Novel anti-CD3 single domain antibodies for the development of T cell engager

In cancer immunotherapy, CD3 T-cell engager (TCE) bispecific antibodies (BsAbs) represent a pivotal direction in drug development due to their ability to directly recruit T cells for precise elimination of tumor cells. Currently, all approved TCE BsAbs are based on conventional anti-CD3 antibodies consisting of both heavy and light chains. However, these TCEs face challenges in bispecific format design and complicate manufacturing, due to their structural complexity. In contrast, TCEs based on anti-CD3 single-domain antibodies (sdAbs, or VHHs) enable modular assembly into compact bispecific molecules. This approach avoids the light chain mispairing issue and allows for more flexible molecular design. Their simpler architecture streamlines production, especially for multi-specific constructs. Moreover, smaller VHHs may facilitate formation of more effective immune synapses. WuXi Biologics has developed a panel of anti-CD3 VHHs with novel sequences derived from immunized llama phage display libraries. These VHHs exhibit a range of binding affinities to CD3 and varying potencies in T-cell activation. TCE molecules constructed using these CD3 VHHs demonstrate potent T cell-dependent tumor cell killing efficacy both in vitro and in vivo. Compared with some marketed TCEs, our VHH-based CD3 TCE molecules show superior in vivo efficacy with comparable cytokine profiles. Additionally, these humanized VHHs display excellent developability characteristics.