Technology

Probing the genomic dark matter

Our Dark Antigens™ derive from vast untapped expanses of genomic ‘dark matter’ beyond the normal coding regions of the genome, which are epigenetically silenced in normal tissue but can become aberrantly activated in cancer.

Genomic dark matter makes up approximately 98% of the human genome compared to the remaining 2% containing genes encoding known proteins in the human body. Genomic dark matter is poorly characterized, but is becoming increasingly implicated in disease, including cancer.

  • Genomic dark matter
  • Coding DNA
  • Dark Antigen™ sequences

Developing Dark Antigens™ for immunotherapy

In cancer, epigenetic alterations lead to the transcription of previously silenced regions of genomic dark matter, with subsequent translation of novel polypeptides. These 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.

Ervaxx’ initial focus is on the discovery and development of cancer vaccines based on antigens derived from endogenous retroviral (ERV) DNA sequences. ERV DNA is a component of genomic dark matter and makes up ~8% of the human genome. Thousands of novel ERV sequences have been identified by Ervaxx and its collaborators with enriched expression in >30 tumor types (including melanoma, lung and ovarian).

Nucleus Polypeptides Peptides Proteosome HLA Antigens Cancer Cell
Cancer Cell CD8 T cell CD8 T cell CD8 T cell CD8 T cell

The Dark Antigen™ difference

High immunogenicity: As Dark Antigens™ are not normally visible to the immune system, they are predicted to be more immunogenic compared to conventional tumor-associated antigens, which are often seen as ‘self’ antigens.

Off-the-shelf approach: Dark Antigens™ have been identified that map to specific cancer types and are shared across patients, unlike mutation-derived neoantigens, allowing for cancer-specific, off-the-shelf vaccines.

Broad coverage: Multiple Dark Antigens™ can be combined into a single off-the-shelf vaccine to provide for broad and deep anti-tumor immune responses.

The EDAPT™ Platform

Ervaxx has developed a differentiated technology platform (EDAPT™ - Ervaxx Dark Antigen Platform Technology) designed to explore the new and expanding Dark Antigen™ repertoire, and to identify and assess its tumor specificity and immunogenic potential to combat cancers.

EDAPT™ is a powerful and proprietary approach combining bioinformatics, immunopeptidomics and state-of-the-art T-cell immunology. The platform systematically examines the entire cancer genome to understand changes in transcription patterns and discover and validate previously hidden Dark Antigens™ for use in immunotherapy.

This approach is built upon pioneering research from the Francis Crick Institute, which is being further developed by Ervaxx and advanced through research collaborations with the University of Oxford, University of Cambridge, and Johns Hopkins University School of Medicine.

Discovery

Bioinformatics and immunopeptidomics

A combination of transcriptomics and mass spectrometry-based immunopeptidomics is deployed comparing primary cancer and healthy tissues to identify and validate Dark Antigens™ presented on tumor cell surfaces. Ervaxx focuses on the genomic dark matter and excludes all sequences relating to known protein-encoding regions of the genome.

Candidate Dark Antigens™

Validation

Immunology and tumor biology

Dark Antigen™ candidates are prioritized by their ability to elicit the strongest and broadest immune response for each cancer type. Peripheral CD8+ T cell responses and tumor infiltrating lymphocytes (TILs) are screened and cognate T cell receptors (TCRs) are discovered and characterized. The transcripts encoding candidate Dark Antigens™ are also assessed through in situ hybridization to further validate specificity and homogeneity across tumor cells within patient samples.

Dark Antigens™ selected for therapy

Vaccine and TCR development

Candidate Dark Antigens™ that are detected across multiple patients, elicit a strong immune response and are predicted to generate epitopes presented by a broad coverage of different HLA alleles are selected for development into a clinical product. Multiple antigens can be combined into a single fusion construct within viral vectors for prime and boost delivery.

By pursuing this approach, Ervaxx seeks to develop off-the-shelf cancer vaccines, and other products including TCR-based therapies, with the potential to elicit broad and deep immune responses against cancer.