TCR-Like antibodies (TCR-LA) also known as TCR-mimic
Immunitrack has established a platform to develop and characterize TCR-LA (T cell receptor-like antibodies).
Conventional monoclonal antibodies (mAb) and chimeric antigen receptor (CAR) T cell therapies are the most successful strategies in cancer immunotherapy so far. However, these current modalities target proteins expressed on the surface of tumour cells, which comprise a limited repertoire of cellular proteins.
A New Avenue for Cancer Treatment
As an alternative TCR-therapies are under development, which enable the targeting of large repertoire of intracellular antigens that are displayed on the cell surface by MHC (Major Histocompatibility Complex). These therapies have on the other hand the disadvantage of cross-reactivity since TCRs are naturally promiscuous. TCR-LAs are a new avenue for cancer treatment by combining the advantages of mAbs with the TCR-like tumour target recognition.
Moreover, TCR-LAs are versatile and can therefore be engineered to a plethora of therapeutic formats such as CAR, ADC (antibody drug conjugate) and Bi-specific T-cell engager formats, among others.
Workflow – development of a TCR-LA
The workflow for early preclinical development of a TCR-LA comprises 7 steps:
- Selection of a tumor target based on its exclusive and abundant expression on tumour cells.
- Selection of an immunogenic epitope within the protein target.
- Production of highly pure and stable MHC-epitopes complexes for positive selection and negative selection.
- TCR-LA discovery using antibody technology or vendor of choice
- Off-target specificity studies on MHC-epitope complexes for TCR-LA clone selection – this is mostly done by ELISA.
- On-target specificity studies on model cell lines for TCR-LA clone selection- this is mostly done by flow cytometry analysis.
- Selection of TCR-LA clones based on effector properties – ex cell based cytotoxic assays (this depends on the antibody format being tested).
The different steps of TCR-LA platform comprise very specific technologies, and we at Immunitrack are specialized in the following ones:
Step 2. We can run NeoScreen assays in high-throughput mode with dozens of MHC alleles and hundreds of peptides simultaneously; this is a powerful and unique technique that allows to discover the most immunogenic epitope within a protein target.
Step 3. We can produce highly pure and stable MHC-peptide complexes from a large library of MHC molecules; for each antibody library screen we produce complexes for positive selection – and recommend a mixture if MHC complexes for negative selection.
Step 5. and 6. We have developed a series of on-target and off-target specificity assays for TCR-LAs, both for screening a high number of unrelated on MHC-peptide complexes and on peptide-loaded model cell lines. We can perform positional scanning assays, alanine and glycine scans and melting assays. Using our thorough specificity assays we are able select very specific TCR-LAs with limited risk of cross-reactivity.
In this application note you will find a short description of our TCR-LA platform