At the heart of the TScan’s discovery process is our proprietary genome-wide, high-throughput target identification screen, designed to rapidly identify the natural targets of T cell receptors
The TargetScan discovery platform enables the identification of the natural target of a T cell receptor, or TCR, using an unbiased, genome-wide, high-throughput screen. We have developed this technology to be extremely versatile and applicable across multiple therapeutic areas, including cancer, autoimmune disorders, and infectious diseases. It can be applied to virtually any TCR that plays a role in the cause or prevention of disease. TargetScan is also designed to identify potential off-targets of a TCR and eliminate those TCR candidates that cross-react with proteins expressed at high levels in critical organs. We believe this will allow us to reduce the risk and enhance the potential safety profile of our TCR-T therapy candidates early in development before we initiate clinical trials.
Overview of Our Proprietary TargetScan Technology
Overview of the TargetScan discovery process:
- T cells expressing a TCR of interest are co-cultured with a genome-wide library of target cells where every cell in the library expresses a different protein fragment. Each protein fragment is processed naturally by the proteasome or immunoproteasome and the resulting peptides are displayed on cell-surface MHC proteins.
- If a T cell recognizes the peptide-MHC complex on a target cell, it attempts to kill the target cell, activating a proprietary fluorescent reporter in the target cell.
- By isolating fluorescent target cells and sequencing their expression cassettes, TargetScan reveals the natural target(s) of the T cell.
See Publications for the original article published in Cell in 2019.
An Adaptable Target Library
Central to TargetScan is the library of protein fragments used for any given screen. Our proprietary libraries are comprised of millions of specific sequences that collectively include most or all of the targets that a TCR could potentially recognize.
Our current Oncology Target Discovery Library (version 3.0) is comprised of over one million clones, including:
- Every human protein encoded in the human genome
- All single nucleotide polymorphisms, or SNPs, observed at over 1% frequency in the human population
- Cancer specific sequences, including:
- Cancer/testis antigens (CTAs)
- Human endogenous retroviruses (HERVs)
- Oncogenic driver mutations
- “Dark matter” – A large collection of sequences that are not translated in normal tissue but are frequently translated in human cancers
Oncology Target Discovery Library (Version 3.0)
We construct our libraries using a tiling pattern of overlapping fragments to provide complete and redundant coverage of every targeted sequence. TargetScan can also screen for any HLA type, enabling target discovery across a wide range of patient demographics.
Off-target Safety Screening
Leveraging our comprehensive human proteome library, TargetScan is also able to fully characterize potential off-target interactions for a TCR. This safety screen may reduce the risk and enhance the potential safety profile of TCR-T therapy candidates.
Example TargetScan Screen
In a proof-of-concept screen using our Oncology Target Discovery Library (Version 2.0), we screened a TCR known to recognize MAGE-A3. As shown below, TargetScan correctly identifies MAGE-A3 as its natural target, and also identified three off-targets. Two off-targets are unrelated at the gene level to MAGE-A3 and would likely not have been identified in a bioinformatic search.