Development of a novel CD3ε-specific human antibody for selective modulation of T cell activation

CD3ε is an essential subunit of the T-cell receptor complex. It is required for T cell activation and immune modulation. Dysregulated CD3ε signaling results in abnormal T cell activation, contributing to the pathogenesis of various immune-related disorders, including autoimmune diseases. Although anti-CD3ε antibodies, such as muromonab-CD3, can effectively modulate T cell responses, their use is often limited by severe adverse effects caused by excessive T cell activation. In this study, we present K108.5, a fully human monoclonal antibody (mAb) specific to human CD3ε (hCD3ε), designed to modulate T cell activity without inducing undesired activation. Using phage display technology, we identified five hCD3ε-specific mAbs. Of these, K108.5 exhibited the highest binding affinity (K_D = 2.4 nM) to hCD3ε. It recognized a different epitope of hCD3ε, distinct from muromonab-CD3. Moreover, unlike muromonab-CD3, K108.5 did not induce T cell activation. It promoted the rapid internalization of CD3ε, resulting in its downregulation on the T cell surface. K108.5 also inhibited T cell activation induced by dendritic cells or muromonab-CD3 engagement. These findings suggest that K108.5 may be effective in modulating T cell activity under conditions of T cell dysregulation.