Non-hormonal contraception based on vaginal delivery of multimeric sperm-binding antibodies

Project SummaryThere is a critical need for improved contraceptive methods in the U Sand worldwideNearly half of all pregnancies in the U Sare unintendedNot surprisinglythe majority of unintended pregnancies occur in women who are non users of contraceptionAlthough there are diverse reasons for non usemany women have a strong aversion to using exogenous hormonesdue to both real and perceived side effectsWe believe that contraceptive satisfaction and use would be substantially increased by the availability of a non hormonaluser controlled contraceptive method that does not require coitally timed actionsnor daily interventionWe believe we can create such a non hormonal contraceptive method by directly delivering to the vaginavia intravaginal ringIVRsperm binding antibodyAbthat agglutinates and traps sperm in mucusthereby preventing sperm from swimming through mucus and reaching the eggAlthough validated in animal models in thes andsthe concept of using Ab as a contraceptive was not yet practical due to high costs of Ab productionformulation hurdles associated with passive immunizationas well as the variability in the intensityand uncertain reversibilityof Ab response induced by active contraceptive vaccinesGiven the remarkable advances in bioprocessing that have greatly reduced the costs of Ab manufacturingwe believe the time is now ripe to develop a non hormonal contraceptive based on sustained passive immunization of the vagina with AbOur approach is based on a well characterized and validated antigen target present on human spermand we have a fully human monoclonal Ab that binds this antigen in allsemen samples testedwe term this IgG mAb human contraceptive antibodyHCAWe have further enhanced the sperm agglutination potency of HCA by engineering a novel multimeric construct comprised of a total of six Fab domainsi eadditional Fabs linked to the parent IgG moleculeWe term this construct MMBy incorporating multiple Fab domains while preserving Fcwe substantially improved its agglutination speed and potency while retaining the stability as well as ease of commercial manufacturing and purification of the parent IgGOur goal in this SBIR is to validate the efficacy of MMin vivoSince MMlike its parent HCAonly binds to human spermthis precludes direct evaluation of contraceptive efficacy in animalsInsteadin this Phase I SBIR applicationwe will scale up the production of MMour multimeric HCA constructAimand assess potential contraceptive efficacy by evaluating progressive motility of human sperm in the sheep vaginaAimwhich is anatomically similar to that of humansMMwill be vaginally deliveredfollowed by human semen and brief episode of simulated intercourseSperm motility in the vaginal secretions will then be assesedIf successfulour proposed work will strongly support development of an IVR that could provide sustained release of MMin a Phase II SBIR proposalSuch a non hormonal contraceptive IVR could address a major unmet need in the marketplace Project Narrative In the U Snearly half of all pregnancies are unintendedwhich represents a cost burden of over $B to the federal and state governmentHerewe will evaluate a novel antibody construct with enhanced sperm blocking potency in human genital secretions and in the sheep vaginal modelSuccessful completion of this project will enable us to begin development of an intravaginal ring providing sustained release of a novel antibody for month long non hormonal contraception