Multivalent antibodies such as sIgA can crosslink motile entities such as sperm and bacteria, creating agglomerates that are too large to permeate the dense mucin matrix in mucus, a process commonly referred to as immune exclusion. Unfortunately, sIgA remains challenging to produce in large quantities, and easily aggregates, which prevented their use in clinical applications. To develop sIgA-like tetravalent antibodies that are stable and can be easily produced in large quantities, we designed two IgGs possessing 4 identical Fab domains, with the Fabs arranged either in serial or in the diametrically opposite orientation. As a proof-of-concept, we engineered these tetravalent IgG constructs to bind a ubiquitous sperm antigen using a Fab previously isolated from an immune infertile woman. Both constructs possess at least 4-fold greater agglutination potency and induced much more rapid sperm agglutination than the parent IgG, while exhibiting comparable production yields and identical thermostability as the parent IgG. These tetravalent IgGs offer promise for non-hormonal contraception and underscores the multimerization of IgG as a promising strategy to enhance antibody effector functions based on immune exclusion.

sIgA 等多价抗体可以交联精子和细菌等活动实体，形成太大而无法渗透粘液中致密粘蛋白基质的团块，这一过程通常称为免疫排斥。不幸的是，sIgA 的大量生产仍然具有挑战性，并且容易聚集，这阻碍了它们在临床应用中的使用。为了开发稳定且易于大量生产的类 sIgA 四价抗体，我们设计了两种具有 4 个相同 Fab 结构域的 IgG，其中 Fab 连续排列或完全相反的方向排列。作为概念验证，我们设计了这些四价 IgG 构建体，使用先前从免疫不孕女性中分离出的 Fab 来结合普遍存在的精子抗原。与亲本 IgG 相比，两种构建体都具有至少 4 倍的凝集效力，并且诱导更快的精子凝集，同时表现出与亲本 IgG 相当的产量和相同的热稳定性。这些四价 IgG 为非激素避孕带来了希望，并强调 IgG 多聚化是一种有前景的策略，可增强基于免疫排斥的抗体效应器功能。