The process of making an ImmTAC molecule begins with a natural human TCR specific for a validated target and involves three proprietary engineering steps.
Click on the ‘info’ symbols below to find out more about each of these steps.
ImmTAC molecules can be manufactured in a high-yield, fully-scalable and low-cost bacterial system. They are extremely stable with a multi-year shelf-life.
In nature, TCRs that recognise cancer antigens typically have a weak (micromolar) affinity for their corresponding antigen (Aleksic et al., 2012), meaning that cancer cells are essentially invisible to the immune system. This problem is further compounded by down-regulation of pHLA by cancer cells. To address this issue, the TCR portion of the ImmTAC molecule is ‘affinity-enhanced’ 1.5 million-fold using a phage display process, which results in picomolar affinity TCRs (Li et al., 2005). Such high affinity recognition means that ImmTAC molecules can effectively recognise cancer cells presenting exceptionally low numbers of pHLA that would normally not be detected by cancer specific T cells (Purbhoo et al., 2006; Liddy et al., 2012; Bossi et al., 2014).
A major barrier to the use of TCRs as therapeutics is their instability as soluble proteins. With ImmTAC molecules, the TCRs are stabilised in a soluble form through the incorporation of a novel interchain disulphide bond (Boulter et al., 2003). The new disulphide bond is buried within the core of the TCR, reducing the risk of immunogenicity, and has been shown by crystallography not to alter the natural TCR structure (Sami et al., 2007).
The low number of pHLA complexes presented by cancer cells means that a T cell-redirecting effector function needs to be particularly potent. By fusing the engineered TCR via a flexible linker to an anti-CD3 antibody fragment (scFv), ImmTAC molecules are able to engage the natural T cell activation pathway and achieve potent T cell redirection against cancer cells presenting as few as 5-10 pHLAs (Liddy et al., 2012). The anti-CD3 scFv and linker portion have been extensively optimised for use in all ImmTAC molecules.