Technologies
T Cell Receptor Profiling for Immunology Discovery with T-FINDER
Our expertise is a critical and complex component of the human adaptive immune system: the T lymphocyte. We have developed a proprietary technology platform – the T-FINDER platform – that allows us to functionally identify and map cognate epitopes of human T cell receptors (TCRs) at unprecedented speed and accuracy. As a result, we can profile patient-derived TCR repertoires against large libraries of putative target epitopes.
Potential Applications of the T-FINDER Platform
- Fast, robust TCR discovery and characterization
- Validation of predicted TCR:epitope interactions
- Functional epitope mapping
- Chimeric antigen receptor (CAR) evaluation
- Safety assessment of TCR therapies
- Immunogenicity profiling of biotherapeutics
- De novo TCR ligand identification, minimal epitope resolution
- Customized TCR-based drug discovery programs
What is unique about our new T-FINDER platform?
Identification of the target epitope(s) of a given T cell receptor (TCR) is a major challenge. In contrast to antibodies, which bind directly to their target, T cells recognize processed peptide epitopes presented by class I and II HLA molecules. Most attempts described in the literature to make this interaction amenable to high-throughput screening are based on engineered variants of the T cell receptors and/or peptide:HLA complexes, or a priori knowledge of the epitope and/or presenting HLA allele, limiting their ability to fully catalog physiologically relevant TCR:target interactions.
In contrast, T-FINDER more closely represents the physiological processes underlying antigen processing, presentation, and ligand-induced T-cell activation.
Our patent-pending platform consists of three major components:
1. T Cell Reporter Construct
Our reporter cassette is designed such that any exogenous TCR or chimeric antigen receptor (CAR) can be inserted into the system. Based on a highly sensitive and specific synthetic promoter, engagement of the inserted receptor produces a fluorescent signal with an unprecedented signal-to-noise ratio easily detected by flow cytometry and/or microscopy. At the same time, the activated T cells produce a secreted label that binds to the cognate antigen-presenting cell(s).
2. Antigen-Presenting Cell Construct
As a starting point for this construct, we use immortalized antigen-presenting cells from the TCR-autologous donor or our biobank, which currently covers approximately 80% of the most frequent HLA alleles. Following transduction with our patent-pending minigene library construct, these cells process and present peptides from the encoded antigens efficiently and persistently on both class I and II HLA. As a unique feature, we have identified and overcome a size limitation constraint on cDNA-derived antigen processing. As a result, we reliably achieve epitope presentation from open reading frames up to 400 amino acids in length, enabling library design that can feasibly cover the entire human reference proteome.
3. Phenotypic Screening Platform
Next-generation sequencing of enriched target antigens is a powerful readout for high-throughput screening, but can be time-consuming and noisy. For targeted applications in which this is undesirable, we have developed a combinatorial phenotypic screening approach that unambiguously identifies the cognate target(s) with up to 98% first-pass confidence. This enables quick and cost-efficient profiling of TCRs against relatively large antigen libraries.
What are the potential applications of the T-FINDER platform?
Our platform is particularly useful in biomedical research and drug discovery in oncology (tumor vaccines, targeted cancer immunotherapy, CAR-T, and TCR-T cell therapy), autoimmunity (autoantigen discovery, targeted immune modulation, regulatory TCR-T cell therapy), and infectious diseases (vaccines, chronic infection). Its modular design additionally provides the platform with the flexibility to easily incorporate alternative antigen-presenting cells, scales of throughput, and multiplexing options. Whenever the specificity of a T cell response in patients is of interest, our technology can provide valuable new insights.
How can we support your research and development?
Our preferred business model is to perform customized research projects on a fee-for-service basis. At the end of a project, our customers acquire full ownership of the results at pre-defined terms without the obligation of royalty or milestone payments.
Publications
- Cetin M, Pinamonti V, Schmid T, Boschert T, Mellado Fuentes A, Kromer K, Lerner T, Zhang J, Herzig Y, Ehlert C, Hernandez-Hernandez M, Samaras G, Torres CM, Fisch L, Dragan V, Kouwenhoven A, Van Schoubroeck B, Wils H, Van Hove C, Platten M, Green EW, Stevenaert F, Felix NJ, Lindner JM (2024):
T-FINDER: A highly sensitive, pan-HLA platform for functional T cell receptor and ligand discovery.
Science Advances - Boschert T, Kromer K, Lerner T, Lindner K, Haltenhof G, Tan CL, Jähne K, Poschke I, Bunse L, Eisele P, Grassl N, Mildenberger I, Sahm K, Platten M, Lindner JM, Green EW (2024):
H3K27M neoepitope vaccination in diffuse midline glioma induces B and T cell responses across diverse HLA loci of a recovered patient.
Science Advances - Tan, CL, Lindner, K, Boschert, T, Meng, Z, Rodriguez Ehrenfried, A, De Roia, A, Haltenhof, G, Faenza, A, Imperatore, F, Bunse, L, Lindner, JM, Harbottle, RP, Ratliff, M, Offringa, R, Poschke, I, Platten, M, Green, EW (2024): Prediction of tumor-reactive T cell receptors from scRNA-seq data for personalized T cell therapy.
Nat Biotechnol
