title: MABGEL 1: first phase 1 trial of the anti-HIV-1 monoclonal antibodies 2F5, 4E10 and 2G12 as a vaginal microbicide.
abstract: BACKGROUND
  Monoclonal antibodies (mAbs) which potently neutralize a broad range of HIV isolates are potential microbicide candidates. To date, topical application of mAbs in humans and their stability in vaginal secretions has not been studied.
  
  
  OBJECTIVE
  To assess the pharmacokinetics and safety of the mAbs 2F5, 4E10 and 2G12 when applied vaginally in women.
  
  
  METHODS
  A randomized, double-blind, placebo-controlled phase 1 trial.
  
  
  METHODS
  Twenty-eight healthy, sexually abstinent women administered 2.5 g of gel daily for 12 days containing either 10 or 20 mg/g of each mAb (MABGEL) or placebo. Main clinical evaluations and sampling occurred at baseline, 1, 8, and 24 hours post-1st dose and 12 and 36 hours post-12th dose.
  
  
  RESULTS
  After adjustment for dilution factors, median levels of 2F5, 4E10 and 2G12 in vaginal secretions at 1 hour post high-dose MABGEL were 7.74, 5.28 and 7.48 mg/ml respectively. Levels of 2F5 and 4E10 declined exponentially thereafter with similar estimated half-lives (4.6 and 4.3 hours). In contrast, 2G12 levels declined more rapidly in the first 8 hours, with an estimated half-life of 1.4 hours during this period. There was no evidence of systemic absorption. There were no significant differences in local or systemic adverse event rates or vaginal flora changes (by qPCR) between active and placebo gel arms. Whilst at least 1 adverse event was recorded in 96% of participants, 95% were mild and none were serious.
  
  
  CONCLUSIONS
  Vaginal application of 50 mg of each mAb daily was safe over a 12 day period. Median mAb concentrations detected at 8 hours post dose were potentially sufficient to block HIV transmission.2G12 exhibited more rapid elimination from the human vagina than 4E10 and 2F5, likely due to poor stability of 2G12 in acidic human vaginal secretions. Further research is needed to develop mAb-based vaginal microbicides and delivery systems.
  
  
  BACKGROUND
  ISRCTN 64808733 UK CRN Portfolio 6470.
authors.affiliation: Centre for Immunology and Infection, Hull York Medical School, University of York, York, United Kingdom.
authors.forename: Georgina C
authors.initials: GC
authors.lastname: Morris
authors.affiliation: Centre for Immunology and Infection, Hull York Medical School, University of York, York, United Kingdom.
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Wiggins
authors.affiliation: Centre for Immunology and Infection, Hull York Medical School, University of York, York, United Kingdom.
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Woodhall
authors.affiliation: Department of Health Sciences, University of York, York, United Kingdom.
authors.forename: J Martin
authors.initials: JM
authors.lastname: Bland
authors.affiliation: Hull York Medical School Experimental Medicine Unit, York Teaching Hospitals NHS Foundation Trust, York, United Kingdom.
authors.forename: Carol R
authors.initials: CR
authors.lastname: Taylor
authors.affiliation: Institute of Tropical Medicine, Antwerp, Belgium.
authors.forename: Vicky
authors.initials: V
authors.lastname: Jespers
authors.affiliation: Polymun Scientific Immunbiologische Forschung GmbH, Vienna, Austria.
authors.forename: Brigitta A
authors.initials: BA
authors.lastname: Vcelar
authors.affiliation: Centre for Immunology and Infection, Hull York Medical School, University of York, York, United Kingdom.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Lacey
mesh_terms: D000293:Adolescent; D000328:Adult; D000890:Anti-Infective Agents / Q000276:immunology*; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000276:immunology* / Q000493:pharmacokinetics; D000080908:Broadly Neutralizing Antibodies; D002584:Cervix Uteri / Q000276:immunology / Q000382:microbiology; D005260:Female; D006194:Gardnerella vaginalis / Q000502:physiology; D015483:HIV Antibodies / Q000009:adverse effects / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007778:Lactobacillus / Q000502:physiology; D010349:Patient Compliance; D013997:Time Factors; D014621:Vagina / Q000276:immunology* / Q000382:microbiology; D055815:Young Adult
chemical_list: C558560:2F5 monoclonal antibody; C529157:2G12 monoclonal antibody; C558559:4E10 monoclonal antibody; D000890:Anti-Infective Agents; D000911:Antibodies, Monoclonal; D000080908:Broadly Neutralizing Antibodies; D015483:HIV Antibodies