Safety, acceptability, and pharmacokinetics of a monoclonal antibody-based vaginal multipurpose prevention film (MB66): A Phase I randomized trial

Abstract

Background MB66 film is a multipurpose prevention technology (MPT) product with monoclonal antibodies (mAbs) against HIV-1 (VRC01-N) and HSV-1 and 2 (HSV8-N). The mAbs were produced by transient expression in Nicotiana benthamiana (N). We conducted a Phase I clinical trial to assess the safety, pharmacokinetics (PK), and ex vivo efficacy of single and repeated doses of MB66 when used intravaginally. Methods and findings The clinical trial enrolled healthy reproductive-aged, sexually abstinent women. In Segment A, 9 women received a single MB66 film which was inserted into the vaginal posterior fornix by a clinician. In Segment B, 29 women were randomly assigned to MB66 (Active) or Placebo film groups and were instructed to insert 1 film vaginally for 7 consecutive days. Visits and clinical sampling occurred predose and at various time points after single and repeated film doses. The primary endpoint was number of adverse events (AEs) Grade 2 or higher related to product use. Secondary endpoints included film dissolution rate, Nugent score (a Gram stain scoring system to diagnose bacterial vaginosis), vaginal pH, post-use survey results, cytokine concentrations in cervicovaginal lavage (CVL) specimens (assessed by Luminex assay), mAb concentrations in vaginal fluid collected from 4 sites (assessed by ELISA), and HIV and HSV neutralization activity of CVL samples ex vivo (assessed by TZM-bl and plaque reduction assay, respectively). The product was generally safe and well tolerated, with no serious AEs recorded in either segment. The AEs in this study were primarily genitourinary in nature with the most commonly reported AE being asymptomatic microscopic hematuria. There were no differences in vaginal pH or Nugent scores or significant increases in levels of proinflammatory cytokines for up to 7 days after film insertion in either segment or between Active and Placebo groups. Acceptability and willingness to use the product were judged to be high by post-use surveys. Concentrations of VRC01-N and HSV8-N in vaginal secretions were assessed over time to generate pharmacokinetic curves. Antibody levels peaked 1 hour postdosing with Active film (median: 35 μg/mL) and remained significantly elevated at 24 hours post first and seventh film (median: 1.8 μg/mL). Correcting for sample dilution (1:20), VRC01-N concentrations ranged from 36 to 700 μg/mL at the 24-hour time point, greater than 100-fold the IC50 for VRC01 (0.32 μg/mL); HSV8-N concentrations ranged from 80 to 601 μg/mL, well above the IC50 of 0.1 μg/m. CVL samples collected 24 hours after MB66 insertion significantly neutralized both HIV-1 and HSV-2 ex vivo. Study limitations include the small size of the study cohort, and the fact that no samples were collected between 24 hours and 7 days for pharmacokinetic evaluation. Conclusions Single and repeated intravaginal applications of MB66 film were safe, well tolerated, and acceptable. Concentrations and ex vivo bioactivity of both mAbs in vaginal secretions were significantly elevated and thus could provide protection for at least 24 hours postdose. However, further research is needed to evaluate the efficacy of MB66 film in women at risk for HIV and HSV infection. Additional antibodies could be added to this platform to provide protection against other sexually transmitted infections (STIs) and contraception. Trial registration ClinicalTrials.gov NCT02579083.

Production and characterization of a human antisperm monoclonal antibody against CD52g for topical contraception in women

“…Our team recently completed a Phase 1 clinical trial in women that tested the safety, pharmacokinetics, and ex vivo efficacy of a topically-applied vaginal film, MB66, containing IgG 1 mAbs against HIV-1 and HSV-2 that had been produced in Nicotiana. Daily vaginal application of MB66 film for seven days did not cause notable adverse events, and the concentration of active mAbs present in vaginal secretions 24 h after film application was sufficient to prevent HIV-1 and HSV-2 infection ex vivo (concentration range: 36À700 mg/ml) [12]. The HCA experiments in the present study were conducted using antibody concentrations within the range of mAbs present in vaginal secretions 24 h post-film application.…”

“…The Nicotiana platform is fast and versatile, and produces a very clean antibody product free from potential contamination with mammalian pathogens. The trial demonstrated that mAbs made in Nicotiana were safe, and that effective concentrations of neutralizing antibodies could be detected in vaginal secretions for at least 24 h after film administration [12]. This study provides proof-of-concept that combinations of pathogen-specific mAbs administered intravaginally could safely protect women against a variety of STIs.…”

“…1 for study overview). Antibodies were tested at concentrations ranging from 1 mg to 100 mg/ml, which were within the range of mAb concentrations detected in cervicovaginal secretions of women 4À24 h after application of a mAb-containing vaginal film [12]. Three functional tests were performed: the agglutination kinetic assay which measured sperm agglutination efficiency in vitro, the sperm escape assay which determined the percentage of progressively motile sperm that escaped agglutination after mAb treatment, and the immobilization test that assessed sperm immobilization in the presence of complement.…”

“…HCA was incubated in cervicovaginal lavage (CVL) supernatant (1:1 vol) for up to 24 h at 37°C. CVLs from healthy women without bacterial vaginosis (BV À ; i.e., Nugent scores between 0À3) and CVLs from women with bacterial vaginosis (BV + ; Nugent scores above 8) were obtained as previously described [12]. Pooled samples from three women with each condition were used for this experiment.…”

Soluble adenylyl cyclase inhibition prevents human sperm functions essential for fertilization

“…Efforts aimed primarily at developing women-controlled products against sexual HIV-1 infection have fueled a rapid growth of intravaginal drug delivery programs, mostly involving antiretroviral drugs 31 . A number of vaginal film and intravaginal ring products are in development for HIV-1 prevention, with some candidates advancing to early-stage clinical trials [32][33][34][35][36][37] . We envision that these antiretroviral agents could be coupled with sAC inhibitors, so that one product can prevent pregnancies and sexually transmitted diseases at the same time.…”