Making a difference for people living with cancer
Within oncology, we are designing ImmTAC® (Immune Mobilizing Monoclonal TCRs Against Cancer) molecules to treat patients with hematologic and solid tumours.
ImmTAC® molecules are engineered to activate a potent and T cell response to specifically kill target cancer cells.
The unique proposed mechanism of action provided by ImmTAC® molecules gives the potential to tackle diverse tumour types, including hematologic tumours and solid tumours, regardless of mutational burden or pre-existing immune infiltration.
We are investigating our ImmTAC® technology to target a diverse range of cancer indications.
Our lead ImmTAC® molecule tebentafusp (IMCgp100) specifically targets gp100, a lineage antigen expressed in melanocytes and melanoma. Tebentafusp has Fast Track Designation and Orphan Drug Designation in the US and Promising Innovative Medicine designation under the UK Early Access to Medicines Scheme for metastatic uveal melanoma.
What is an ImmTAC® molecule?
One subset of Immunocore's proprietary T cell receptor (TCR) technology is generating a novel class of bispecific biologics called ImmTAC® molecules that are designed to redirect the immune system to recognise and kill cancerous cells.
One of the greatest challenges in cancer immunotherapy is the identification of new and specific target antigens. Most antibody-based therapies, including bispecific and CAR-T cells, recognise cell surface antigens, which account for ~10% of potential disease targets. Naturally, TCRs have the ability to recognise antigens presented on the cell surface as peptide-HLA complexes, which theoretically should permit access to potentially all proteins/new cancer targets.
Defining features of an ImmTAC® molecule;
"Off the shelf" usability
Infused directly into patients intravenously with no prophylaxes required in clinical trials to date.
Do not require ex vivo manipulation
ImmTAC® molecules are engineered to recognise intracellular cancer antigens with ultra-high affinity and selectively kill these cancer cells via an anti-CD3 immune-activating effector function. Based on the observed activity of T cell infiltration into human tumours during pre-clinical studies, the hypothesized ImmTAC mechanism of action holds the potential to treat hematologic and solid tumours, regardless of mutational burden or immune infiltration, including immune “cold” low mutation rate tumours.
Visualising ImmTAC®-redirected T cell killing of antigen-positive cells in vitro (lab-based setting)
These videos show real cancer cells being killed by ImmTAC®-redirected T cells.
- Antigen-positive target cell: Non-small cell lung cancer adenocarcinoma (from metastatic site: liver)
- Antigen-negative cell: normal cell
- T cells
- Cell death marker
ImmTAC® molecules are designed to initiate potent T cell redirection and cancer cell killing
Soluble ImmTAC® molecules are infused.
The high-affinity TCR domain of the bispecific ImmTAC® molecule recognises and binds to the HLA-presented antigen on the surface of the cancer cell. The anti-CD3 effector function engages CD3 on T cells. An immune synapse is formed, and the T cell is induced to lyse the ImmTAC®-labelled target cell.
The T cells are activated and release lytic granules, killing the cancer cell.
Engineering an ImmTAC® molecule
The process of making an ImmTAC® molecule begins with a natural human TCR specific for a validated target and involves three proprietary engineering steps.
TCR affinity enhancement
The natural immune system removes high affinity, self-recognizing T-cells in order to mitigate the risk of autoimmune disease. As cancer cells can closely resemble normal "self" cells and also may present low numbers of peptide-HLA, high affinity TCRs are required to target them. The TCR component of an ImmTAC is affinity-enhanced up to several millionfold (µM to pM), which potentially allows ImmTAC® molecules to overcome the limitations of the natural immune system.
Creating soluble and stable TCRs
A major barrier to the use of TCRs as therapeutics is their instability as soluble proteins. ImmTAC® molecules are stabilized in a soluble form through the incorporation of a novel interchain disulphide bond buried within the core of the TCR.
T cell-redirecting effector function
ImmTAC® molecules engage the natural T cell activation pathway via an anti-CD3 antibody fragment, scFv (single chain fragment variable), fused to the TCR via a flexible linker. The anti-CD3 effector function mediates potent redirection of T cells to target cells presenting as low as 5-10 pHLA complexes (Liddy et al., 2012).