Sustained vaginal delivery of monoclonal antibodies for preventing HIV transmission

Project SummaryDespite immense efforts in behavioral interventions to promote safe sexual practicesvaginal HIV transmission continues to be pandemic worldwideAn HIV specificsafeeffective and discreet vaginal method that does not require daily or sex associated dosing may provide a powerful prevention tool addressing the current gap in behavioral and pharmacological interventionsHuman monoclonal antibodiesmAbdelivered locally to the vagina offer exceptional promise combining safetyefficacy and unparalleled specificityImportantlyby delivering mAb to the vagina rather than systemicallyfar lower doses of mAb are needed to reduce the risks of vaginal HIV transmissionleading to orders of magnitude in cost savingsAdding further to the promise of vaginal applications of mAbthe Lai and Cone Labs recently discovered a novel IgG effector function in mucusIgGs that trap individual pathogens in mucusand have pioneered a technology enhancing the potency of mAb in mucosal secretions based on carefully tuned affinity between IgG Fc and mucinsWe have shown that engineered mAb can consistently trap Herpes viruses in human cervicovaginal mucusCVMacross the menstrual cycle and from women with diverse vaginal microbiotawithfold greater potency than protection by neutralizationTrapping alonewith a non neutralizing mAbdirectly prevented vaginal Herpes transmission in miceIn pilot studieswe also found that anti HIV mAb VRCcan similarly trap HIV in CVMCurrentlythe major hurdle to translating this vaginal immunoprophylaxis strategy for HIV is a method for sustained delivery of mAb at low dosesVaginal microbicide trials have shown that methods that do not require daily or sexassociated dosingsuch as intravaginal ringsIVRare far more likely to maximize user complianceUnfortunatelymost current IVRs are designed to deliver small molecule drugsand are ill suited for delivering mAbparticularly at low release ratesTo address thisMucommune has been developing a unique capsulecontaining IVR system that can provide sustained release of appropropriate doses of mAb for overdayswhile protecting the encapsulated mAb from degradation in the vaginal environmentOur goal here is to design and formulate a capsule IVR that can continuously release into human CVMmg day of two promising broadly neutralizing mAb against HIVVRCand NIn Aimwe will load mAb into capsulesmeasure release kinetics in vaginal simulant bufferand characterize mAb integrity before after loading and after releaseIn Aimwe will incubate mAb loaded capsules in fresh human CVMand measure the HIV neutralization and trapping potency of encapsulated and released mAbSuccessful completion of these studies will lead to a Phase II proposalwith the goal of developing a shelf stable capsule IVR that slowly releases mAb against HIVproviding effective protection against vaginal HIV transmission with convenient once a month applicationBy enabling enhanced mAb function in mucuswe expect Mucommune will help pave the way for mAb based potent protection against a broad array of pathogens at major mucosal surfaces NarrativeAntibodies made by the immune system and secreted into mucus secretions protect all mucosal surfaces against a wide array of pathogensWe are developing a vaginal capsule ring that will provide sustained release of low doses of anti HIV monoclonal antibodies stably into vaginal secretions for at leastdays to block vaginal transmission of HIV AIDS