Therapeutic antibodies are a well-established and successful segment of the global therapeutics market. Antibodies, being too large to enter a cell, can only target the subset of proteins which are present on the cell’s exterior (extra-cellular). Cell biology, however, occurs inside the cell and many changes that are found in virally infected or cancerous cells are not in cell-surface proteins.
However, the immune system does have a method to ‘peek’ inside the cell via Major Histocompatibility Complexes (MHCs), also known as HLA in humans. Intracellular proteins are broken into fragments by the proteasome and are loaded onto empty MHCs and displayed on the outside of the cell as peptide-MHC complexes (pMHCs) for interrogation by T-cells.
pMHCs are thus a window into the cell: when a cell has been infected by a virus or has become cancerous, peptides from the overexpressed or mutated proteins are displayed externally to the immune system. The immune system screens the pMHC for ‘non-self’ using an antibody-like molecule, the T-Cell Receptor (TCR), which generally has low affinity for its target. Unfortunately, virally-infected or cancerous cells often manage to avoid this ‘immune surveillance’ and the immune response is insufficient to kill the target cells.
Screening for high affinity molecules such as antibodies or TCRs specifically against pMHCs of diseased cells is, therefore, a potential way to target these cells. The problem arises, however, that the pMHCs displaying the peptides of healthy cells and those of diseased cells may only differ by a single amino acid in the displayed peptide.
Discovery of antibodies specific to a pMHCs is, therefore, a particularly difficult task in antibody engineering, requiring discrimination of a single complex from the vast repertoire of the entire human proteome displayed as pMHCs. No company has thus far managed to routinely and rapidly address pMHC with both high affinity and selectivity. Until now.
Affinity BIO has successfully employed it’s ReD3 screening system against a range of oncology and viral pMHC targets, generating single-chain antibodies (scFv) that have both high-affinity AND high-specificity to a single pMHC. The ability of the ReD3 system to do this can be explained by a combination of attributes that are significantly differentiated from standard antibody discovery technologies such as phage display.
The ability to target intra-cellular proteins creates a host of new therapeutic options, potentially enabling new treatments of various forms of cancer, viral infections and autoimmune diseases.