Chimeric-antigen receptor (CAR)-T cell immunotherapy is a promising type of cancer therapy which consists of a target binding domain of an antibody that is specific to the target antigen on the cancer cell surface. This domain extends out of the engineered T cell into the extracellular space, where it can recognize target antigens. Traditionally, the target binding domain consists of a single-chain variable fragment, or scFv, of an antibody comprising variable domains of heavy and light chains joined by a short linker.
However, there are a number of disadvantages to scFv-based CARs including the limited availability of scFv, their potential to elicit antibody responses, and their association with tonic signaling due, in part, to inherent instability and flexibility of the structure and the potential for both VH/VL domain swapping and multimer formation through framework region interactions. Thus, replacement with alternative binding technologies may improve CAR-T efficacy in the clinic.
We are utilizing our technology platform to use Pronectins™ as alternative scaffold molecules that bind protein targets with high affinity and specificity, similar to scFv molecules. Unlike scFv, Pronectins™ are smaller, derived from human fibronectin 3 domains and are predicted to have no immunogenicity. As Pronectins™ are 1/3 the size of scFv molecules, they provide flexibility for the creation of multi-specificity CARs. Pronectins™ can be isolated against virtually any antigen through ex vivo panning of an extensive Pronectin™ library, yielding many distinct binders with a range of affinities and target epitopes.