PD-1-CD28 Fusion Protein for Tumor-Targeted T Cell Co-Stimulation

The patent merges the PD-1 extracellular and transmembrane domains with the CD28 intracellular domain into a single fusion protein construct. This combining of functional domains from different proteins (PD-1's ligand-binding capability with CD28's co-stimulatory signaling) creates a unified therapeutic agent that simultaneously enables tumor recognition and potent T cell activation, resolving the contradiction by integrating multiple functions into one molecular entity.

The fusion protein represents a composite molecular construct combining elements from two distinct proteins (PD-1 and CD28). The extracellular and transmembrane domains of PD-1 are linked to the intracellular domain of CD28, creating a chimeric protein with properties of both parent molecules. This composite structure allows the protein to bind PD-L1/PD-L2 while simultaneously activating co-stimulatory signaling pathways, achieving enhanced therapeutic effect despite increased structural complexity.

The fusion protein enables localized PD-1 pathway blockade specifically at the tumor site where PD-L1/PD-L2 is expressed. By requiring direct engagement between the PD-1 extracellular domain and tumor-expressed PD-L1/PD-L2, the therapeutic effect is confined to tumor-reactive T cells encountering the tumor, rather than causing systemic T cell activation. This spatially restricted mechanism improves tumor efficacy while minimizing off-target toxicity.

The PD-1 extracellular domain acts as an intermediary that confers tumor-specific targeting capability to the CD28 co-stimulatory signal. Instead of directly activating all T cells (which would cause systemic side effects), the PD-1 domain serves as a selective gatekeeper that only allows CD28 signaling when bound to tumor-expressed PD-L1/PD-L2, thereby mediating tumor-specific immune activation without widespread systemic effects.