Bispecific T cell Engaging Receptors (TCER™)
Bispecific T cell engaging receptors (TCER™) are off-the-shelf biologics that leverage the body’s immune system by redirecting and activating T cells towards cancer cells expressing specific tumor targets. The design of these novel biologics allows any T cell in the body to become activated and attack the tumor, regardless of the T cells’ intrinsic specificity.
TCER™ at a glance:
- Expanded target space compared to classical T cell engagers. TCER™ compounds target tumor-associated peptides presented by HLA-molecules on the tumor cell surface exploiting the whole proteome.
- Active at low levels of target expression. TCER™ are designed to induce the killing of tumor cells even when presenting physiological low copy numbers of the target.
- High affinity and preclinical activity. Very low concentration (low pM range) required for in vitro killing of tumor cells expressing physiological levels of target pHLA and significant tumor growth inhibition in vivo in therapeutic model.
- Extended half-life. The TCER™-scaffold is designed to exhibit a long functional half-life in the patient’s bloodstream in order to achieve clinical activity without the requirement for daily and/or continuous intravenous application.
- Modularity. The TCER™-scaffold is designed to offer modularity. This enables the efficient exchange of tumor-targeting and T cell engaging binders.
- Off-the-shelf therapeutics. TCER™ are biologics designed for cost-effective manufacturing and immediate application availability.
- Manufacturing activities for IMA401 have started. The TCER™-scaffold is designed to be produced in CHO-cells relying on well-established processes used in the production of antibody-based therapeutics. Manufacturing development for Immatics’ lead TCER™ candidate, IMA401, is ongoing and submission of an IND is planned for the end of 2021. The planned first-in-human clinical trial with IMA401 is designed to assess safety and tolerability, establish a suitable dose and potentially observe initial signs of clinical activity.
Mode of Action
Immatics’ TCR Bispecifics, called TCER™ (T Cell Engaging Receptors), are designed to leverage the therapeutic potential of T cell engagers exhibiting a well validated mode of action and off-the-shelf usage of bispecific antibodies as well as combine this mechanism with the expanded target space opened by T cell therapies to pHLA targets.
Once administered, TCER™ compounds are supposed to bind to the tumor cells presenting the target peptide in context of HLA and simultaneously recruit, activate and stimulate the patient’s own T cells to attack the tumor cells. This is expected to result in T cell expansion and tumor shrinkage.
Engineering and Manufacture
A TCER™ consists of three distinct elements:
(i) an affinity and stability improved T cell receptor recognizing the target presented by HLA-molecules on tumor cells, (ii) a T cell stimulating and recruiting domain derived from an antibody, and (iii) an effector function silenced Fc-part based on human IgG conferring preferential stability, serum half-life and manufacturability.
Immatics’ TCER™ molecules can be produced and purified utilizing established processes to manufacture antibodies.
Immatics’ TCER™ scaffold is the result of a campaign to engineer and evaluate various molecular scaffolds incorporating binding domains derived from affinity and stability enhanced TCRs and from T cell recruiting antibodies, respectively. The TCER™ architecture, in Immatics’ in vitro testing, proved to be superior to other tested scaffolds with respect to preclinical efficacy, stability and physio-chemical properties, so called “developability”. TCER™ molecules can readily be expressed in CHO-cells with titers comparable to antibody-based biologics. The TCER™ protein can be purified using common chromatographic techniques and size-exclusion-chromatography, facilitating the cGMP-compliant manufacturing in established plants.