In vivo dose finding for an antibody based nonhormonal contraceptive intravaginal ring

SummaryNearly half of all pregnancies in the U.S. are unintended, and most occur in women who are not using contraceptives. There are diverse reasons for not using contraceptives; one common reason is that many women have a strong aversion to using exogenous hormones due to real and perceived side effects. It is likely that contraceptive use and satisfaction would substantially increase if there were a non-hormonal, user- controlled contraceptive method that does not require coitally-timed actions nor daily dosing. Such product does not currently exist. We believe we can create such a non-hormonal contraceptive based on an intravaginal ring (IVR) releasing an anti-sperm monoclonal antibody (mAb) that agglutinates and traps sperm in mucus, thereby preventing sperm from reaching the egg. Topical passive immunization based on vaginal delivery of anti-sperm Ab was validated in animal models in the 80andapos;s-90andapos;s, and directly overcomes the variable intensity and uncertain reversibility of contraceptive vaccines. However, this strategy was not practical until recently due to the high costs of mAb production, and modest agglutination potencies of IgG. Given the remarkable advances in bioprocessing that have greatly reduced the manufacturing costs of mAb, we believe the time is now ripe to develop an IVR for sustained passive immunization of the vagina with a potent anti-sperm mAb. We are targeting a well characterized and validated antigen target present on human sperm, and we have a fully human mAb that binds this antigen and agglutinates within seconds all human sperm, and does so in over 100 semen samples from diverse semen donors. We have further increased the sperm-agglutination potency andgt;50-fold by engineering a novel high-valency mAb construct comprised of ten Fab domains (i.e. 8 additional Fabs linked to the parent IgG molecule); we termed this construct MM008. The greatly increased potency is expected to directly translate to markedly-reduced dose and costs, supporting a commercially viable product. Indeed, MM008 reduced progressively motile sperm by 99.9% in the sheep vagina in 2 mins at a dose of just 33 ug per sheep. We have enhanced the safety profile by incorporating Fc mutations that reduce binding to FcgR, mitigating the likelihood of developing immunity against sperm. MM008 possess comparable thermal stability and production and purification yield as IgG. Based on these promising attributes, in Aim 1, we will produce MM008 and formulate capsule-IVRs offering sustained release of MM008 with different release rates for at least 25 days, in support of the dose- finding studies. In Aim 2, we will evaluate the pharmacokinetics, efficacy and safety of different MM008- IVRs to determine if we can sustain contraceptive concentrations in the sheep vagina, which is anatomically similar to the human vagina, for at least 25 days. If successful, the work will strongly support further preclinical and clinical evaluation of our non-hormonal contraceptive IVR that could address a significant unmet need in the marketplace, and lay the foundation for future multifuntional IVRs that also protects against STIs.Narrative Statement In the U.S., nearly half of all pregnancies are unintended, incurring a cost burden of over $20B to the federal and state governments each year. Here, we will develop our capsule-intravaginal ring (IVR) technology for sustained release of an engineered sperm-binding antibody for non-hormonal contraception, evaluate its potency in human genital secretions and in the sheep vagina, and engage in further preclinical development in preparation for eventual clinical evaluation. Successful completion of this project will enable us to initiate GMP manufacturing, GLP tox studies and clinical development of a non-hormonal contraceptive IVR.