ProTIA(Protease Triggered Immune Activator)
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.
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.
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)
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.