Immatics has established two proprietary target and TCR discovery platforms: XPRESIDENT® and XCEPTOR®. Our thesis is that for the development of safe and effective TCR-based immunotherapies, two fundamental steps are required: (i) picking a true cancer target that is naturally and specifically expressed at significant levels on the tumor, and (ii) developing the right, potent TCR that specifically recognizes the selected cancer target with minimal or no cross-reactivity with healthy tissues. Both discovery platforms are empowered by our immunoinformatics platform, XCUBE™, which provides the necessary computational methods to enable the development of TCR-based immunotherapies and builds upon the broad target and TCR data sets – “AI is where the data is”®.
Based on the unique interplay between Immatics’ target and TCR discovery platforms XPRESIDENT® and XCEPTOR®, we have the capability to identify and engineer the right T cell receptors with the desired affinity and specificity. Together with our platform XCUBE™, these technology platforms serve as the foundation for our product pipeline and our leading position in the field of TCR-based immunotherapies. Over time, we have published our discoveries in multiple peer-reviewed, high-impact publications including Nature, Nature Medicine, Nature Biotechnology, Nature Communications, and Lancet Oncology.
One of the largest target discovery databases
Immatics’ primary tissue database is comprised of thousands of cancer and normal tissue samples covering the most relevant organs. From these tissues, Immatics has gathered a multitude of in-depth data sets that cover the whole genome, proteome, immunopeptidome and transcriptome that enables us to identify the most relevant tumor-associated pHLA targets. The compiled database is the foundation for Immatics’ target discovery platform.
Identification of true target peptides for TCR-based immunotherapies
XPRESIDENT® is built to identify “true target” peptides that are proven to be displayed on patient tumors and are not, or to a far lesser extent, present on normal tissues. The platform provides quantitative information on peptide copy numbers on the cell surface, which allows differentiation between peptides originating from the same parent protein. Immatics has prioritized a pool of 200 pHLA targets encompassing all known target classes.
Favorable target characteristics
True targets discovered and validated by XPRESIDENT® are: (i) naturally presented on tumors; (ii) presented in sufficient copy numbers; (iii) highly prevalent in several cancer patient populations; and (iv) expressed in the tumor tissue with quantitatively low or no expression in normal tissue to avoid potential toxicities that could occur if healthy tissue were attacked by product candidates.
Right TCRs for ACT and TCR Bispecifics
Immatics’ proprietary XCEPTOR® platform enables fast, efficient, and highly sensitive discovery of natural TCRs with high affinity and high specificity. With its significant protein engineering capabilities, Immatics has the expertise to design TCRs with increased preclinical activity for Adoptive Cell Therapy and TCR Bispecifics product candidates.
Unique interplay between Immatics’ target and TCR discovery platforms enables early de-selection of cross-reactive TCRs. Immatics believes that XPRESIDENT®-guided on- and off-target toxicity screening, enabled by the large normal tissue immunopeptidome database, minimizes safety risks in clinical development.
Integrated, AI-powered immunoinformatics
Immatics’ proprietary XCUBE™ platform combines data processing, data engineering, and data science and tightly integrates with our XPRESIDENT® and XCEPTOR® platforms. By unlocking high-throughput discovery data, it facilitates the discovery and development of pHLA-targeting TCR therapeutics.
Cancer Target Discovery Platform
Immatics’ approach to opening new avenues of treatment for cancer patients starts with the discovery and validation of true targets using the XPRESIDENT® platform. XPRESIDENT® integrates a high-throughput, ultra-sensitive mass spectrometry (LC-MS/MS) coupled with a proprietary sample preparation workflow. The platform is centered on the identification of HLA-bound peptides (pHLA targets) presented on tumor cells, and not or to a far lower amount on the cell surface of normal tissue. XPRESIDENT® is capable of detecting pHLA targets down to attomolar amounts.
All XPRESIDENT® peptides are sourced from native tumors (> 20 major cancer indications) including primary tissues and metastatic biopsies as well as tissues derived from healthy organs (>40 most relevant organs of the human body). The vast collection of over 2000 tissue samples combined with XPRESIDENT®’s high-throughput approach has led to the generation of one of the largest target databases known in the industry.
