We are leading the development of Dark Antigen® immunotherapies by interrogating both sides of the immune synapse - the interface of recognition between cancer cells and T cells.
From the tumor cell side, we look beyond the known proteome into the genomic dark matter to identify and characterize Dark Antigens that are uniquely presented on the surface of cancer cells by HLA receptors, shared across broad patient populations, and homogenously expressed within tumors.
On the T cell side, we are discovering and characterizing T-cell receptors (TCRs) that induce potent anti-tumor responses against our Dark Antigen targets.
These discoveries are fuelling a pipeline of targeted immunotherapies designed to improve treatment outcomes for broad patient populations.
Dark Antigen discovery
Enara Bio® has developed a differentiated antigen discovery platform (EDAPT - Enara Dark Antigen Platform Technology) designed to explore the Dark Antigen landscape and validate HLA presentation and tumor specificity.
Bioinformatics: We have created a set of proprietary bioinformatic databases to mine the genomic dark matter for novel cancer antigens derived from sequences outside 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 confirm the presence of Dark Antigens 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 against our Dark Antigens, and to 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 candidate TCRs for therapeutic development.
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 that Dark Antigens are not normally visible to the immune system. They are thus predicted to be more immunogenic compared with conventional tumor-associated antigens, which are often seen as ‘self’ antigens.
Homogenous intra-tumoral expression: We are prioritising Dark Antigens that are homogenously expressed within tumors, which we believe will be important to improve treatment outcomes for patients.
Shared across patients and tumor types: Many Dark Antigens are shared across patients, meaning that larger populations of patients could benefit from Dark Antigen-directed therapies than conventional tumor-associated antigens and mutation-derived neoantigens.
Broad anti-tumor potential: We have identified putative Dark Antigen transcripts across all major solid tumor types, irrespective of the immune status of the tumor, suggesting that Dark Antigen-directed immunotherapies will have a key role in the future treatment of multiple types of cancer.
Abbott et al, 2022. Identification of tumor-reactive T cells targeting melanoma Dark Antigens® validates this novel class of targets for development of immunotherapies. Journal for ImmunoTherapy of Cancer
Abbott et al, 2022. Identification of novel NSCLC Dark Antigens® with expression in multiple tumor types, as promising targets for immunotherapies. Journal for ImmunoTherapy of Cancer
Jupp et al, 2019. Discovery of immunogenic ERV-derived antigens as targets for melanoma immunotherapy. Journal for ImmunoTherapy of Cancer