Vaginally-delivered fast-dissolving antibody tablets (FDAT) for on-demand non-hormonal contraception and multi-purpose protection

Abstract

There are limited options available for safe and effective non-hormonal contraceptives or methods that block sexually transmitted diseases such as herpes simplex virus (HSV). Direct vaginal delivery of monoclonal antibodies (mAb) represents a promising approach toward both goals, but clinical translation has been limited by the lack of convenient dosage forms that can quickly and stably deliver mAbs without mess. Here, we report the development of fast-dissolving antibody tablets (FDAT) that allow for the complete release of fully functional mAbs within seconds in vaginal fluid simulants, and within two minutes in fresh human cervicovaginal mucus ex vivo. As proof-of-concept, we developed two FDAT formulations: one for HSV8, a potent neutralizing mAb against both HSV Type 1 and 2, and a second for MM008, a unique 10-Fab anti-sperm mAb that induces sperm agglutination and inhibits progressive sperm motility with picomolar potency. In sheep studies, vaginally inserted HSV8-FDAT achieved uniform distribution in different parts of the vagina within minutes, while fully maintaining HSV8 neutralization activity. Similarly, MM008-FDAT completely eliminated all progressively motile sperm within 2 min of human semen instillation. Finally, the FDATs were stable for at least 3 months of storage at room temperature within desiccated water-impermeant foil pouches, and repeated daily application of FDATs for 7 days was safe and well tolerated in sheep. These results underscore the potentials of the FDAT platform for delivery of biologic interventions to reinforce female reproductive health.

Highlights

Fast-dissolving antibody tablet (FDAT) was developed with different antibodies.

FDAT disintegrates in less than 20 s and can be stored (RT) for over 3 months.

MM008-FDAT completely eliminated human motile sperm in sheep vaginal model.

HSV8-FDAT distributed uniformly and retained anti-herpes efficacy in sheep model.

Introduction

Roughly half of global pregnancies are unintended [1,2], underscoring the strong need for effective methods of contraception that meet the diverse needs of hundreds of millions of women. Likewise, there are no effective vaccines or microbicides against the majority of common sexually transmitted infections (STIs), including Herpes Simplex Virus (HSV), chlamydia, and gonorrhea [3]. In both cases, on-demand, fast-acting, safe, effective, and discreet vaginally-active interventions may help address the gap not currently met by behavioral and pharmacologic interventions. Human monoclonal antibodies (mAbs) offer exceptional promise toward these goals, since mAbs combine a long history of safety, anti-viral effectiveness, and unparalleled target specificity [[4], [5], [6], [7], [8], [9]]. Indeed, mAbs can inactivate numerous sexually transmitted pathogens including both HIV [10,11], HSV [12] and gonorrhea [13], and can block transmission [14,15]. Anti-sperm antibodies (ASA) are also the basis of immune infertility, a clinical condition where endogenously produced ASA prevent sperm from reaching the egg by either crosslinking sperm to mucins or by clumping sperm into large aggregates [16,17]. Leveraging that principle, previous works have illustrated the potential contraceptive efficacy of vaginally administered ASA [[18], [19], [20], [21]].

To be effective at inhibiting pathogens or sperm, sufficient amounts of mAbs must be present in the female reproductive tract (FRT) to either bind and neutralize viruses in semen before the viruses can reach target cells in the sub-epithelium, or bind and agglutinate sperm to limit sperm ascension to fertile eggs in the upper tract. To date, nearly all mAb interventions for indications across disease areas have been dosed systemically. However, only a small fraction of systemically administered mAbs actually distribute to the secretions lining the FRT [22], making systemic dosing highly inefficient for addressing targets in the FRT. In contrast, by delivering mAbs directly into the vagina, it is possible to achieve highly protective concentrations of mAb locally in the FRT despite using orders-of-magnitude lower doses compared to systemic administration, and consequently lower costs. Effective prevention of vaginal STI transmission via direct vaginal delivery of mAbs has been repeatedly shown for HSV [15,[23], [24], [25], [26]] as well as other viral STIs such as HIV [11]. Similarly, direct vaginal delivery of anti-sperm mAbs is highly effective at reducing progressively motile sperm, not only in large animal studies [20,27,28] but also in women following unprotected intercourse [19]. Importantly, direct vaginal delivery of mAbs appear to be well-tolerated [19,29], and unlikely to alter the vaginal microbiome.

Due to the diverse lifestyle needs and preferences of women, there is strong market demand for diverse contraceptive formats, ranging from intrauterine devices (IUD) to intravaginal ring (IVR) to implants, patches, injectables, and oral pills. While many women prefer long-lasting contraceptive options that do not require daily reminders, many others, particularly those who are less sexually active, may prefer on-demand interventions. Gels and creams are common on-demand formats due to their relative ease in formulation [30,31]. However, they are also messy, do not achieve uniform distribution, and generally offer only very short duration (~1 h) protection. It is also difficult to maintain the stability of mAbs in liquid products like gels without refrigeration. Vaginal films, which we have worked on in the past [19,32], while affording relatively less messy insertion, pose substantial formulation challenges for mAbs that may limit the scalability of manufacturing, and typically require a wait period to dissolve (15–30 min) that poses a major inconvenience to users, limiting widespread adoption. We were thus motivated to develop a delivery format that allows easy insertion into the vagina without mess, can effectively deliver mAbs within minutes, and is compatible with conventional scalable manufacturing processes.

Based on these design requirements, we began to explore engineering tablets that can be easily inserted into the vagina with or without a vaginal applicator, can disintegrate and release mAbs upon contact with cervicovaginal mucus (CVM), fully preserve mAb activity, and can be readily produced via conventional tableting processes using excipients with a long history of safe use in humans.

We term this dosing format “fast-dissolving Ab tablet” (FDAT™). Although there have been many previous investigations of rapidly disintegrating vaginal tablets and inserts [[33], [34], [35]], their focus has traditionally been on delivery of small molecule antiviral agents or microbicides, and their formulation was therefore not optimized for antibodies. Many also investigated only after at least 30 min [33,35]. To illustrate the robustness and versatility of our FDAT, we report here in vitro and large animal studies of FDAT formulations of two mAbs, the “HSV8” mAb that possesses broad neutralizing activity against both HSV-1 and HSV-2 [29,36], and a highly multivalent anti-sperm mAb “MM008” that agglutinates sperm with picomolar affinity [27]. Our results underscore FDATs as a promising, safe, and robust delivery format that potentially provides instant on-demand protection against various sexually transmitted diseases as well as non-hormonal immunocontraception.

Keiichiro Kushiro, Scott Hammers, Yong Zhu, Haley Flowers, Lauren Dawson, Alysha Panjwani, Alison Schaefer, David Quan, Katherine Gibb, Morgan McSweeney, Richard Cone, Thomas Moench, Kathleen Vincent, Samuel K. Lai,
Vaginally-delivered fast-dissolving antibody tablets (FDAT) for on-demand non-hormonal contraception and multi-purpose protection, Journal of Controlled Release, 2025, 113662, ISSN 0168-3659, https://doi.org/10.1016/j.jconrel.2025.113662.

excipients formulation