In the race to access the wealth of intracellular molecular targets once considered undruggable, Eureka Therapeutics Inc. is pioneering TCR-like antibodies that capitalize on the ability of TCRs to recognize tumor antigens. But the company will need to satisfy concerns about off-target binding that sank earlier TCR-based therapies against the same class of antigens.
Last month, Eureka and its partners at Memorial Sloan Kettering Cancer Center published a study in the Journal of Clinical Investigation demonstrating that its TCR-mimicking (TCRm) antibodies can recognize and kill cancer cells expressing the intracellular PRAME tumor antigen in mice.
While most approaches to hitting intracellular targets involve cell-penetrating compounds, TCRms work from outside the cell, recognizing and binding intracellular tumor antigens after they are broken down and presented on the cell surface by MHC molecules (see "Toxic Presentation").
Figure: Toxic presentation
Eureka Therapeutics Inc. is one of the first companies to use TCR mimic (TCRm) antibodies to target intracellular tumor antigens without needing to enter the cell. Like chimeric antigen receptor (CAR) and engineered TCR therapies, the TCRm technique hijacks antigen presentation -- the body’s natural mechanism for flagging pathogen-infected cells -- to specifically kill tumors.
Within the cytosol of the cancer cell, intracellular proteins including tumor antigens are systematically broken down by the proteasome into short peptide fragments about nine amino acids in length. The short peptides are then transported to the endoplasmic reticulum and bound to MHCI molecules, which are transported as an MHCI-peptide complex to the cell membrane, where MHCI presents the peptides to T cells for immune surveillance. When an abnormal or pathogenic peptide sequence is detected, the T cells eliminate the abnormal or infected cell.
To increase T cell-mediated antitumor immunity, at least eight companies have engineered TCRs that recognize specific intracellular tumor antigen-MHCI complexes, including PRAME, WT1, MAGEA10 or NY-ESO-1 peptides.
A. Eureka and at least three other companies are designing antibodies, instead of cell therapies, that target the same intracellular tumor