Many women risk unintended pregnancy because of medical contraindications or dissatisfaction with contraceptive methods, including real and perceived side effects associated with the use of exogenous hormones. We pursued direct vaginal delivery of sperm-binding monoclonal antibodies (mAbs) that can limit progressive sperm motility in the female reproductive tract as a strategy for effective nonhormonal contraception. Here, motivated by the greater agglutination potencies of polyvalent immunoglobulins but the bioprocessing ease and stability of immunoglobulin G (IgG), we engineered a panel of sperm-binding IgGs with 6 to 10 antigen-binding fragments (Fabs), isolated from a healthy immune-infertile woman against a unique surface antigen universally present on human sperm. These highly multivalent IgGs (HM-IgGs) were at least 10- to 16-fold more potent and faster at agglutinating sperm than the parent IgG while preserving the crystallizable fragment (Fc) of IgG that mediates trapping of individual spermatozoa in mucus. The increased potencies translated into effective (>99.9%) reduction of progressively motile sperm in the sheep vagina using as little as 33 μg of the 10-Fab HM-IgG. HM-IgGs were produced at comparable yields and had identical thermal stability to the parent IgG, with greater homogeneity. HM-IgGs represent not only promising biologics for nonhormonal contraception but also a promising platform for engineering potent multivalent mAbs for other biomedical applications.

由于医学禁忌症或对避孕方法不满意，包括与使用外源性激素相关的真实和感知副作用，许多女性面临意外怀孕的风险。我们追求直接阴道递送精子结合单克隆抗体 (mAb)，它可以限制女性生殖道中进行性精子运动，作为一种有效的非激素避孕策略。在这里，受多价免疫球蛋白更强的凝集能力以及免疫球蛋白 G (IgG) 的生物加工简便性和稳定性的推动，我们设计了一组精子结合 IgG，其中包含 6 到 10 个抗原结合片段 (Fab)，从健康的免疫系统中分离出来。 - 不孕妇女对抗普遍存在于人类精子上的独特表面抗原。这些高度多价的 IgG (HM-IgG) 在凝集精子方面的效力和速度至少比亲本 IgG 高 10 到 16 倍，同时保留了 IgG 的可结晶片段 (Fc)，后者介导了单个精子在粘液中的捕获。使用低至 33 μg 的 10-Fab HM-IgG，增加的效力转化为有效 (>99.9%) 减少绵羊阴道中逐渐运动的精子。HM-IgG 的产量相当，与亲本 IgG 具有相同的热稳定性，同质性更高。HM-IgG 不仅代表了用于非激素避孕的有前途的生物制剂，而且还是为其他生物医学应用设计有效的多价 mAb 的有前途的平台。