Immatics’ proprietary technology platforms for the discovery of true targets (XPRESIDENT®) and development of right TCRs (XCEPTOR®):
XPRESIDENT® offers the potential exploitation of the whole tumor-associated antigen repertoire exhibiting an approximately 300% increased cancer target space and greater application potential compared to CAR-T and classical antibody approaches which can target surface antigens only.
Novel Cancer Targets
Beyond the identification of true targets from well-known tumor antigens (such as the MAGE antigen family used in IMA201 and IMA202), XPRESIDENT® also identifies novel cancer targets (such as the tumor stroma target COL6A3 exon 6 used in IMA204 designed to disrupt the tumor microenvironment). In addition, Immatics is utilizing XPRESIDENT® to unlock new target spaces through novel target classes such as crypto-targets and shared neoantigens.
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. These technology platforms are the foundation for strengthening the product pipeline and Immatics’ leading position in the field of TCR-based therapies. Over time Immatics has published its 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
The primary tissue database is comprised of thousands of cancer and normal tissue samples covering most relevant organs. From these tissues a multitude of data is gathered (including genome, proteome, immunopeptidome, in depth transcriptome) and compiled in Immatics’ database, building the foundation for its target discovery.
Identification of true target peptides for TCR-based immunotherapies
XPRESIDENT® is built to identify the peptides actually presented on real tumors, and provides quantitative information on copy numbers, which allows differentiation between peptides originating from the same parent protein. Thus, Immatics believes XPRESIDENT® enables the identification of the most relevant tumor-associated pHLA targets.
Large pool of prioritized targets
Immatics has prioritized more than 200 pHLA targets encompassing all known target classes.
Favorable target characteristics
Targets discovered and validated by XPRESIDENT® are (i) naturally presented in real tumors; (ii) presented in sufficient copy numbers; (iii) highly prevalent in several cancer patient populations; and (iv) expressed in tumor tissue with no or quantitatively lower expression in normal tissue to avoid potential toxicities that might 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.
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® is a high-throughput technology platform based on ultra-sensitive mass spectrometry (LC-MS/MS), coupled with a proprietary sample preparation workflow and a proprietary immunoinformatics platform. 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 (in 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 HLA-restricted targets discovered by XPRESIDENT® on any allele are proven to be present on patients’ cancer tissues in contrast to those predicted 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 antigen is the most promising one, which 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.
T cell Receptor Discovery
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 parental, membrane-bound TCRs with optional engineering to serve ACT modalities, and further engineering via affinity-maturation for TCR Bispecifics (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 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 TCR identification and candidate screening ensures selection of specific and potent TCRs, e.g. by providing information on TCR-motif and target similar peptide expression on healthy tissue, or calibrated tumor cell lines with physiological target levels as screening tool.
Qualified TCRs are subject to further engineering, including affinity maturation, engineering towards CD8 independency or chain pairing enhancement, if needed.
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).