Peptides are analyzed and identified through a combination of quantitative HLA peptidomics (mass spectrometry) complemented by quantitative transcriptomics (mRNA sequencing), enabling the analysis of differential expression and presentation of these potential drug targets between tumor and normal tissue.
All pHLA targets discovered by XPRESIDENT® are proven to be present on patients’ cancer tissues in contrast to predictions made by in silico techniques.
Immatics’ proprietary AbsQuant® technology allows absolute quantification of target peptide copy numbers per cell. This is one important parameter to determine which peptide target of a given source cancer antigen is the most promising one and is a key strength of the XPRESIDENT® platform.
T cell Receptor Discovery and Engineering Platform
Immatics’ XCEPTOR® platform enables fast and efficient discovery, engineering and validation of a large number of high-affinity and highly specific natural TCRs that can be used for Adoptive Cell Therapies i.e. ACTengine®, ACTallo® and TCR Bispecifics.
TCRs naturally recognize human HLA-bound peptides (“pHLA targets”) derived from foreign and endogenous proteins, regardless of their extracellular or intracellular localization. Immatics has established XCEPTOR®, a next-generation technology platform designed to discover, engineer and validate TCRs. The process comprises the discovery and selection of highly specific, membrane-bound TCRs with optional engineering to serve ACT modalities, and further engineering via affinity-maturation for the TCR Bispecifics modality (TCER®).
Many unique TCRs are identified for each target in a high throughput approach and for several targets in parallel.
Multiple TCR sources are used for each target, such as blood cells from many different HLA-matched and HLA-mismatched healthy donors or patients.
TCRs are re-expressed in human donor cells, extensively screened in vitro (e.g. testing of killing of tumor cell lines vs normal cells to establish a therapeutic window) and qualified as candidates for Adoptive Cell Therapies or TCR Bispecifics.
Information exchange with the XPRESIDENT® platform throughout the TCR identification and candidate screening process ensures selection of specific and potent TCRs. This is done by information transfer on TCR-motif and target-similar peptide expression on healthy tissue, or as a screening tool using calibrated tumor cell lines with targets expressed at physiological levels.
Qualified TCRs are subject to further engineering including affinity maturation and engineering towards CD8 independency depending on the TCR Bispecific or ACT modality.
To further advance its technologies, Immatics has developed TCR Scout®, a new member of the Immatics’ platform technologies, that allows high-throughput kinetic screenings of pHLA ligands and potential clinical lead candidates (TCRs, antibodies).
XPRESIDENT® and XCEPTOR® enable high-throughput generation of target and TCR data, with over 50 million peptide MS/MS spectra from thousands of cancer and normal tissues and numerous TCRs against different targets. Since “AI is where the data is”®, we have been using machine learning and computational methods over the past decade and developed XCUBE™, an AI-powered end-to-end software platform that enables the transformation of the vast amount of XPRESIDENT® and XCEPTOR® data into valuable therapeutic knowledge.
XCUBE™ integrates (i) data processing to transform raw mass-spectrometry and next-generation sequencing data into useful information, (ii) data engineering to collect and integrate this information into our accessible data warehouses, and (iii) data science including statistical and machine learning models to optimize and automate the target and TCR pipeline.
XCUBE™ automates the processing of mass spectrometry and next-generation sequencing data and is optimized for the discovery of HLA-presented peptides. This immunopeptide-centric approach ensures high quality and deep analysis of tumor and normal samples.
XCUBE™ connects our target and TCR discovery pipeline by providing proprietary database models, data warehouses, and user interfaces to enable target and TCR selection and characterization.
XCUBE™ harnesses the power of statistical methods and machine learning models to automate, optimize and streamline scientific workflows, to gain a deep understanding of the multimodal discovery data and to develop predictive models that support therapeutic decision making, such as patient treatment based on biomarker-positivity.
Immatics has brought together its technology platforms XPRESIDENT®, XCEPTOR®, and XCUBE™ within one interdisciplinary team, the Immatics DISCOVERY UNIT. The team is focused on all early-stage preclinical pipeline and collaboration programs.