(Protease Triggered Immune Activator)
Fig 1 ProTIA

Our XTEN platform allowed us to develop a unique class of bispecific T cell activators with long half-life and superior safety compared to other bispecific formats. XTENylation prevents T cell activation by ProTIA therapeutics until the molecule reaches tumor tissue and XTEN is released by tumor-associated proteases.

ProTIA molecules combine three mechanisms to widen their therapeutic window: 1) The bulky size of XTEN contributes to preferred extravasation of ProTIA molecules in a tumor environment compared to healthy tissues with well-organized vasculature; 2) ProTIA molecules are preferentially activated in the tumor environment by tumor-associated proteases; 3) ProTIA molecules do not bind healthy cells which show no or limited expression of tumor antigens.

Fig 2 ProTIA

ProTIA molecules can be efficiently produced by microbial fermentation. The hydrophilic nature of XTEN facilitates proper folding of the tumor- and T-cell binding domains and minimizes the formation of multimers and aggregates.

Fig 3 ProTIA
Fig 4 ProTIA

ProTIA molecules are designed to be activated by proteases with known overexpression in the tumor environment. ProTIA molecules can be activated by XTEN release at a designed cleavage site (MMP-2, MMP-9, Matriptase shown) or degradation of XTEN (Neutrophil elastase shown)

Fig 5 ProTIA

XTENylation effectively blocks synapse formation between T-cells and tumor cells. Once the XTEN polymer has been released from ProTIA by one of multiple tumor-associated proteases, the activated bi-specific T-cell/tumor cell binder exhibits IC50 values in the low picomolar range.