med Virol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"100608","DOI":"10.1016\/j.gore.2020.100608","article-title":"Topical Therapies for the Treatment of Cervical Intraepithelial Neoplasia (CIN) 2\u20133: A Narrative Review","volume":"33","author":"Desravines","year":"2020","journal-title":"Gynecologic Oncol Rep"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2012.05.091","article-title":"Therapy of Human Papillomavirus-Related Disease","volume":"30","author":"Stern","year":"2012","journal-title":"Vaccine"},{"key":"B13","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1038\/nri.2017.148","article-title":"Passive Immunotherapy of Viral Infections: \u2018Super-Antibodies\u2019 Enter the Fray","volume":"18","author":"Walker","year":"2018","journal-title":"Nat Rev Immunol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"1703531","DOI":"10.1080\/19420862.2019.1703531","article-title":"Antibodies to Watch in 2020","volume":"12","author":"Kaplon","year":"2020","journal-title":"MAbs"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.27663","article-title":"Human Papillomavirus Types in Glandular Lesions of the Cervix: A Meta-Analysis of Published Studies","volume":"132","author":"Guan","year":"2013","journal-title":"Int J Cancer"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.25396","article-title":"Human Papillomavirus Type Distribution in 30,848 Invasive Cervical Cancers Worldwide: Variation by Geographical Region, Histological Type and Year of Publication","volume":"128","author":"Li","year":"2011","journal-title":"Int J Cancer"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-020-0673-7","article-title":"Analysis of Ugandan Cervical Carcinomas Identifies Human Papillomavirus Clade-Specific Epigenome and Transcriptome Landscapes","volume":"52","author":"Gagliardi","year":"2020","journal-title":"Nat Genet"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.32038","article-title":"Genetic Variations in Human Papillomavirus and Cervical Cancer Outcomes","volume":"144","author":"Rader","year":"2019","journal-title":"Int J Cancer"},{"key":"B19","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1186\/s13000-018-0727-7","article-title":"Development and Characterization of an HPV18 Detection Kit Using Two Novel HPV18 Type-Specific Monoclonal Antibodies","volume":"13","author":"Zhang","year":"2018","journal-title":"Diagn Pathol"},{"key":"B20","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1093\/abt\/tbz004","article-title":"Induction of Neutralizing Antibodies by Human Papillomavirus Vaccine Generated in Mammalian Cells","volume":"2","author":"Wu","year":"2019","journal-title":"Antibody Ther"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1101\/pdb.prot103184","article-title":"Electro Cell Fusion for Hybridoma Production","volume":"2019","author":"Greenfield","year":"2019","journal-title":"Cold Spring Harb Protoc"},{"key":"B22","doi-asserted-by":"publisher","first-page":"3382","DOI":"10.1038\/srep03382","article-title":"Cell Electrofusion Using Nanosecond Electric Pulses","volume":"3","author":"Rems","year":"2013","journal-title":"Sci Rep"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1385\/1-59259-982-6:445","article-title":"Generation of HPV Pseudovirions Using Transfection and Their Use in Neutralization Assays","volume":"119","author":"Buck","year":"2005","journal-title":"Methods Mol Med"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1128\/CVI.00222-13","article-title":"Human Antibody Neutralizes Severe Fever With Thrombocytopenia Syndrome Virus, an Emerging Hemorrhagic Fever Virus","volume":"20","author":"Guo","year":"2013","journal-title":"Clin Vaccine Immunol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.176.7.4221","article-title":"Complete Sequence Assembly and Characterization of the C57BL\/6 Mouse Ig Heavy Chain V Region","volume":"176","author":"Johnston","year":"2006","journal-title":"J Immunol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1080\/02648725.2013.801235","article-title":"Antibody Humanization Methods -\u00a0A Review and Update","volume":"29","author":"Safdari","year":"2013","journal-title":"Biotechnol Genet Eng Rev"},{"key":"B27","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1089\/mab.2013.0080","article-title":"Antibody Humanization Methods for Development of Therapeutic Applications","volume":"33","author":"Ahmadzadeh","year":"2014","journal-title":"Monoclon Antib Immunodiagn Immunother"},{"key":"B28","doi-asserted-by":"publisher","first-page":"188","DOI":"10.3390\/pharmaceutics10040188","article-title":"Ascorbyl Palmitate Hydrogel for Local, Intestinal Delivery of Macromolecules","volume":"10","author":"Zhai","year":"2018","journal-title":"Pharmaceutics"},{"key":"B29","doi-asserted-by":"publisher","first-page":"127","DOI":"10.3390\/pharmaceutics11030127","article-title":"Evaluation of a Methylcellulose and Hyaluronic Acid Hydrogel as a Vehicle for Rectal Delivery of Biologics","volume":"11","author":"Aprodu","year":"2019","journal-title":"Pharmaceutics"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.actbio.2012.01.028","article-title":"An in Situ Cross-Linking Hybrid Hydrogel for Controlled Release of Proteins","volume":"8","author":"Epstein-Barash","year":"2012","journal-title":"Acta Biomater"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.75.3.1565-1570.2001","article-title":"Human Papillomavirus Infection Requires Cell Surface Heparan Sulfate","volume":"75","author":"Giroglou","year":"2001","journal-title":"J Virol"},{"key":"B32","doi-asserted-by":"publisher","first-page":"7333","DOI":"10.1038\/s41598-019-43849-5","article-title":"Features of the Cervicovaginal Microenvironment Drive Cancer Biomarker Signatures in Patients Across Cervical Carcinogenesis","volume":"9","author":"Laniewski","year":"2019","journal-title":"Sci Rep"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.4161\/hv.27619","article-title":"Correlation Between ELISA and Pseudovirion-Based Neutralisation Assay for Detecting Antibodies Against Human Papillomavirus Acquired by Natural Infection or by Vaccination","volume":"10","author":"Zhao","year":"2014","journal-title":"Hum Vaccines Immunotherapeutics"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(17)31821-4","article-title":"Final Efficacy, Immunogenicity, and Safety Analyses of a Nine-Valent Human Papillomavirus Vaccine in Women Aged 16-26 Years: A Randomised, Double-Blind Trial","volume":"390","author":"Huh","year":"2017","journal-title":"Lancet"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.678318\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,6,24]],"date-time":"2021-06-24T06:35:33Z","timestamp":1624516533000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.678318\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,24]]},"references-count":34,"alternative-id":["10.3389\/fimmu.2021.678318"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.678318","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,24]]},"article-number":"678318"}}