CD28 x Nectin-4

Class

CD28 x Nectin-4 bispecific antibody (tumor-localized T-cell co-stimulator)

Pathway

T-cell co-stimulation, tumor-localized via Nectin-4 expression

CD28 is a co-stimulatory receptor expressed on T cells that provides a necessary second signal for full T-cell activation. When a T-cell receptor recognizes an antigen (signal one), engagement of CD28 by its ligands amplifies proliferation, survival, and effector function; without this second signal, T cells become anergic or fail to respond effectively. Nectin-4 is a cell-adhesion protein that is markedly overexpressed on the surface of several epithelial-derived tumors, while being far more restricted in normal adult tissue. A bispecific antibody that binds both CD28 and Nectin-4 is designed to deliver co-stimulatory signaling specifically at sites where Nectin-4-expressing tumor cells are present, using the tumor as a physical scaffold to cluster CD28 on nearby T cells. This tumor-localized approach aims to boost anti-tumor T-cell activity within the tumor microenvironment while limiting the diffuse, body-wide T-cell activation that non-targeted CD28 agonism can cause. This mechanism is relevant to solid tumors of epithelial origin, particularly where Nectin-4 expression is high, and reflects a broader strategy in oncology of pairing immune co-stimulatory signals with tumor-restricted targeting to improve the therapeutic margin between anti-tumor efficacy and systemic immune toxicity.