SignificanceWeak transient interactions are fundamental to immune responses, enabling avidity-driven triggers for pathogen neutralization and cellular regulation. In contrast to obligate binding interactions that can be directly investigated structurally, the low or transitory abundance of weak interactions make them difficult to identify and characterize. This study leverages receptor agonism systems that are sensitive to oligomerization to investigate transient homotypic interfaces between antibody Fab regions. Our results show that self-association determinants are encoded naturally by the antibody germline through light chain complementarity determining region 2 (CDRL2), and these determinants can be engineered into antibodies to enhance their therapeutic properties. Insights into avidity-driven interactions create opportunities for optimization, and accordingly this work expands the engineering toolbox for antibody-based drugs.