Engineering Decavalent, Sperm-Binding Laminin-IgG Hybrid Antibodies for Potent Non-Hormonal Contraception

Nearly half of pregnancies globally are unintended, reflecting the current unmet need in safe, effective non-hormonal contraception. While anti-sperm IgM is responsible for infertility in many women, stability and bioprocessing challenges with IgM make them ill-suited for non-hormonal contraception. Similarly, IgG lacks sufficient sperm agglutination potencies. To overcome these shortcomings, a novel, multivalent mAb platform is developed, based on fusing the Laminin 511 heterotrimerization domains to Fabs and IgG1-Fc, allowing for tuning of Fab valency (from 2-12) with molecular specificity. 'LamH10', the most potent mAb among the panel of polyvalent antibodies against CD52g on human sperm, comprises 10 Fabs per molecule, and achieves nanomolar potencies at physiological temperatures and retains stability in the acidic environment of human cervicovaginal mucus. In sheep, LamH10 reduced progressively motile sperm in the vagina by >99% within 2 min at just 33 µg per sheep. LamH10 utilizes the same conventional bioprocessing as IgGs, and can be formulated into rapidly dissolving tablets for on-demand contraception, achieving 100% sperm agglutination within minutes of vaginal dosing. The laminin-IgG hybrid platform not only forms the basis of the most potent biologic for nonhormonal contraception to date, but also represents a promising platform for multivalent mAbs for other applications.