Bispecific antibodies occupy a distinct position among immunotherapies. Unlike cell-based medicines, they do not introduce new cellular actors into the system. Instead, their activity derives from their ability to bring existing cells into close proximity and to shape how those cells interact. In simple terms, bispecific antibodies are engineered to bind two different target cells at the same time. A widely used class are bispecific T cell engagers, often referred to as BiTEs. BiTEs are designed to bind a target antigen on a malignant cell and a T cell marker, most commonly CD3, thereby physically linking a T cell to its target and promoting immune-mediated killing. BiTEs are one format within a broader landscape of bispecific antibody designs, which also includes IgG-like bispecifics with different architectures and pharmacokinetic properties.This makes bispecific antibody therapies, and BiTEs in particular, inherently interaction-driven. Their function is not encoded in a single cell type, but in the formation, stability, and outcome of physical cell-cell interactions that would otherwise not or only rarely occur. In the context of T cell engaging bispecific antibodies, therapeutic activity depends on the antibody’s ability to simultaneously bind a target cell and an effector immune cell. Small differences in how these interactions form can have critical consequences. The duration of contact, the geometry of the interface, and the balance between activating and inhibitory signals all influence whether a productive immune synapse and therefore an immune response is initiated. The same bispecific antibody can therefore produce very different functional outcomes in different patients.

Much of the current evaluation of bispecific antibodies focuses on molecular and biochemical properties such as binding strength, target specificity, and serum stability. These parameters are essential, but they do not fully capture how bispecific antibodies behave at a cellular level, meaning once they operate within a cellular context such as the bone marrow, blood or tumor microenvironment. Furthermore, functional assays often only aggregate cellular interactions by reading out cytokine release, target cell killing, or bulk activation markers. All these features provide evidence that engagement has occurred, but they offer limited insight into how individual cell-cell interactions unfolded. This becomes particularly relevant when bispecific antibodies show unexpected toxicity or limited efficacy. Excessive or prolonged interactions (with the wrong target cell)  can drive cytokine release syndromes, while unstable or inefficient engagement may result in inefficient target cell killing. In both cases, the underlying issue lies not simply in binding, but in how cell-cell interactions are formed and regulated over time. Importantly, these interactions are shaped by more than the bispecific antibody itself. Target cell frequency, effector cell state, competing cell populations, and local inhibitory signals all influence interaction behavior. As a result, the functional activity of bispecific antibodies and BiTEs reflects properties of the system as a whole rather than attributes of the molecule alone. From this perspective, understanding bispecific antibody therapies requires moving beyond static descriptions of binding events or simply assessing biochemical properties. It requires attention to the dynamic and contextual nature of cell-cell interactions that mediate therapeutic effect. Without direct insight into these interactions, attempts to optimize efficacy or mitigate toxicity rely heavily on indirect inference. This does not diminish the value of existing characterization strategies. Molecular profiling and functional assays remain indispensable. However, they may benefit from being complemented by approaches that capture physical cell interaction more directly. this becomes particularly relevant as bispecific antibodies continue to expand into new therapeutic areas.

Collectively, bispecific antibodies therefore illustrate perhaps more clearly than any other therapeutic modality, how central cell-cell interactions are to immunotherapeutic function. They highlight the need for novel analytical approaches that reflect how therapies operate in living cellular systems, rather than solely how they are designed on paper.