We are developing new immunotherapies for cancer by interrogating both sides of the immune synapse - the interface of recognition between a cancer cell and a T-cell.
From the tumor cell side, we look beyond the known proteome into the genomic dark matter to identify and characterize Dark Antigens™ uniquely presented on the surface of cancer cells by MHC receptors. We are also focused on unconventional targets such as monomorphic MR1, an exciting target that presents unconventional and cancer-specific ligands to T-cells.
On the T-cell side, we are discovering and characterizing T-cell receptors (TCRs) that induce potent anti-tumor responses against cognate Dark Antigens or other unconventional cancer targets, such as MR1-presented cancer ligands.
These discoveries are fuelling a pipeline of targeted immunotherapies designed to reach a broad patient population.
Dark Antigen discovery
Enara Bio™ has developed a differentiated antigen discovery platform (EDAPT - Enara Dark Antigen Platform Technology) designed to explore the new and expanding Dark Antigen repertoire, and to validate MHC presentation and tumor specificity.
Bioinformatics: We have created a set of proprietary bioinformatic databases to mine the cancer-specific genomic dark matter for novel cancer antigens providing novel, immunogenic targets outside sequences of the known protein coding regions of the genome.
Immunopeptidomics: We use cutting-edge mass spectrometry-based methods to interrogate primary human cancer and healthy tissues to identify and validate Dark Antigens presented on the tumor cell surface.
Tumor biology: We assess transcripts encoding candidate Dark Antigens through in situ hybridization to further validate tumor cell specificity and homogeneity within patient samples.
By combining this suite of technologies, we generate proprietary, unique and high-quality antigen targets to support the development of TCR-directed immunotherapies and therapeutic vaccines
Through building our immunology capabilities, Enara Bio has established a TCR discovery platform that enables us to characterize the immune response elicited by Dark Antigens and MR1-presented cancer ligands and discover cognate TCRs to these compelling targets that can be advanced for therapeutic development.
Dark Antigen TCR discovery: Dark Antigen candidates are prioritized by their ability to elicit the strongest and broadest immune response for each cancer type. We screen peripheral CD8+ T-cells and tumor-infiltrating lymphocytes (TILs) in functional assays to discover cognate TCRs which are then extensively characterized.
TCR screening: Concurrently, we have established technologies to functionally screen T-cell libraries against cancer cells as an antigen-agnostic method to identify TCRs with potent and broad pan-cancer activity against tumor cells. This methodology has led to the discovery of several unconventional candidate TCRs for therapeutic development, including those that target cancer-specific MR1-presented ligands.
Shining a light on new immunotherapy targets.
In cancer, epigenetic alterations lead to the transcription of previously silenced regions of genomic dark matter, with subsequent translation of novel polypeptides. These small proteins are processed within the cancer cell and selectively presented by HLA molecules on the cell surface. Our Dark Antigens thus represent a new class of antigenic real estate that distinguish cancer cells from healthy cells and are expected to make ideal targets for cancer immunotherapy.
High immunogenicity: Our emerging data suggest Dark Antigens are not normally visible to the immune system. They are thus predicted to be more immunogenic compared to conventional tumor-associated antigens, which are often seen as ‘self’ antigens.
Off-the-shelf applicability: Dark Antigens map to specific cancer types and are shared across patients, unlike mutation-derived neoantigens, allowing for cancer-specific, off-the-shelf cancer treatments for a wider potential patient benefit.
Broad anti-tumor activity: Multiple Dark Antigens can be combined into a single immunotherapy product, such as a cancer vaccine or an autologous polyclonal T-cell product (ex vivo stimulation) with the aim of providing deep and durable anti-tumor immune responses.
We are also exploring unconventional, cancer-specific antigenic targets on the surface of tumor cells. These targets range from aberrant metabolites presented by monomorphic MHC-like receptors, such as MR1, to known membrane proteins that are antigenic when assembled in an unorthodox manner on cancer cells. These types of unconventional targets have the potential to unlock pan-cancer, pan-population T-cell therapies.
Attig et al, 2019. LTR retroelement expansion of the human cancer transcriptome and immunopeptidome revealed by de novo transcript assembly. Genome Research.
Crowther et al, 2020. Genome-wide CRISPR–Cas9 screening reveals ubiquitous T-cell cancer targeting via the monomorphic MHC class I-related protein MR1. Nature Immunology.